AN ABSTRACT OF THE DISSERTATION OF
Peter Hrnciar for the degree of Doctor of Philosophy in Chemistry presented
on
August 18. 1998.
Title: Synthetic Studies on Alkaloids. Part I: Asymmetric Synthesis of (+)Codeine. Formal Synthesis of (+)-Morphine. Part II: A Unified Asymmetric
Approach Toward Synthesis of Polyhydroxylated Pyrrolizidine Alkaloids,
Australine and Alexine.
Redacted for Privacy
Abstract approved:
James D. White
Part I. An asymmetric synthesis of the unnatural enantiomer 57 of the
analgesic agent morphine is described. Asymmetry was introduced by
hydrogenation over a chiral catalyst of the Stobbe condensation product 4 4
of dimethyl succinate with isovanillin, and the resultant carboxylic acid 73 of
(S) configuration was converted to tetralone 90. Robinson annulation of this
material with methyl vinyl ketone gave the hydrophenanthrenone 74, which
was brominated and cyclized to the benzofuran 100. After reduction of the
ketone and hydrogenation of the furan moiety, the derived diazoketone 1 1 8
was treated with rhodium(II) acetate to give the pentacyclic C-H insertion
product 119. Beckmann rearrangement of the oxime brosylate 140 derived
from 136 afforded 5-lactam 138, which underwent N-methylation,
deprotection, and oxidation to 144. The latter was converted to enone 135,
which upon reduction furnished ent-codeine (76). Demethylation of 76 to (+)-
morphine follows a procedure previously described previously
in the
literature.
Part II. A new asymmetric approach toward synthesis of the polyhydroxylated
pyrrolizidine alkaloids, australine, alexine, and 7-deoxyalexine is presented.
Ring-closing metathesis of diene 50, prepared in five steps from the known
epoxy alcohol 41, gave the azacyclooctene 51. The corresponding dibenzyl
ether 65 underwent stereoselective epoxidation to yield 66 which, after
opening of the oxazolidinone, suffered spontaneous transannular cyclization
to di-O-benzyl australine (67). The latter was converted upon hydrogenolysis
to the
naturally
occurring
tetrahydroxypyrrolizidine
(+)-australine
(7).
Analogous ring-closing metathesis of diene 86 failed, thus obstructing an
approach to alexine (5). Diene 95 underwent facile ring-closing metathesis
to afford azacyclooctene 96. The latter was advanced to the epoxide 100
which upon cleavage of the oxazolidinone gave 2- O- benzyl-7- deoxyalexine
(101).
Synthetic Studies on Alkaloids:
Part I: Asymmetric Synthesis of (+)-Codeine. Formal Synthesis of (+)Morphine.
Part II: A Unified Asymmetric Approach Toward Synthesis of
Polyhydroxylated Pyrrolizidine Alkaloids, Australine and Alexine.
by
Peter Hrnciar
A DISSERTATION
submitted to
Oregon State University
in partial fulfillment of
the requirements for the
degree of
Doctor of Philosophy
Completed August 18, 1998
Commenced
Jun e 1999
Doctor of Philosophy dissertation of Peter Hrnciar presented on August 18.
1998.
APPROVED:
Redacted for Privacy
Major P o essor, Representing Chemistry
Redacted for Privacy
Chairrn of the Department of Chemistry
Redacted for Privacy
Dean of Graduate Schoo
I
understand that my dissertation will become part of the permanent
collection of Oregon State University libraries. My signature below authorizes
release of my dissertation to any reader upon request.
Redacted for Privacy
Peter Hrnciar, Author
TABLE OF CONTENTS
Page
Chapter I
General Introduction
PART I
Asymmetric Synthesis of (+)-Codeine. Asymmetric Synthesis
1
of (+)-Morphine
2
Chapter II
Introduction
2
Chapter III
Results and discussion
23
3.1 Retrosynthetic Analysis
23
3.2 Asymmetric Synthesis of the Phenanthrene
Derivative 59. Construction of the ABC-Ring
System of Morphine
31
3.3 Construction of the Dihydrobenzofuran Derivative 112
41
3.4 Rhodium Catalyzed Carbenoid Insertion. Construction
of the Pentacyclic Framework of Morphine
51
3.5 Final Elaboration of Pentacycle 119 to Morphine
63
3.6 Studies on the Transformation of Lactone 139
75
3.7 References
84
Chapter IV
Experimental Section
88
PART II
A Unified Asymmetric Approach Toward Polyhydroxylated
Pyrrolizidine Alkaloids, Australine and Alexine
148
Chapter V
Introduction
148
Chapter VI
Results and Discussion
157
6.1 Retrosynthetic Analysis
157
6.2 Synthesis of Carbamate 38, the Precursor
to Alexine and Australine Alkaloids
166
6.3 Approach Toward Australine
171
TABLE OF CONTENTS (continued)
Page
6.4 Approach Toward Alexine and 7-Deoxyalexine
183
6.5 References
197
Chapter VII Experimental Section
201
Chapter VIII Conclusion
255
Bibliography
256
Appendices
263
Appendix A Supplementary Crystallographic Information
for Epoxide 62
264
Appendix B Supplementary Crystallographic Information
for Epoxide 66
271
LIST OF FIGURES
Figure
Page
3.1
AM1-Optimized Geometry of Diazoketone 59
28
3.2
AM1-Optimized Geometry of Diazoketone 70
29
3.1
AM1-Optimized Geometry of Carbamate 30a
162
3.2
AM1-Optimized Geometry of Carbamate 31a
162
6.3
ORTEP Representation from X-Ray Structure of Epoxide 62
177
6.4
ORTEP Representation from X-Ray Structure of Epoxide 66
180
LIST OF TABLES
Table
3.1
3.2
3.3
3.4
6.1
Page
Structure-Selectivity Relationship in the Asymmetric
Reduction with Rhodium Complexes 79 and 80
33
Effect of Catalyst Concentration on Selectivity and Yield
of Asymmetric Reduction of Benzylidene Succinate 44
37
Estimated Relative Energies of Isomeric Products that
could Arise from Reduction of the Benzofuran 100
46
Dependence of Product Distribution on Catalyst During Catalytic
Decomposition of Diazoketone 119
53
The Influence of the R Substituent on the Ratio of
Carbamates 46 and 47
169
LIST OF APPENDIX TABLES
Table
Page
Appendix A Supplementary Crystallographic Information
on Epoxide 62
264
Crystal Data and Structure Refinement for Epoxide 62
265
Atomic Coordinates ( x 104) and Equivalent Isotropic
Displacement Parameters for Epoxide
266
3
Bond Lengths [A] and Angles [°] for Epoxide 62
267
4
Anisotropic Displacement Parameters (A2 x 103)
1
2
for Epoxide 62
5
Appendix B
269
Hydrogen Coordinates ( x 104) and Isotropic Displacement
Parameters (A2 x 103) for Epoxide 62
270
Supplementary Crystallographic Information
on Epoxide 66
271
1
Crystal Data and Structure Refinement for Epoxide 66
272
2
Atomic Coordinates ( x104) and Equivalent Isotropic
Displacement Parameters (A2 x 103) for Epoxide 66
273
3
Bond Lengths [A] and Angles [0] for Epoxide 66
276
4
Anisotropic Displacement Parameters (A2 x103)
5
6
for Epoxide 66
282
Hydrogen Coordinates ( x 104) and Isotropic
Displacement Parameters (A2 x 103) for Epoxide 66
285
Torsion Angles [0] for Epoxide 66
287
Synthetic Studies on Alkaloids. Part I: Asymmetric
Synthesis of (+)-Codeine. Formal Synthesis of (+)Morphine. Part II: A Unified Asymmetric Approach Toward
Synthesis of Polyhydroxylated Pyrrolizidine Alkaloids
Australine and Alexine
Chapter I. General Introduction.
The primary goal of organic synthesis as a scientific discipline is
development of effective sequences of chemical transformations applicable
to the construction of structurally diverse and often very complex natural
products and other molecular assemblies, important for medicine and other
crucial areas of human life.
The Ph.D. dissertation presented in the following pages is directed
toward synthesis of three alkaloidal natural products. The first part of
describes a formal asymmetric synthesis of (+)-morphine, the enantiomer of
the naturally occurring alkaloid, the most important analgesic used in
medical practice for treatment of patients in severe pain. The second part of
the presented research is dedicated to the synthesis of polyhydroxylated
pyrrolizidine alkaloids australine, alexine, and 7-deoxyalexine. This novel
class of natural products have shown a variety of biological activities,
including inhibition of the HIV virus and anti tumor activity.
2
Asymmetric Synthesis of (*Morphine.
Chapter II. Introduction
Opium, a milky extract obtained from the opium poppy (Papaver
somniferum) by incision of the seed pod, is an abundant source of alkaloids.
The primary alkaloidal component of opium is morphine (1), which covers
approximately 10 % of its dry concentrate. Morphine was first isolated from
opium as a pure substance by Sertarner in 1805.1 Subsequently, morphine
has become the most important analgesic utilized in medical practice
throughout the world. The correct structure of morphine was proposed by
Gulland and Robinson
in
1925 and was later confirmed by X-ray
crystallographic analysis, which also established the absolute configuration
of the alkaloid.2
HO
OH
1
Administration of morphine for relief of pain is associated with several
side effects, including development of physical dependence as well as
respiratory depression. These side effects often present a limit to the dosage
level that can be tolerated. Numerous studies have been dedicated to the
development of a morphine analog with improved analgesic properties, and
3
several active structural analogs of morphine are in use today. Morphine,
however, maintains its position as the most prominent analgesic used in
medicine throughout the world.
Studies on the principles of action of this powerful drug have provided
insight which has led to rational design of new generations of analgesics with
improved pharmacological profiles. The biological activity of opiates is
associated with at least three principal recognition sites which selectively
bind morphine or its structural substitutes. These are located not only in the
central nervous system (CNS) but also in many other tissues. Radio-ligand
binding techniques have located a high density of opioid binding and
recognition sites in the dorsal horn of the spinal cord and certain subcortical
regions of the brain.3 The opioid action occurs through activation of mu (g),
kappa (lc), and delta (5) receptors located on primary afferent neurons, which
are closely linked with the cAMP system and changes in Ca2+ and K+ flux.
Analgesia at the supraspinal level, as well as euphoriant, respiratory
depressant, and physical dependence properties are primarily associated
with the mu and delta receptors.4 The kappa receptor is believed to be
implicated in analgesia at the spinal level. The hallucinogenic and cardiac
stimulant effects of morphine are attributed
to a fourth
and
rather
controversial sigma (a) receptor. At the cellular level the effects of opioids are
associated with reduction of the nerve transmitter release by stimulating K+
efflux and Ca2+ influx into the presynaptic nerve endings.5 The very high
diversity of effects caused by opioids functioning with different potencies as
agonists, partial agonists and antagonists is closely linked with further
division of opioid receptors into subclasses such as pi, g2, and 123. Recent
4
studies also show that some opioids, including morphine and codeine, can
be present as endogenous substances in mammalian tissue.6
The clinical importance and structural complexity of morphine have
inspired many syntheses and synthetic studies dedicated to construction of
its intriguing ring-framework. Despite the considerable synthetic effort in this
area, there has not been a particularly wide range of approaches. In fact,
syntheses of morphine can be divided into three general categories
(Scheme 1). The first two elaborate an appropriate isoquinoline derivative
analogous to 2 or 3, and are usually designated as "isoquinoline
approaches".
Several
later
syntheses
of
morphine
incorporate
the
phenanthrene skeleton of the molecule, illustrated by structure 4, as the key
intermediate from which the pentacyclic framework of the alkaloid
is
elaborated. The primary difference between the individual synthetic studies
of morphine lies in the selection of the methodology for construction of one of
the related key intermediates. Consequently, the structural diversity of
morphine derivatives accessible through these studies is limited.7
5
<==
OR
2
3
OR
4
Scheme 1
Most of the successful syntheses of morphine and other morphinan and
benzomorphan alkaloids utilize an isoqinoline intermediate represented by
structure 2 (Scheme 1). This route to morphine was inspired by elucidation
of its biosynthesis, where the key intermediate, reticuline (5), undergoes an
intermolecular
oxidative
coupling
to
salutaridine
(6).
The
latter
is
subsequently transformed into morphine and related alkaloids (Scheme
2).8
6
MeO
HO
MeO
OMe
Scheme 2
Although it was difficult, due to regioselectivity problems, to successfully
mimic this transformation under laboratory conditions,9 it was later found that
an analogous transformation can be accomplished by exposure of
isoquinoline 7 to strong acids.10 This so-called Grewe cyclization was
subsequently
utilized
in
numerous approaches
to
morphinans
and
benzomorphans and has found industrial application in the production of
several artificial analgesics such as dextrorphan (8) (Scheme 3). Grewe
cyclization was also the key transformation in the first practical synthesis of
racemic morphine by Rice.11
H3PO4
HO
OH
7
Scheme 3
7
Subsequently, asymmetric construction of this isoquinoline framework
afforded entry into asymmetric syntheses of several artificial morphinans and
benzomorphans and finally resulted in the first asymmetric synthesis of
morphine by Overman in 1993.
The first synthesis of enantiomerically enriched (>98 e.e.) morphinans
was reported by Meyers as an outgrowth of his studies dedicated to the
synthetic application of chiral formamidines. The chiral carbanions generated
from these structures by deprotonation with strong bases such as nbutyllithium were found to undergo alkylation in a highly stereoselective
manner (scheme 4). This methodology was successfully applied to
asymmetric synthesis of various chiral /3-carbolines, piperidines,
and
pyrrolidines. Combination of this strategy with the Grewe cyclization afforded
a concise asymmetric route to benzomorphans and morphinans, such as
dextrorphan (8).12
n-BuLi
N
H
E
p-Me0BnCI
MeO
t-BuO
Scheme 4
Noyori offered another approach to several artificial benzomorphans,
such as (-)-matazocin (9) and (-)-phenazocine (10), which are potent but
nonaddictive
narcotic
analgesics.
Noyori's
route
was
extended
to
8
morphinans,
including
dextrorphan
(8)
and
its
levorotatory
isomer,
levarorphan.13
HO
Me
9 R = Me
10 R = CH2CH2C6H5
KiesNR
Noyori's strategy was based upon an asymmetric hydrogenation of
enamines using Ru(OCOCF3)2[(R)-tolbinap] as a catalyst under an initial
hydrogen pressure of 100 atm. The reduction proceeded in quantitative yield
and very high selectivity, in many cases exceeding 99% e.e. (Scheme 5).
POCI3
Ru(OCOCF3)2[(R)- tolbinap]
NCHO
H2
= CH3
R = R = (CH2)2
Scheme 5
The enamine
substrates
were
prepared
by
a
Bischler-Napieralsky
cyclization14 of the corresponding amide. The resultant chiral amines were
subjected to Grewe cyclization to afford morphinans and benzomorphans.
9
Stereocontrolled alkylation of chiral pyridinium salts with a Grignard
reagent provided the basis for the synthesis of (+)-normethazocine (14a) and
(+)-nordextrorphan (14b) reported by Marazano.15 The chiral pyridinium
derivatives originated from Zincke salts 11a and 11 b upon treatment with
(+)-1-phenylethylamine in refluxing dichloromethane. The resulting salts 1 2a
and 12b underwent addition of para-methoxybenzylmagnesium chloride
followed by reduction with sodium borohydride to give chiral amines 1 3a
and 13b with good stereoselectivity. Grewe cyclization and reductive
cleavage of the chiral auxiliary afforded (+)-normethazocine and
nordextrorphan, respectivelly.
1.p-Me0C6H4CH2MgC1
2. NaBH4
Ni'
PlitMe
(11a, b R = DNP
12a, b R = (S)-1-Phenylethyl
13a (82 % d.e.)
13b (78 % d.e.)
1. H+
2. Pd/C, H2
a: Ri = Me
b: Ri = R = -(CH2)214a, b
Scheme 6
(+)-
10
The first asymmetric synthesis of morphine which did not incorporate optical
resolution of an intermediate was accomplished by Overman in 1993
(Scheme 7). The key intermediate in this approach was the isoquinoline
derivative 18, prepared in high optical purity by an allylsilane cyclization of
iminium ion 17. The latter was prepared by condensation of the allylsilane
15 with aryl aldehydel6.
Ar
SiMe2Ph
Me2PhSi
"r
ZnI2, EtOH
IbBS
15
17
ds > 20 : 1
10% Pd(OCOCF3)2(Ph3P)2
MeO
19
Scheme 7
In contrast to the previous approaches, cyclization of isoquinoline derivative
18 to the morphinan skeleton was accomplished by means of an
11
intramolecular Heck reaction. This afforded 19 which was transformed in
several steps to dihydrocodeinone.16 The conversion of dihydrocodeine into
morphine was previously reported by Rice.17
A different approach to morphine was pioneered by Evans.18, 20 In this
approach, the key C10-C11 bond was formed by an intramolecular
electrophilic aromatic substitution of the arylisoquinoline derivative 3. For this
purpose, Evans developed two strategies (Schemes 8, 9). The first utilized
electrophilic
opening
of
an
aziridine
ring,
formed
by
addition
of
diazomethane to iminium salt 20, by chloride anion. Subsequent treatment of
the resulting chloromethyl derivative 21 with aluminum chloride gave 21a.18
A similar sequence was later employed by Rapoport in a formal synthesis of
morphine.19
CH2N2
Ph
20
LiCI
Ph
NI.Me
CH2CI
21a
21
Scheme 8
12
The second method designed to accomplish the
same bond
construction envisioned aldehyde 22 as a substrate. Upon treatment with
boron
trifluoride
etherate,
22
gave
morphinan
23
(Scheme
9).
Transformation of the latter to dihydrocodeine was accomplished in several
steps, which included removal of the C9-hydroxyl group, oxidative cleavage
of the exo-methylene group, and closure of the benzofuran ring.20
Me0
OH
Me0
BF3-Et20
Me0
N' Me
22
23
Scheme 9
Hudlicky recently reported a chemoenzymatic approach to the morphine
skeleton,21 which employed asymmetric biooxidation of ortho-bromobenzyl
bromide (24) as the key step (Scheme 10). The resultant dihydroxy
cyclohexadiene 25 was advanced to oxazolidinone 26, radical cyclization of
which gave the tetracyclic structure 27. The latter was transformed into the
aldehyde 28, which, following the Evans' synthesis, was converted to a
substance with the morphine framework.
13
Br
OTBS
24
25
26
n-Bu3SnH, AIBN
Ph -H,0
28
27
Scheme 10
A conceptually new approach to the morphine skeleton was developed by
Fuchs (Scheme 11).22 His synthesis was based upon construction of the
phenanthrene derivative 30 by a nucleophilic tandem reaction initiated by a
metal-halogen exchange of the aromatic bromine substituent. The resulting
sulfone 30 was advanced to the amine 31, which upon deprotection afforded
the nitrogen heterocycle 32.
14
n-BuLi
THF, -78 °C
30
O
OR
1 1
NRMe
Me0
32
31
Scheme 11
A radical tandem reaction of 33, similar to that used in Fuchs' approach,
was employed by Parker in her formal total synthesis of morphine (Scheme
12). The sulfoneamide 34 underwent a serendipitous cyclization to the
morphine skeleton under Birch conditions, which were originally expected to
cleave only the tosyl protecting group.23
15
Bu3SnH
PhS
AIBN
OR
34
Scheme 12
The tetracycle 34 has become the key intermediate in several approaches to
morphine, including a recently reported synthesis by Mulzer.24
The optically pure phenanthrene derivative 37 was envisioned by
d'Angelo as an ideal intermediate for the asymmetric synthesis of several
new morphinans (Scheme 13). This compound was obtained from the
bridged ketol 36, which, in turn, arose from enantioselective Michael addition
of methyl vinyl ketone (MVK) to the chiral enamine 35.
16
OMe
OMe
1. MVK
2. AcONa, AcOH
36
1. pyrrolidine,
acetone, A
2. AcONa, AcOH
37
Scheme 13
The phenanthrene 37 was subsequently advanced in several steps to azide
38 which underwent Staudinger reduction to give morphinan 39 (Scheme
14).25
OMe
OMe
PPN, THF; H2O
I
OO
Bn0
Bn0
38
HO
39
Scheme 14
=1.4
17
Of the numerous studies dedicated to the synthesis of morphine, only a
few attempts have been made to assemble the alkaloid from a phenanthrene
derivative, which would afford feasible C13-C15 bond formation (Scheme
15).26
Me
RO
OH
OR
Scheme 15
In fact, the so-called phenanthrene route has generally been considered the
most technically difficult of all the synthetic approaches to morphine. The
primary reason for this perception is the extreme steric hindrance in the
vicinity of C13. This combined with strong electronic interaction with the
adjacent aromatic ring causes this center to be inert to conventional chemical
transformations. Nonetheless, an attractive feature of a synthetic enterprise
along this line would be the creation of structurally interesting molecules not
previously seen en route to morphine. Such an approach would provide
access to novel morphine analogs which could find application in affinity
studies of opioid receptors and perhaps provide a basis for the development
of new drugs.
It was principally for these reasons, that research was initiated in these
laboratories on the design of a new asymmetric route to morphine (Scheme
18
16). Construction of the C13-C15 bond was to be the crucial element in this
plan. The strategy envisioned as a direct precursor of morphine pentacycle
40, which, in turn, would originate from phenanthrenone derivative 41. We
surmised that this structure could be readily prepared in asymmetric fashion
from a chiral succinic acid derivative 42.
HO
MeO
OH
1
40
O
OR
MeO
MeO
OH
42
Scheme 16
A short route affording 41 in racemic form had already been developed by
Stappenbeck.27 In that work, isovanillin 43 was subjected to Stobbe
condensation with dimethyl succinate to give the benzylidene succinate half
ester 44. The latter was transformed into saturated carboxylic acid 45 by
means of catalytic hydrogenation (Scheme 17). Bromination of 45, followed
by Friedel-Crafts cyclization accomplished in neat sulfuric acid gave tetralone
19
46. The bromination step in this sequence was mandatory in order to
override the intrinsic preference of 45 for cyclization para
to the phenol
functionality.
CO2Me
(MeO2CCH2)2
MeO
Me0Na, Me0H
OH
MeO
v
CO2H
OH
87%
44
43
Pd/C, H2
Me0H, 99
()/0
CO2Me
CO2Me
Br2, AcOH
MeO
CO2H
CO2H
81 %
OH
45
H2SO4, 80 %
CO2Me
MeO
OH 0
46
Scheme 17
Tetralone 46 was first formylated with methylformate to give the 0-keto
aldehyde 47 (as its enol tautomer), which was reacted with a methyl vinyl
ketone (MVK) (Scheme 18). The resulting adduct 48, upon treatment with
20
aqueous sodium hydroxide gave the phenanthrene derivative 49. The
relative stereochemistry of 49 was established by X-ray crystallographic
analysis.
NaH, HCO2Me
OH 0
OH 0
46
47
MVK, Et3N
86 %
NaOH, H20-THF
86 %
49
Scheme 18
In the approach to morphine pursued by Stappenbeck, the goal was
pentacyclic ketone 52 which was to be prepared from diazoketone 50 by
cyclopropanation of the C5-C13 double bond. Subsequent nucleophilic
attack by the phenolic oxygen on the cyclopropane intermediate 51 was
expected to give 52 (Scheme 19).
21
COCHN2
MeO
OH
110
MeO
50
52
51
Scheme 19
Although there is literature precedent for such a transformation,27
serious
geometrical constraints
in
the
case of
50
prevented
this
transformation from occurring. The first complication appeared when it
proved impossible to prepare diazoketone 50 without protection of the
phenol functionality. Furthermore, when diazoketone 53 was treated with
rhodium(II) acetate, no product from carbenoid addition to the double bond
could be detected in the reaction mixture (Scheme 20). Instead, the major
product was cyclobutanone derivative 54. In light of this result, considerable
effort was devoted to expansion of the cyclobutanone
54
to
the
corresponding five-membered cycle. By rather forceful means and at the
expense of elegance, a pathway transforming cyclobutanone 54 to the
tetracyclic structure 56 was eventually developed which involved reduction
of diketone 54 to diol 55. Upon treatment with boron trifluoride etherate in
hot toluene, 55 was converted to alcohol 56 in low yield. Although 56 can
be envisioned as a potential morphine precursor, the inefficiency of the
pathway brought this line of investigation to an end.
22
Rh2(OAc)4
Me()
55 %
54
53
0
NaBH4, CeC13-7H20,
Me0H, 88 %
BF3-Et02
toluene, A
36 %
MeO
OAc
55
56
Scheme 20
OH
23
Chapter III. Results and Discussion
3.1. Retrosynthetic Analysis
As a continuation of the earlier studies in these laboratories, the design
of a fundamentally new asymmetric route to morphine remained our primary
synthetic goal. Since we were interested in pharmacological properties of the
unnatural enantiomorph, the focus of our work has been (+)-morphine 57.
/>Me
HO
57
OH
The conceptual connection to the previous synthetic endeavors in these
laboratories was phenanthrene derivative 58, an important intermediate
available in large quantities by a concise sequence amenable to asymmetric
modification. In contrast to the foregoing approaches, however, a new
strategy for construction of the crucial C13-C15 bond of morphine was
envisioned. The key reaction in this new synthetic plan was to be a
regioselective rhodium-catalyzed carbenoid insertion of diazoketone 59,
which, in a stereospecific
manner,28 would
establish
the
requisite
stereochemistry at the C13 quaternary center of morphine. This sequence,
however, had to incorporate a stereoselective reduction of 58 which would
24
establish the cis-B,C-ring junction of the molecule, indispensable for the
success of the subsequent insertion step (Scheme 22).
,,CO2 Me
H
reduction
MeO
OR
59
58
0
insertion
0
HO
57
OH
60
Scheme 22
The most challenging part of this approach was in the control of
regioselectivity during the transformation of diazoketone 59 to tetracyclic
ketone 60 (Scheme 23). The main complication would probably arise by
preferential formation of one or more of the three possible isomeric ketones
61, 62 or 63 by carbenoid insertion at the wrong site. Another potential
difficulty was cyclopropanation of the aromatic ring, a reaction that is well
precedented.28
25
2
Rh(II)
MeO
MeO
MeO
MeO
OR
61
62
OR
63
Scheme 23
Numerous examples of carbenoid insertion into a C-H bond are
described in the literature.28 As a result of these studies it can be concluded
that the major mode of carbenoid insertion is such that a five-membered ring
is formed preferentially. The prerequisite for such an outcome, however, is a
cis-pseudodiaxial
relationship
of the C-H bond and the diazoketone
functionalities. An illustration of this principle can be found in a study by
Agosta and Wolf who examined carbenoid insertion of diazoketone 6 4
(Scheme 24). Here, the axial disposition of the diazoketone functionality
was reinforced by two equatorially oriented methyl groups. Exposure of 64 to
copper(II) sulfate in refluxing hexane gave rise to bicyclo[3.2.1]octanes 6 5
and 66 in very good yield. It is also interesting to note that C-H insertion in
this reaction took place predominantly at the more substituted carbon.29
26
COCHN2
64
O
Cu(II)
65
66
58%
20%
Scheme 24
Rhodium-catalyzed carbenoid insertions are generally superior to those
based on copper or silver catalysts both in terms of yield and selectivity. As
with the other metals, rhodium catalysts display a clear preference for the
formation of five-membered cyclic ketones when the necessary geometrical
requirements are fulfilled. An illustration of this property is found in a study by
Ceccherelli, who examined the regioselectivity of Rh(II)-mediated insertion in
several polycyclic structures. Especially noteworthy is the transformation of
diazoketone 67 in the presence of rhodium(II) acetate dimer, which not only
gave exclusively the five-membered ketone 68, but also regioselectively
preferred the activated allylic methylene. This transformation parallels the
insertion process designed for 59 (Scheme 25).30
27
Rh2(OAc)4
67
Scheme 25
The foregoing studies, as well as other examples from the literature,
suggest that the key step in our synthetic strategy would be feasible if two
major criteria were satisfied. First, complete stereocontrol would have to be
maintained in the reduction of enone 58 so that the cis-B,C-ring junction is
obtained exclusively. The second requirement is that, if the previous step
were successful, the most stable conformation of the resulting ketone would
need to have the benzylic methyne and diazoketone functionalities in parallel
cis-pseudoaxial orientations. Our initial studies indicated that enone 5 8
fulfills neither of these criteria. Not only was it impossible to achieve the
required cis-B,C-junction in the reduction of 58, but also molecular modeling
studies predicted that the preferred conformation of diazoketone 59 could not
give rise to the insertion with the desired regioselectivity (Figure 3.1).
28
Figure 3.1. AM1-Optimized Geometry of Diazoketone 59.
In order to attain the conformation necessary for benzylic CH insertion
as well as selectivity in the reduction step, it was imperative to close the
benzofuran ring prior to these transformations. The structural assembly
represented by 70 would guarantee the proper conformation of the molecule
necessary for success of the insertion step (Figure 3.2). In addition, closure
of the benzofurane ring would also ensure the desired selectivity in the
reduction of a,f3-unsaturated ketone 69, as judged from a comparison of the
thermodynamic stability of the resulting saturated ketones.
29
Figure 3.2. AM1-Optimized Geometry of Diazoketone 70.
After considering these issues, a new synthetic pathway was designed
in which the phenanthrene derivative 58 is first transformed into the
benzofuran 69. The latter is then advanced in several simple steps to
diazoketone 70, which according to our predictions, was expected to
undergo the desired transformation to pentacyclic ketone 71. Beckmann
rearrangement30 of the derived oxime followed by several simple functional
group interconversions, including N-methylation and installment of the
morphine double bond, should give the enone amide 72. Reduction of 72 to
(+)-codeine and final demethylation according to a known procedure should
afford to (+)-morphine (Scheme 27).31
t3o
,,,,Cr'
101
44o
Soh°IN
?,
31
3.2. Asymmetric Synthesis of the Phenanthrene Derivative 59.
Construction
of the ABC-Ring System of Morphine.
As outlined above, a short route has been developed for the synthesis
of phenanthrene derivative 49 in racemic form.27 One of the key
intermediates in this sequence is carboxylic acid 73, which is produced by
hydrogenation of the benzylidene succinate half-ester 44 and is the first
chiral intermediate in our sequence. In principle, the configuration of all
subsequent stereochemically important intermediates in our synthetic
scheme relates to that of 73. The relative stereochemistry at C14 in 74 is set
under thermodynamic control in the final stage of the Robinson annelation.
The configuration of carbons C13 and C5 in the tetracyclic ketone 75 arises
from substrate controlled asymmetric reduction of the corresponding
benzofuran derivative, and the final configuration at C6 in ent-codeine 76 is
established by a well precedented metalo-hydride reduction. The latter
should take place exclusively from the less hindered face of the
corresponding carbonyl compound. Since the bridged ring of 76 is
established in a stereospecific manner in the carbenoid insertion step,
control of stereochemistry in the catalytic hydrogenation step would be a
necessary and sufficient condition for completion of a morphine synthesis in
asymmetric fashion (Scheme 27).
32
CO2Me
CO2Me
asymmetric reduction
Me0
CO2 H
Me0
OH
CO2H
OH
44
(-)-S 73
CO Me
Me0
NMe
Me0
1.00
6
0
74
75
OH
76
Scheme 27
The MOD-DIOP-Rh(I) complex33 seemed the most suitable catalyst for
accomplishing asymmetric reduction of the benzylidene derivative 44. This
catalyst was designed by Achiwa and evolved from systematic modification of
the standard DIOP ligand 77.32 Both the neutral [CIRhCOD]2 + (4R,5R)MOD-DIOP (79) and cationic [RhCOD(4R, 5R)-MOD-D1013]+BF4- (80) forms
of this catalyst show very good selectivity in asymmetric reduction of
substituted benzylidenesuccinate half esters (Table 3.1).
In a typical
procedure, reductions were carried out in the presence of one equivalent of
triethylamine at atmospheric pressure and room temperature with a catalystto-substrate ratio of 2x10-3.33,
33
_
P
P
MeO
77: (4R,5R)-DIOP
Ar
CO2Me
78: (4R,5R)-MOD-DIOP
79 or 80
)"-
Ar
CO2H
CO2Me
CO2H
Scheme 28
Catalyst
Ar
Yield (%)
e.e. (%)
Product
configuration
r-O
80
79
100
100
90
94
S-(-)
S-(-)
80
100
91
S-(-)
80
100
94
S-(-)
OMe
HO
CI
Table 3.1: Structure-Selectivity Relationship in the Asymmetric
Reduction with Rhodium Complexes 79 and 80
34
For the purpose of asymmetric synthesis of ent-morphine we needed to
introduce S configuration at C3 of 73. The empirical results reported by
Achiwa indicated that the (4R,5R)-MOD-DIOP (78) ligand was required for
this configuration in the reduction of 44 (Table 3.1).
The synthesis of this ligand began from 4-bromo-2,3-dimethylphenol,
which was 0-methylated with dimethyl sulfate under standard conditions. The
resultant anisole derivative 82 was transformed into a Grignard reagent,
which was reacted with diethyl phosphite to give the diaryiphosphine oxide
83. The latter was further reduced to the crude diphenylphosphine derivative
84. Without purification, 84 was deprotonated with tert-butyllithium at low
temperature and was treated with
1,4-di-O-tosy1-2,3-0-isopropylidene
threitol34 (85) to give (4R,5R)-MOD-DIOP 78 in 19 % overall yield from the
phosphine oxide (Scheme 29).33, 35 Despite the relatively low yield, this
sequence furnished satisfactory quantities of the chiral ligand for the
purposes of asymmetric reduction of 44 and was not further optimized.
35
OH
Me2SO4, TBAB
1. Mg, THE
NaOH, CH2Cl2 -H20
2. (Et0)2P(0)H
OMe
70 %
81
60%
82
CI3SiH, Et3N;
NaOH,H20
20Ts
1. t-BuLi
78
2.85
OTs
19 % from 83
85
Scheme 29
Although most of Achiwa's experiments were done with the cationic
complex 80, we decided for reducion of 44 to use the neutral complex 79,
which is prepared by an experimentally simpler procedure. Our first attempts
at asymmetric reduction of 44 met with only moderate success. It was found
that the catalyst-to-substrate ratio suggested by Achiwa necessitated an
extended reaction time (40 h) and did not provide the expected selectivity.
Chiral HPLC analysis of the reaction at various intervals indicated that the
enantiomeric
purity of the product gradually
decreased
during
the
hydrogenation. This suggested that over prolonged periods the chiral catalyst
was chemically transformed to a species that was still catalytically active but
36
had lower or no selectivity. This observation is in accord with results
published by Glaser who reported that the ability of [CIRhCOD]2 + DIOP
catalyst to induce asymmetric induction in several catalytic hydrogenations
diminished over a 48 h time period.36 It was clear that in order to achieve
results qualitatively comparable to those published by Achiwa, the rates of
our reaction would need to be significantly enhanced. By gradually
increasing the catalyst-to-substrate ratio, we found that an almost three-fold
increase in the amount of catalyst was necessary to obtain Achiwa's reported
yields and selectivity (Table 3.2). It is of interest to note that, in contrast to
Achiwa's observations, we found the presence of triethylamine in the
reaction mixture to be unnecessary. The absolute configuration of the
product was assigned as S by comparing the sign of optical rotation with that
of known analogs (Table 3.1).
CO2Me
MeO
H
H2, 79
Me0H, r.t.
CO2 H
MeO
OH
CO2Me
CO2H
OH
44
73
Scheme 30
[Rh]/substrate
time
2.0 x10-3
3.8x10 -3
10 h
10 h
5.6x10-3
7-10h
yield ( %)
10
50
100
% e.e.
90
92
94
[substrate]
0.6 M (Achiwa)
0.6 M
0.6 M
Table 3.2: Effect of Catalyst Concentration on Selectivity and
Yield of Asymmetric Reduction of Benzylidene Succinate 44.
37
Optimization of the asymmetric hydrogenation step concluded with a
final yield of 100 % and 94 % enantiomeric excess. The enantiomerically
enriched ester 73 was advanced to the phenanthrene derivative 49
(Scheme 31) according to the previously developed strategy.27 However, it
was later discovered that significant racemization had occurred during this
sequence of reactions.
H
Me0
OH
CO2Me
1. Br2, AcOH
CO2H
2. H2SO4
62 `)/0 two
steps
73
OH 0
86
NaH,HCO2Me
PhCH3
1. Et3N, MVK
2. NaOH, THE -H20 Me0
60 % from 86
49
OH 0
87
Scheme 31
After careful analysis of intermediate compounds in this sequence, by
chiral HPLC, it was established that racemization had occurred between 86
and 49, but it was impossible to determine unequivocally at which of the
three steps involved in this transformation that racemization took place. This
38
led to a decision to saponify the methyl ester of 86 prior to formylation in the
expectation that the racemization could be avoided. It was also found
convenient to debrominate the tetralone 86 in order to facilitate handling of
the latter intermediates. Finally, the yield of the Friedel-Crafts acylation was
enhanced by replacing the sulfonic acid catalyst with the milder Ms0H-P205
mixture.37
1. Br2, AcOH
2. MsOH -P205
Me0
OH
0CO2Me
Me0
75%
OH 0
73
86
Pd(OH)2/C, H2
Me0H, 99 %
soCO2H
sCO2Me
LiOH
Me0
OH 0
THE -H20
100 %
90
MeO
OH 0
89
Scheme 32
The carboxylic acid 73 was reacted with bromine in acetic acid38 to
give in 98 % yield the corresponding bromoderivative, which was subjected
to Friedel-Crafts acylation in the presence of MsOH -P205 to afford tetralone
86 in good yield. Subsequent debromination of 86 by means of catalytic
hydrogenolysis, using hydrogen gas in the presence of Pearlman's
catalyst39 gave the methyl ester 89, which was saponified with lithium
39
hydroxide to produce tetralonecarboxylic acid 90
in
quantitative yield
(Scheme 32).
It was found that sodium hydride was not sufficiently basic to achieve
complete deprotonation of the acid 90. However, potassium hydride proved
satisfactory in this respect and generated the trianion of 90, which underwent
a vigorous reaction with excess methyl formate to afford the /3- ketoaldehyde
91
in excellent yield. Treatment of 91 with methyl vinyl ketone in the
presence of two equivalents of triethylamine initially afforded the tricyclic
lactone 92, which readily afforded the phenanthrene carboxylic acid 74 yield
upon exposure to aqueous sodium hydroxide (Scheme 33).
sCO2H
1. KH, THF; HCO2Me
OH 0
94 %
90
OH 0
91
MVK, Et3N
NaOH, THF-H20
70 % from 91
74
Scheme 33
Neither of the tetralone derivatives 86 and 89 could be enhanced in purity by
crystallization, due to the very strong propensity for these compounds to
40
crystallize as a pair of enantiomers. Fortunately, crystallization of the
phenanthrene carboxylic acid 74 after reaction work-up afforded optically
pure material as determined by chiral HPLC.
41
3.3. Construction of the Dihydrobenzofuran Derivative 112.
With the phenanthrene derivative 74 in hand, we turned our attention to
closure of the benzofuran ring and to its subsequent reduction. It was
expected that this would yield the dihydrobenzofuran 75 with the desired R
configuration at C13 (Scheme 34). This configuration is required in order to
accommodate the key carbenoid insertion leading to the bridged pentacyclic
framework of the alkaloid.
MeO
-- MeO
74
69
75
Scheme 34
The basis for our approach to benzofuran 69 was the known alkaline
decomposition of 3-halo-, 4-halo-, and 3,4-dihalocoumarins to afford
coumarillic acids in high yield (Scheme 35).40
R
OH"
Br
I
CO2
Scheme 35
\
0
CO2H
42
During this transformation the a-carbon bearing the bromine substituent must
undergo temporary sp3 hybridization, which is followed by rapid ring-closure
by means of SN2 substitution. The change of hybridization may be the result
of tautomerism or conjugate addition of a nucleophile to the activated double
bond (Scheme 36). In the case of 94, this transformation was not
significantly affected by the nature of the R substituent and could be
accomplished with bulky amine bases such as morpholine or piperidine,41
which are known to be poor nucleophiles in conjugate addition. This leaves
each of the structures 95, 96, and 97 as a plausible intermediates
preceding closure of the furan ring. On this basis, it appeared that this
reaction should have broader application to the synthesis of benzo[b]furans
and we therefore decided to incorporate an analogous ring-closure in our
synthetic plan.
o
0-
Base
Br
/
0"
0 Br
OH
94
95
0-
96
Scheme 36
The success of this strategy depended on selective introduction of a
bromine substituent at the a-position of the enone functionality. To this end,
43
the phenanthrenecarboxylic acid 74 was first carefully methylated with
diazomethane in ethyl acetate, and the resulting methyl ester 98 was treated
with bromine in chloroform. Analysis of the product showed that the desired
bromination of the double bond did not occur, but instead aromatic
substitution and a'-bromination took place to give 98a. Presumably, the
hydrobromic acid formed during electrophilic aromatic substitution catalyzes
the undesired mode of bromination at the a' position of 98. This complication
was circumvented by simply buffering the reaction mixture with sodium
bicarbonate. Bromination under these conditions gave the desired abromoenone 99. Unfortunately, electrophilic substitution of the aromatic ring
occurred at approximately the same rate as addition to the conjugated
enone, and two equivalents of bromine were necessary to drive the reaction
to completion.
CH2N2
MeO
EtOAc - Et20
99 %
MeO
Br2, CHCI3
NaHCO3
Br2, CHCI3
80%
1
MeO
MeO
99
98a
Scheme 37
44
The dibromophenanthrenone 99 underwent facile ring-closure upon
exposure to sodium methoxide in refluxing methanol to give the desired
benzofuran 100 in high yield. Unfortunately, chiral HPLC showed that
double epimerization had occurred during this transformation. Numerous
attempts were made to find the most appropriate conditions to accomplish
the ring-closure without loss of stereochemistry, and it was finally discovered
that 1,8-diazabicycloundec[5.4.0]-7-ene (DBU) in benzene was the most
suitable base for mediating this transformation (Scheme 38). Under these
conditions the cyclization proceeded virtually without loss of stereochemistry.
Presumably, formation of the ester-enolate in this case is substantially
slower due to the lower concentration of the base and possibly to the larger
steric requirement of DBU in the transition state of the deprotonation.
DBU, benzene
MeO
68 °C, 80
MeO
100 0
99
Scheme 38
The next step in our synthetic plan was stereoselective reduction of the
benzofuran derivative 100. Molecular modeling studies indicated that the
thermodynamic stability of ketone 75 is significantly higher than that of any
other stereoisomers 101, 102, and 103, which could be formed by
45
reduction of the furan double bond. The relative energies of the four possible
reduction products, as determined by an AM1 calculation, are shown in
Table 3.3.
Me0
Me0
75
Me0
Me0
103
A E (kcal/mol)
75
101
102
103
0
3.11
12.06
14.25
Table 3.3: Estimated Relative Energies of Isomeric Products that
could Arise from Reduction of the Benzofuran 100.
On the basis of these calculations, we expected that reduction of enone
100 under thermodynamic conditions should afford exclusively the desired
isomer 75. Dissolving metal reduction42 appeared to be the most promising
way to accomplish this transformation, and when 100 was exposed to
sodium amalgam in aqueous sodium hydroxide a single product was formed.
However, it was found that the product was the result of rupture of the furan
ring, yielding 105 (Scheme 39).
46
s.0O2Me
1. Na-Hg, NaOH -H20
MeO
2. CH2N2
OH
85 %
100
105
Scheme 39
A similar result was obtained when sodium amalgam was replaced with
lithium in liquid ammonia as the reducing agent. This led us to explore other
possibilities to accomplish this transformation. It is clear that reduction of the
double bond of 100 will disrupt aromaticity of the furan ring, and for this
reason, a strong tendency for 100 to undergo 1,2-reduction of the keto group
would be expected. It was thought that complexation of the carbonyl group
with a strong Lewis acid would enhance the polarization of the enone and
thus facilitate the desired 1,4-reduction. Surprisingly, when 100 was treated
with triethylsilane in the presence of titanium(IV) chloride43 only the
deoxygenated product 106 was isolated (Scheme 40).
Et3SiH, TiC14
MeO
CH2Cl2
MeO
90 %
100
106
Scheme 40
47
Catalytic hydrogenation appeared to be another possibility for acquiring
75, since the large difference in energies of the two possible stereoisomeric
reduction products should influence both the rate at which the palladium
complexes with the two individual faces of the double bond as well as the
stability
of
all
organopalladium
intermediates
formed
during
the
hydrogenation. When enone 100 was exposed to the conditions of catalytic
hydrogenation, a mixture of three structurally different compounds, 107, 108,
and 109 in a 6:1:1 ratio, was produced (Scheme 41). Examination of the
major product (107) by NMR spectroscopy revealed that hydrogenation had
taken place from the desired face, as could be inferred from a 7% NOE
between hydrogens attached to C13 and C14. However, in addition to
reductive removal of the bromine substituent, cleavage of the carbonyl
oxygen had also taken place in the course of this reaction.
MeO
MeO
100
107
MeO
OMe
OH
109
108
Scheme 41
48
Two side products 108 and 109, each in approximately 10% yield,
were isolated from this reaction. The structures of these compounds provided
an insight into the order of events that took place during the overreduction.
Very likely, 1,2-reduction of the carbonyl group occurred first to provide an
allylic alcohol with the axial hydroxyl group perpendicularly oriented to the
plane of the adjacent double bond. A structural assembly such as this would
have a high propensity towards displacement of the allylic hydroxyl group by
a formal oxidative addition to give n-ally! complex 110 (Scheme 42). The
presence of this intermediate is strongly supported by the formation of the
methoxy derivative 108, which must originate from nucleophilic attack of
methanol on the ic -allyl complex.110
MeO
Pd(0), H2
Pd(II) -H
110
Me0H
MeO
Scheme 42
49
It is generally accepted that successful formation of a n-ally1 transition
metal complex requires a perpendicular orientation of the leaving group with
respect to the plane of the double bond.44 This crucial alignment is
attainable in open chain systems by virtue of the rotational flexibility of the
structure. However, in a rigid system such as 100, where there is little
conformational freedom, orientation of the substituent relative to the double
bond is controlled by the configuration of the carbon to which the leaving
group is attached. It was conjectured that reduction of the carbonyl group of
100 from the axial direction would force the hydroxyl group to adopt a
parallel orientation with respect to the double bond, an alignment which
should completely suppress overreduction to 107.
The enone 100 was first subjected to 1,2-reduction with sodium
borohydride to give equatorial alcohol 111 as the sole product (Scheme
43). The stereochemistry of this product was rationalized on the basis of
numerous examples from the literature describing enhanced axial attack in
1,2-reduction of a,(3- unsaturated ketones.45 As predicted, exposure of 1 1 1
to catalytic hydrogenation afforded the desired dihydrobenzofuran 112 in
good yield along with its stereoisomer 113 in the ratio 22:1, respectively. No
overreduction product was detected in the reaction. In practice, it was
convenient to carry out the hydrogenation of 111 in the presence of sodium
bicarbonate to avoid exposure of the product to hydrobromic acid formed by
hydrogenolisis of the bromine substituent. Unfortunately, sodium bicarbonate
substantially decreased the rate of hydrogenation and had to be removed by
aqueous work-up in order to drive the reduction to completion.
50
CH2Cl2- i -PrOH
99 %
OH
111
100
H2, Pd/C
NaHCO3
78%
,,CO2Me
MeO
H
112
113
Scheme 43
OH
51
3.4. Rhodium Catalyzed Carbenoid Insertion. Construction of the
Pentacyclic Framework of Morphine.
The successful preparation of the dihydrobenzofuran 112 set the stage for
construction of the bridging C9-C13 component of the morphine skeleton by
application of the pivotal metallocarbene insertion. This step envisioned
attack by ketocarbenoid 114 at the benzylic methyne to forge the carbon-
carbon bond that completes the pentacyclic nucleus 115 of morphine
(Scheme 44).
OR
112
OR
114
115
OR
Scheme 44
First, the methyl ester 112 was transformed into diazoketone 118 by a
short sequence, which included protection of the secondary alcohol as a
methoxymethyl (MOM) ether,46 saponification of the methyl ester, and
subsequent treatment of the resulting carboxylic acid 117 with oxalyl
chloride and diazomethane (Scheme 45). An analogous sequence was
carried out on the corresponding methoxyethoxy methyl ether (MEM),
prepared by treatment of 112 with chioromethyl methoxyethyl ether in the
presence of diisopropylethylamine.47 However, this latter series proved to
be less useful than the MOM-protected intermediates due to difficulties with
the subsequent removal of the MEM group.
52
(Me0)20H2
Me0
P205
80 %
Me0
OH
OMOM
116
112
Li0H, 99 `)/0
1. (C0C1)2
Me0
2. CH2N2
OMOM
Me0
63 % two steps
OMOM
118
117
Scheme 45
The first attempt to convert diazoketone 118 to pentacyclic ketone 119
was made with dirhodium(II) tetraacetate (Rh2(OAc)4)48 in dichioromethane
as the catalyst and afforded 119 in an encouraging 50 % yield along with
three side products identified as 120, 121, and 122 (Scheme 46). The
pathways leading to these side products are discussed below.
O
Rh2(OAc)4
Me0
50 %
OMOM
118
119
OMOM
53
Me0
Me0
Me0
OMOM
OMOM
120
OMOM
121
122
Scheme 46
119 (%)
120 (%)
121 (%)
122 ( %)
Rh2(TFA)4
<2
28
40
-
Rh2(TPA)4
38
19
11
Rh2(OAc)4
50
20
15
<3
Rh2(acam)4
65
4
4
-
3.4: Dependence of Product Distribution on Catalyst
During Catalytic Decomposition of Diazoketone 119.
Table
CR3
0 --
CH3
CR3
Rh-
.o
1:th
R3C
0--
RIh
_01,-CH3
dR
Or-0
.NH
H
CR3
R = H: Rh2(OAc)4
R = Ph: Rh2(TPA)4
R = F: Rh2(TFA)4
CH3
Rh2(acam)4
54
Recent studies of rhodium-catalyzed carbenoid insertion have shown
'that the ligands attached to the metal exert a strong influence on the
selectivity of these reactions. For this reason, we decided to examine several
rhodium-based catalysts in an attempt to improve the yield of the pentacycle
119.
The
least
favorable
result
was
obtained
with
dirhodium(II)
tetra(trifluoroacetate) (Rh2(TFA)4),49 which afforded predominantly methyl
ketone 120 and olefin 121 in an approximate ratio 1.5:1. These products
accounted for 70% of the mass recoverery; only traces of the ketone 119
were detected. This experiment supported our premise that increased
reactivity of the catalyst would favor formation of the undesired side-products.
A slightly better result was obtained with dirhodium(II) tetra(triphenylacetate)
(Rh2(TPA)4)50 as catalyst, which afforded 40 % of 119. In this case, a larger
quantity of the cyclobutanone 122 was produced, which together with the
olefin
121
accounted for approximately 30 % of the overall
mass.
Interestingly, no 120 was isolated from this reaction (Table 3.4). The
enhanced propensity for this catalyst to promote attack by the carbene on the
less hindered benzylic methylene can be rationalized by the increased steric
bulk of the triphenylacetyl ligands.
In recent studies published by Doyle, dirhodium(II) tetrakis(acetamide)
(Rh2(acam)4)51 catalyst, which has significantly decreased reactivity, was
found to show a high propensity for promoting carbene insertion into
electron-rich methyne carbon-hydrogen bonds. In fact, when 118 was
exposed to this catalyst, the desired pentacylic ketone 119 was isolated in
65 % yield, and only a traces of 120 and 121 were produced. A slightly
decreased mass recovery from this reaction can be explained by
55
oligomerization processes which intervened due to the fact that the reaction
time was substantially prolonged.
The side-products isolated from this reaction provide an important insight
about processes which take place during the decomposition of 118. In the
insertion mechanism proposed by Taber,52 the new carbon-carbon bond is
formed directly via a four-membered transition state in which concomitant
transfer of hydride on to the metal affords an intermediate 123 that
undergoes fast reductive elimination to give the insertion product 124
(Scheme 47).
H
reductive
eliminatiom
,C
R
H
124
Scheme 47
The structure of ketone 120 suggests that an intramolecular hydrogen
transfer occurred from the dihydrobenzofuran moiety to the carbene carbon
in the course of this reaction. According to Taber's mechanism, formation of
the double bond in 120 would be preceded by hydride abstraction from the
C13 carbon by the rhodium metal to form a carbocation, which would
undergo transformation to the olefin via an external proton transfer (Scheme
48).
56
H
+
H
-
RhLn
..RhLn
+
-C--..
Ar
/
-C
i --'
Ar
H -->,4
(---R
Base
Scheme 48
Although the adjacent aromatic ring could provide a degree of
stabilization to this carbocation, the lack of flexibility in the structure would not
allow the intermediate carbocation to assume a planar geometry. Indeed, it
would be much easier to view )3-hydride elimination as the step responsible
for incorporation of the benzofuran double bond. This, however, would
require formation of a metallocarbene 127, which is in contradiction with the
Taber mechanism (Scheme 49). The metallocycle 127 would originate by
insertion of the metal into the carbon hydrogen bond, followed by transfer of
the hydrogen atom to the carbon substituent. Reductive elimination of 127
would subsequently liberate the final insertion product.
hydrogen
transfer
HH
Rh
125
126
Scheme 49
)C
127
57
Both the formation of an intermediate 125 as well as an equilibrium
between 126 and 127 have been postulated in transformations of other
organometallic compounds. Coordination of a C-H bond to a metal was
documented in several complexes of osmium and ruthenium,53 and an
equilibration analogous to that between 126 and 127 was postulated for a
neopentyl-tantalum complex 128 (Scheme 50).54
t-Bu
t-Bu
LnTa
H
128
Scheme 50
In the normal course of the reaction the metallocyclic intermediate 127
would undergo reductive elimination to form the cyclic ketone 119. In the
case of 129 formation of the aromatic benzofuran ring is the driving force
which facilitates /3-hydride elimination to yield 120 (Scheme 51).
58
reductive
elimination
MeO
119
0-hydride
elimination
OMOM
0
OMOM
129
OMOM
Scheme 51
To test this mechanistic hypothesis it was decided to carry out rhodium-
catalyzed decomposition of diazoketone 132
(Scheme
53).
It was
expected that the carbonyl group at C6 should not have a significant
influence on the formation of the carbocationic intermediate shown in
Scheme 48, but should strongly retard /3- hydride elimination.
Ketone 132 was prepared by a short sequence which involved
oxidation of the secondary alcohol 112 by Dess-Martin periodinane to
ketone 130,55 saponification of the methyl ester with aqueous lithium
hydroxide, and treatment of the resultant carboxylic acid 131 successively
with oxalyl chloride and diazomethane (Scheme 52).
59
Dess-Martin
periodinane
MeO
92%
f.:
OH
112
130
Li0H, THE -H2O
99%
CO2H
1. (C00O2
MeO
2. CH2N2
MeO
831%
132
131
Scheme 52
Interestingly,
when
ketone
132 was exposed
to
dirhodium(II)
tetraacetate no benzofuran analogous to 120 was produced in the reaction.
The desired five-membered ketone 133 was obtained in 54% yield along
with 5% of cyclobutanone 135a and 17% of the olefin 135b.
60
0
135a
135b
Scheme 53
Again, formation of olefins 121 and 135b can be rationalized by the
metallocyclic intermediate 136 (Scheme 54), which in this case undergoes
electrocyclic fragmentation liberating a molecule of ketene.
It
is difficult to
account for such a transformation in terms of Taber's mechanism.
Me0
Me0
OR
OR
136
Scheme 54
61
In the final analysis, it is concluded that although Taber's mechanism
can explain formation of the insertion products, involvement of a metallocyclic
intermediate in this reaction should be considered as a plausible alternative.
In our case, the metallocycle pathway provides a better rationale for
formation of the olefinic side products.
Incorporation of the diketone 133 into our planned route to morphine
was strategically attractive due to the elimination of several steps which
required the use of protecting groups. We reasoned that the six-membered
cyclic ketone
should
be more amenable to enolization than the
cyclopentanone thus providing an opportunity for selective incorporation of
the C7-C8 double bond. On the other hand, the resulting conjugated ketone
should be less reactive towards nucleophilic attack (Scheme 55). This
would allow the five-membered ketone to be transformed selectively into the
corresponding oxime in preparation for Beckmann rearrangement leading to
the expanded 6-lactam.
MeO
MeO
133
134
Scheme 55
Indeed, when diketone 133 was treated with phenylselenyl chloride in
the presence of hydrochloric acid17 the phenylselenylation took place almost
62
exclusively at C7. Oxidative elimination of the resulting selenide gave the
desired enone 134, but the reaction proceeded very slowly and afforded
only a modest yield. More surprisingly, it was discovered that the resulting
five-membered cyclic ketone 134 was unreactive towards hydroxylamine at
room temperature (Scheme 56).
0
PhSeCI
MeO
MeO
HCI cat., Et0Ac
O
80 %
SePh
133
MeO
MeO
X
134
Scheme 56
Since there is no significant steric hindrance in the vicinity of the
cyclopentanone carbonyl group of 134, the explanation for its unexpectedly
low
reactivity
toward
hydroxylamine
must
be
sought
elesewhere.
Conformational constraints which could prevent formation of an sp3intermediate during oxime formation may account for the failure of this ketone
to form an oxime.
63
3.5. Final Elaboration of Pentacycle 119 to Morphine
After the successful assembly of pentacycle 119 only a few steps
remained for completion of our synthetic route to morphine. These involved
insertion of a nitrogen atom into the five-membered cyclic ketone via a
Beckmann rearrangement and N-methylation of the resulting lactam.56
Installation of the C7-C8 double bond was envisioned after deprotection and
oxidation of the secondary alcohol by introducing a phenylselenyl substituent
a to the ketone, as already demonstrated with 133. Subsequent oxidative
elimination would furnish 135 (Scheme 57). It was anticipated that
reduction of both the lactam and ketone could be accomplished in a single
step with lithium aluminum hydride to give (+)-codeine 76; transformation of
the latter to morphine would follow a procedure developed by Rice.31
NMe
MeO
MeO
119
1100,
el
reduction
8
Me0
7
OMOM
135
76
OH
Scheme 57
In contrast to 134, exposure of 119 to hydroxylamine gave the desired
oxime 136 in good yield but as a mixture of anti and syn isomers in a 1.2:1
ratio, respectively (Scheme 58).
64
NOH
H2NOH -HCI
Me0
NaOAc
90%
OMOM
119
136
OMOM
Scheme 58
With oxime 136 now at hand, it appeared to be but a short step to the
morphine skeleton. However, all initial attempts to carry out the Beckmann
rearrangement on the mixture of oximes were completely unsuccessful. For
example, treatment of the oxime mixture with tosyl chloride in pyridine at
elevated temperature57 was fruitless. Equally disappointing was reaction of
the oxime tosylate, prepared from 136 and tosyl chloride, with aqueous
sodium hydroxide.58 The first hint of the formation of lactam 138, although in
very low yield, was obtained when the oxime 136 was transformed into its
carbonyl imidazole derivative 137. The latter afforded a small amount of the
desired 8-lactam upon treatment with methyl iodide at elevated temperature
(Scheme 59).59 *Unfortunately, all attempts to improve the yield of this
reaction failed.
The low reactivity of oxime 136 in the Beckmann rearrangement can be
explained by the rigidity of this pentacyclic skeleton, which does not provide
adequate conformational freedom for the 1,2-migration to nitrogen.
65
0
N
MeO
90 %
MeO
OMOM
136
OMOM
137
Mel
Ph-H, A
V
N-0
MeO
5%
138
)it
0
N
+
`'t
Me
MeO
OMOM
OMOM
Scheme 59
In view of the disappointing outcome with oxime 136, an alternative to
Beckmann rearrangement, namely Baeyer-Villiger oxidation60 of ketone
119 was attempted to ascertain whether the resistance of the five-membered
ring towards enlargement was a more general phenomenon. To our
gratification, Baeyer-Villiger oxidation of 119 proceeded smoothly and gave
a high yield of lactone 139 along with its regioisomer 140 in a 11:1 ratio,
respectively.
66
0
m-CPBA
MeO
84%
119
MeO
+
OMOM
Me0
OMOM
139
OMOM
140
Scheme 60
The outcome of the Baeyer-Villiger reaction suggested that ring
enlargement of oxime 136 is possible
in principle
but requires sp3-
hybridization of the migrating carbon during the rearrangement. This led us to
suppose that a Schmidt reaction61 might offer better prospects for acquiring
the desired lactam since this rearrangement is believed to proceed via a
mechanism similar to that of the Baeyer-Villiger oxidation involving 1,2migration of a sp3 carbon. However, when ketone 119 was treated with
sodium azide in the presence of trifluoroacetic acid at elevated temperature
no reaction was observed.
Another way to achieve rehybridization of the migrating carbon would
invoke transformation of ketone 119 into its N-methylimine oxide. Upon
tosylation or activation by other means this species should undergo
rearrangement to give a N-methyl lactam.62 This reaction is thought to
proceed through addition of water to the oxime C=N bond, followed by 1,2-
migration of the sp3 carbon with concomitant displacement of tosylate as
shown in Scheme 61.
67
TsCI
H2O
R
N\ 'SOH
COTS
Scheme 61
The modification of the Beckmann rearrangement outlined in Scheme 61
would be an attractive strategy for reaching our goal since it incorporates the
N-methyl group of morphine directly in the course of the rearrangement.
Unfortunately, treatment of 119 with hydroxymethylamine provided only a
very low yield of a mixture of the isomeric imine oxides. These proved to be
too susceptible to hydrolysis to be useful as Beckmann rearrangement
substrates.
Our last resort for accomplishing Beckmann rearrangement envisioned
activation of the oxime oxygen as a sulfonate ester and subsequent exposure
to strong acid in the hope that 1,2-addition to the imine double bond would
occur to drive the rearrangement towards the desired lactam (Scheme
62).63
68
HNXOEWG
EWGOH
MeO
MeO
OMOM
OMOM
+OEWG
,NH
H2O
MeO
MeO
138
OMOM
Sit
OMOM
Scheme 62
Before attempting Beckmann rearrangement according to this protocol,
oxime 136 was first transformed to its brosylate 140; the latter was expected
to provide a sufficiently reactive leaving group to accommodate the
rearrangement. When the brosylate 140 was treated with a variety of acids in
several different solvents no Beckmann rearrangement was observed.
However, it was discovered that 140 undergoes facile rearrangement when
exposed to concentrated acid. The ratio of the two isomeric lactams 138 and
141 depended strongly on the acid used. Exposure of 140 to glacial acetic
acid gave the most satisfactory result, affording a 6.5:1 mixture of 138 and
141, respectively. On the other hand methanesulfonic acid or concentrated
69
aqueous hydrochloric acid gave only a 2:1 mixture of the two 8-lactams
(Scheme 63). A slightly better ratio (11:1) of the desired lactam (138) to its
isomer could be obtained when the proportion of the anti oxime parabromobenzenesulfonate was enhanced by thermal equilibration in toluene at
75 °C prior to the rearrangement.
o,
0.-',s
BsCI, TEA
MeO
DMAP
MeO
OMOM
OMOM
136
140
AcOH
r.t.
69 % from 136
O
MeO
MeO
OMOM
OMOM
141
138
Scheme 63
The major lactam 138 was purified by chromatography on silica gel. N-
Methylation of 138 was readily accomplished with methyl iodide and sodium
hydride in refluxing benzene to afford lactam 142. After deprotection of the
MOM ether with aqueous (48%) hydrobromic acid in acetonitrile, oxidation of
70
the resulting alcohol 143 with Dess-Martin periodinane afforded the desired
ketone 144 in 98% yield (Scheme 64).
Mel, NaH
MeO
Ph-H
95 %
138
OMOM
142
OMOM
HBr, CH3CN
96 %
0
.ss
MeO
Ne
1400
lil
periodinane
99%
144
143
OH
Scheme 64
Although lactam 144 was now available for further transformation
towards morphine, we decided to explore the chemistry of lactone 139,
available from the Baeyer-Villiger oxidation of ketone 119, as a possible
analog of the natural analgesic.
Selective removal of the MOM protecting group from 139 was readily
accomplished without interference with other functionality by aqueous
hydrobromic acid in acetonitrile and provided the secondary alcohol 145.
Dess-Martin periodinane proved to be the oxidant of choice to advance 145
to the corresponding ketone 146. In analogy with the procedure reported by
71
Rice for the transformation of (-)-codeinone into (-)-codeine,17 146 was
converted into a,(3- unsaturated ketone 147 via phenylselenation under
acidic conditions. Ketone 146 reacted readily with phenylselenyl chloride in
the presence of a catalytic amount of aqueous hydrochloric acid in ethyl
acetate, and afforded the desired a-phenylselenyl derivative with good
regioselectivity. Oxidative elimination furnished the enone 147 in good
overall yield (Scheme 65).
139
OMOM
145
6H
Dess-Martin
periodinane
97%
MeO
000
1. PhSeCI, HCI
2. Na104
Me
56 %
two steps
147
146
Scheme 65
Stereoselective 1,2-reduction of the a,(3-unsaturated ketone 147 was
accomplished with L-selectride and afforded an allylic alcohol as a single
isomer. It was presumed on steric grounds that hydride delivery occurred
72
from the less hindered face of the ketone, and the configuration of the product
was therefore assigned as shown in 148 (Scheme 66).
L-selectride
MeO
MeO
81 %
147
148
Scheme 66
Based on the foregoing model studies we anticipated that the keto
lactam 144 would undergo facile a-phenylselenation when exposed to
phenylselenyl chloride under acidic conditions. Indeed, when 144 was
initially treated with phenylselenyl chloride in the presence of a catalytic
amount of acetic or methanesulfonic acid, the desired a-phenylselenyl
derivative was obtained in approximately 70% yield. However, this reaction
was found to be characterized by significant variations in yield. This lack of
reliability prompted a search for a more reproducible means for introduction
of the phenylselenyl substituent. Kinetic deprotonation of the ketone 144 with
strong
bases
such
bis(trimethylsilyl)amide,
as
lithium
followed
by
diisopropylamide
treatment
of the
or
sodium
enolate
with
phenylselenyl chloride, gave a 1:1 mixture of the two isomeric selenides 149
and 150, reflecting a complete lack of regioselectivity in formation of the
enolate (Scheme 67).
73
1. NaHMDS
MeO
2. PhSeCI
70 %
144
Scheme 67
However, it was found that deprotonation of 144 under thermodynamic
conditions with potassium tert-butoxide in the presence of tert-butanol
resulted exclusively in the desired enolate, which upon exposure to
phenylselenyl chloride afforded the selenide 149 in 75% yield. Oxidation of
149 with sodium periodate gave the expected enone 135 in an overall 68%
yield from ketone 144. Treatment of 135 with lithium aluminum hydride
accomplished
stereoselective
1,2-reduction
of
the
enone
and
also
transformed the lactam to an amine, producing (+)-codeine (76), [423
+137.5 (c 0.16 EtOH), in 70% yield (Scheme 68).
74
Ne
1. t-BuOK, t-BuOH
Me0
2. PhSeCI
75 %
144
hNlMe
LiAIH4
Me0
OH
76
Scheme 68
Demethylation
of (+)-codeine
to
(+)-morphine
developed by Rice (Scheme 69).31
i\sNMe
BBr3
Me0
98
76
O
OH
Scheme 69
follows
the
procedure
75
3.6. Studies on the Transformation of Lactone 139.
Although we were able to transform the pentacyclic ketone 119 into
lactam 138 using a Beckmann rearrangement, an alternative route to
accomplish our synthetic goal via 139 was also investigated. As mentioned
previously, the Baeyer-Villiger oxidation of 119 proceeded smoothly and
afforded lactone 139 in high yield. The latter structure offered several options
for incorporation of the morphine nitrogen atom. Of these, opening of the
lactone with methylamine and subsequent ring-closure of the amide 151,
seemed to be the most direct pathway (Scheme 70). A prerequisite for
success with this plan is inversion of configuration at C9 so that the
secondary alcohol can be transformed into a suitable leaving group.
MeHN.0
139
9 OH
MeNH2
4.-
MeO
11010
111
OMEM
151
OMEM
Scheme 70
When lactone 139 was treated with methylamine at elevated temperature
amide 151 was formed in nearly quantitative yield (Scheme 71). Efforts
then focused on inversion of the secondary alcohol in order to obtain a
substrate amenable to cyclization by displacement. However, this plan was
76
thwarted when it was found that the hydroxyl group of 151 had a strong
propensity towards elimination.
MeNH2
MeO
Me0H, A
98 %
OMEM
139
151
OMEM
12, Ph3P,
imidazole
89 %
Me0
152
OMEM
Scheme 71
Thus, exposure of 151 to iodine in the presence of triphenylphosphine and
imidazole,64 or transformation of 151 into the corresponding mesylate and
treatment with sodium iodide,65 afforded olefin 152 as the sole product. Not
surprisingly,
the alcohol was unreactive
under Mitsunobu
inversion
conditions,66 as a consequence of the severe steric hindrance at this center.
Amide 152 could be reduced and tosylated to give aminosulfonate 153
(Scheme 72),24 an intermediate analogous to 34 in Parker's synthesis of
77
morphine,23 thus accomplishing a formal synthesis of (+)-morphine by this
route.
Ts,
NHMe
reduction,
tosylation
-1-
MeO
OMEM
152
153
OMEM
Scheme 72
Inversion of configuration
at C9 in
151
could in principle
be
accomplished by an oxidation-reduction sequence, since reduction of ketone
154 should give predominantly the desired equatorial alcohol when carried
out with a sterically undemanding reducing agent such as sodium
borohydride.67 Interestingly, when 151 was treated with Dess-Martin
periodinane the desired ketone 154 was formed rapidly, but underwent
spontaneous cyclization to the hydroxy lactam 155 (Scheme 73). Attempts
to reduce transform 155 to amine 156, led only to intractable mixtures.
78
Dess-Martin
periodinane
MeO
MeO
OMEM
151
154
OMEM
78%
reduction
OMEM
156
155
OMEM
Scheme 73
Reductive amination68 of keto ester 157 appeared to offer yet another
prospective route to the desired 8-lactam since reduction of the intermediate
imine 158 with a more bulky reagent such as L-selectride69 would be
expected to occur exclusively from the equatorial face due to the severe
steric 1,3-interaction which arises from the axial acetic ester substituent at
C13 (Scheme 74).
79
Me0
OMEM
157
158
OMEM
reduction
Me0
OMEM
OMEM
Scheme 74
With this pathway in mind, 139 was converted to ketone 157 via a short
sequence which involved hydrolysis of the lactone and methylation of the
resulting carboxylic acid with diazomethane, followed by immediate oxidation
of the secondary alcohol with Dess-Martin periodinane (Scheme 75).
80
LiOH
MeO
THE -H20
MeO
OMEM
OMEM
139
Dess-Martin
periodinane
80 %
from 139
Me0
OMEM
OMEM
157
Scheme 75
To our surprise, exposure
of
ketone 157 to methylamine
in
tetrahydrofuran did not give the desired imine but instead led to rapid
epimerization at C14. The low reactivity of this ketone towards nucleophilic
attack can again be attributed to high steric hindrance around the carbonyl
group at C9.
81
MeNH2, THF
MeO
157
OMEM
OMEM
Scheme 76
The previously described model studies with lactone 148 provided this
material in a sufficient quantity to allow its further transformation into ketone
160. Our plan for this substance was incorporation of the nitrogen atom
along lines similar to those envisioned for ketone 159.
MeO
MeO
OH
OMOM
148
160
reduction
MeO
MeO
162
OMOM
161
Scheme 77
OMOM
82
It was anticipated that the double bond in 160 would very likely undergo
migration
to form
the
a,r3-unsaturated
ketone
this
during
process.
Nonetheless, we hoped that this would not prevent formation of the
methylimine 161, which could then be reduced and cyclised to give lactam
162 (Scheme 77). First, the secondary alcohol of 148 was protected as its
MOM ether and the lactone was hydrolyzed with aqueous lithium hydroxide.
Treatment of the resulting carboxylic acid with diazomethane followed by
oxidation of the secondary alcohol with Dess-Martin periodinane afforded
163 in good overall yield (Scheme 78).
(MeO)2CH2
MeO
P205, CHCI3
MeO
90 %
148
OH
160
OMOM
1.LiOH
2. CH2N2
0 OMe
0
MeO
Dess-Martin
periodinane
82 %
from 160
163
OMOM
OMOM
Scheme 78
83
As expected, exposure of ketone 163 to methylamine in tetrahydrofuran
caused rapid migration of the double bond to give 04/3-unsaturated ketone
164, but even after an extended reaction time none of the methyl imine 165
could be detected (Scheme 79).
O OMe
0
MeO
Olt
O
163
MeNH2
THF, r.t.
100 %
MeO
OMOM
164
OMOM
MeO
OMOM
161
Scheme 79
The disappointing outcome of studies with lactone 148 afforded
convincing evidence that the most practical way to construct the pentacycle
138 was via Beckmann rearrangement of 119. On the positive side
however, these alternative routes provide access to several structurally
unique morphine analogs. It is possible that some of these may ultimately
find application in pharmacological research in the area of analgesics.
84
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Willey: New York, 1971, pp 405 - 434.
62.
Brown, R.T., Carter, N.E.; Lumbard, K.W.; Scheinmann, K. Tetarhedron
Lett. 1995, 36, 8661.
63.
Nguyen, H.T.; Raspoet, G.; Vanquicke, N.B. J. Am. Chem. Soc. 1997,
119, 2552.
64.
Corey, E.J., Pyne, S,C.; Su, W. Tetrahedron Lett. 1983, 24, 4882.
65.
Pos, A.J.; Better, R.K. J. Org. Chem. 1987, 52, 4810.
66.
Lal, B.; Pramanik, B.; Manhas, M.S.; Bose, A.K. Trahedron Lett. 1977,
1977.
67.
Lansbury, P.T.; Macleay, R.E. J. Org. Chem. 1963, 28, 1940.
68.
a) Smith, R.L.; Lee, T.; Gould, N.P.; Gragoe, E.J. Jr. J. Med. Chem.
1977, 20, 1292.
b) Anderson, P.S.; Christy, M.E.; Colton, C.D.; Shepard, K.L. J. Org.
Chem. 1978, 43, 3719.
c) Abded-Magid, A. F.; Harris, B.D.; Maryanoff, C.A. Synlett. 1994, 81.
69.
Brown, H.C.; Krishnahurthy, S. J. Am. Chem. Soc. 1972, 94, 7159.
88
Chapter IV. Experimental Section
Starting materials and reagents were obtained from commercial sources
and, unless otherwise stated, were used without further purification. Solvents
were dried by distillation from the appropriate drying agents immediately
prior to use.
benzophenone
Tetrahydrofuran and ether were distilled from sodium and
under
an
argon
atmosphere.
Diisopropylamine,
triethylamine, acetonitrile and dichloromethane were distilled from calcium
hydride under argon. All solvents used for routine isolation of products and
chromatography were reagent grade.
Moisture and air sensitive reactions
were carried out under an atmosphere of argon. Reaction flasks were flame
dried under a vacuum then backfilled with argon gas, and syringe needles
were oven dried at 120 °C and cooled in a dessicator over anhydrous
calcium sulfate prior to use.
Unless otherwise stated, concentration under reduced pressure (or in
vacuo) refers to a rotary evaporator at water aspirator pressure.
Analytical thin layer chromatography (TLC) was performed using
precoated aluminum E. Merck TLC plates (0.2 mm layer thickness of silica
gel 60 F-254). Compounds were visualized by ultraviolet light, and/or by
heating the plate after dipping in a solution of 14% ammonium molybdate
tetrahydrate and 1.4% cerium(IV) sulfate in 1.6M sulfuric acid in water or 1%
solution of potassium permanganate in 2% 1N sodium hydroxide in water.
Flash chromatography was carried out using E. Merck silica gel 60 (230-400
mesh ASTM).
Melting points were measured using a Btichi melting point apparatus,
and are uncorrected.
Infrared (IR) spectra were recorded with a Nicolet
89
5DXB FT-IR spectrometer. Proton and carbon nuclear magnetic resonance
(NMR) spectra were obtained using either a Bruker AC-300 or a Bruker AM-
400 spectrometer. All chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane using the d scale.
1H NMR spectral data
are reported in the order: chemical shift, multiplicity (s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet and b=broad), coupling constant (J) in Hertz
(Hz), and number of protons.
Chemical ionization (CI) high and low resolution mass spectra (HRMS
and MS) were obtained using a Kratos MS-50 spectrometer with a source
temperature
of 120 °C and methane gas
Perfluorokerosene was used as a reference.
as
the
ionizing
source.
Electron impact (El) mass
spectra (HRMS and MS) were obtained using a Varian MAT311 or a
Finnegan 4000 spectrometer. X-ray crystallographic data were collected on
a Siemens P4 spectrometer, and these data were interpreted using the direct
methods program contained in the SHELXTL (Silicon
Graphics/Unix)
software package. Elemental analyses were performed by Desert Analytics,
Tucson, Arizona.
90
MeO
OH
3-(- 3- Hydroxy- 4- methoxybenzyl) -4- methoxy- 4- oxo -3- butenoic
Acid (41). To a solution of NaOCH3, prepared from sodium metal (12.0 g,
0.52 mol) and Me0H (150 mL), isovanilin (20.0 g, 0.13 mol) and dimethyl
succinate (25 g, 0.17 mol) were added, and the reaction was refluxed for 6 h.
The mixture was poured into a stirred aqueous solution of HCI (5%, 250 mL)
maintained at 0°C, and the product was extracted with EtOAc (4x 100 mL).
The combined organic extracts were washed with water, and the obtained
solution was extracted with a saturated aqueous solution of NaHCO3 (450
mL). The aqueous solution was separated, washed with EtOAc (1x 100 mL)
and acidified with an aqueous solution of HCI (10%). The product was
extracted with EtOAc (4x 100 mL), and the combined organic extracts were
washed with water and a saturated solution of NaCI, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
recrystallized from a EtOAc- hexane mixture (2:1) to afford 23.8 g (68%) of the
product as a yellow crystalline compound: m.p. 182-183 °C; IR (KBr) 3347,
2883, 2939, 1733, 1687; 1606, 1588, 1511, 1444, 1278, 1212, 1163, 1126,
1022, 811 cm-1; 1H NMR(300 MHz, CDCI3) 83.65 (m, 2H), 3.82 (s, 3H), 3.90
(s, 3H), 6.60 6.95 (m, 3H), 7.81 (s, 1H); 13C NMR (75 MHz, CDCI3) 8 33.5,
52.3, 55.9, 110.7, 115.3, 121.9, 123.4, 127.9, 142.4, 145.6, 147.5, 168.2,
177.0; MS (El) nilz 266 (M+), 222, 175, 167, 163, 162, 147, 131, 119, 103, 91;
HRMS (El) m/z 266.0790 (calcd for C1 3H1406: 266.0790); Anal. Calcd for
C13H1406: C, 58.65; H, 5.30. Found: C, 58.54; H, 5.27.
91
Me0
OH
(3S)-3-(3-Hydroxy-4-methoxybenzyI)-4-methoxy-4-oxobutanoic
Acid (73). In a 50 mL, one-necked, round-bottom *flask, fitted with a rubber
septum
and
a
magnetic
stirrer
bar,
under
argon
atmosphere,
chlororhodium(I) (4R,5R)-MOD-DIOP complex was prepared from chloro(1,5-
cyclooctadiene)rhodium(1) dimmer (18 mg, 0.036 mmol) and (4R,5R)-MOD-
DIOP (54 mg, 0.074 mmol) in oxygen free THE (4 mL). The complex was
prehydrogenated for 10 min, and a solution of 44 (1.75 g, 6.57 mmol) in
oxygen free Me0H (8 mL) was injected through 'the septum via syringe. The
resulting mixture was stirred under a hydrogen atmosphere at room
temperature until TLC indicated quantitative conversion (ca 10 h). The
mixture was concentrated under reduced pressure and the residue was
chromatographed (300 g silica gel, EtOAc- hexane - HCOOH, 1:1:0.01) to
afford 1.77 g (100%) of butanoic acid 73 as a colorless oil: [a]023 -27.2 (c
1.34, Me0H); IR(neat) 3447, 3234, 2980, 1724, 1715, 1513, 1274 cm-1;
1 HNMR(300 MHz, CDCI3) 8 2.44 (dd, J = 5,17 Hz, 1H), 2.63 - 2.73 (m, 2H),
2.98 (dd, J = 6, 13 Hz, 1H), 3.03 - 3.11 (m, 1H), 3.69 (s, 3H), 3.86 (s, 3H),
6.02 (dd, J = 2, 8 Hz, 1H), 6.70 (d, J = 2Hz, 1H), 7.00 (d, J = 8 Hz, 1H); 13C
NMR(75 MHZ, CDCI3) 6 36.9, 42.8, 52.0, 55.9, 110.8, 115.2, 120.5, 131.1,
145.4, 145.5, 174.7, 177.0; MS tn/z 268 (M+), 208, 137, 131, 122, 103, 94, 77;
HRMS m/z 268.0947 (calcd for C13H1606: 268.0947).
92
5-Bromo-2-methoxy-1,3-dimethylbenzene
(82).
To a solution
of
sodium hydroxide (4.6 g, 0.12 mol) in H2O (100 mL), 4-bromo-2,6dimethylphenol
(81)
(20g,
0.100
mol),
CH2Cl2
(100
mL),
tetrabutylammonium bromide (20 mg), and dimethyl sulfate (10.4 mL, 0.11
mol) were added, and the mixture was intensively stirred for 10 h at room
temperature. The organic solution was separated and treated with
n-
propylamine (5 mL). After stirring for another 30 min, the solution was
washed with an aqueous solution of HCI (5%, 2x 50 mL), a saturated solution
of Na2CO3 (1x 50 mL), a saturated solution of NaCI (1x 50 mL), and dried
over anhydrous Na2SO4. Vacuum distillation of the residue (65 °C/0.1 mm)
afforded 15g (70%) of 4-bromo-2,6-dimethoxy anisol (82) as colorless oil: IR
(neat) 2943, 1471, 1215, 1174, 1015, 856 cm-1; 1H NMR (300 MHz, CDCI3)
5 2.26 (s, 6H), 3.71 (s, 3H), 7.15 (s, 2H); 13C NMR (75 MHz, CDCI3) 8 16.1,
59.9, 116.5, 131.6, 133.3, 156.3; MS (CI) 214 (M++1), 185, 171, 135, 120,
103, 92, 89, 77; HRMS (CI) m/z 213.9992 (calcd for C9H1i OBr: 213.9994).
93
Bis(4-methoxy-3,5-dimethylphenyl)(oxo)phosphorane (83).
Magnesium turnings (0.92 g, 38.4 mmol), dry THF (10 mL) and a crystal of
iodine were placed into a 100 mL round-bottom flask equipped with a
magnetic stirring bar. The flask was flushed with argon, a solution of 4bromo-2,6-dimethyl anisol (82) (7.7 g, 36.0 mmol) in dry THF (30 mL) was
added over a period of of 60 min, and the mixture was stirred for another 3h
at ambient temperature. The solution of the Grignard reagent was transferred
via cannula into a dry 100 mL round-bottom flask, flushed with argon and
equipped with a reflux condenser and magnetic stirring bar. To a stirred
solution of the Grignard reagent, a solution of diethyl phosphite (1.15 mL,
12.0 mmol) in dry THF (15 mL) was added dropwise over a period of 1h. The
resulting mixture was stirred
for 3 h at room temperature and was
subsequently refluxed for 30 min. The mixture was added dropwise into an
intensively stirred aqueous solution of HCI (10%, 200 mL) and the product
was extracted with EtOAc (5x 50 mL). The combined organic extracts were
washed with a saturated solution of NaCI, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Chromatography of the residue
(40 g of silica gel, EtOAc- hexane, 2:1) afforded 2.2 g (60%) of the
phosphorane 83 as colorless oil: IR (neat) 2945, 1489, 1289, 1230, 1127 cm1; 1H NMR (300 MHz, CDCI3) 8 2.28 (s, 12H), 3.72 (s, 6H), 7.32 (d, J = 14 Hz,
2H), 7.89 (d, J = 477 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 16.2, 59.7, 126.5
(d, J = 103 Hz), 131.4 (d, J = 12 Hz), 132.1 (d, J = 14 Hz), 132.8 (d, J = 10 Hz),
94
160.7 (d, J = 3Hz); MS m/z 318 (M+), 303, 287, 256, 176, 167, 136, 121, 105,
91, 77, 69; HRMS m/z 318.1384 (calcd for C181-12305P: 318.1385).
OMe
Me0
Me
Me
OMe
Me0
[((4R,5R)-5-{[Bis(4-methoxy-3,5-
dimethylphenyl)phosphino]methy1}-2,2-dimethyl-1,3-dioxolan-4yOmethyl][bis(4-methoxy-3,5-dimethylphenyl)]phosphine.
(4R,5R)-MOD-DIOP.
(78).
To
a
solution
of
bis44-methoxy-3,5-
dimethoxyphenylKoxo)phosphorane 83 (1.0 g, 3.14 mmol) in dry benzene
(25 mL) under argon atmosphere, trichlorosilane (0.67 mL, 6.60 mmol) and
triethylamine (1.31 mL, 9.42 mmol) were added, and the mixture was refluxed
for 4 h. The solution was cooled to room temperature and washed with a
degassed aqueous solution of NaOH (10 g NaOH, 15 mL of H20). The
benzene solution was transferred via cannula to a flask flushed with argon
and equipped with a short path distillation head and a receiver. The solvent
was removed by distillation, and the residue was dissolved in oxygen free
THF (20 mL). The flask was cooled to -30 °C and the distillation head was
replaced with a rubber septum. A 1.7 M solution of tert-butyllitium in pentane
(1.8 mL, 3.14 mmol) was added, and the mixture was stirred for 30 min at - 30
°C. To the mixture, a solution of 1,4-di-G-tosyl-2,3-0-isopropylidene-L-threitol
(0.3 g, 0.64 mmol) in dry oxygen free THF (7 mL) was added, and the
95
reaction was stirred for 18 h at room temperature. All volatiles were removed
under reduced pressure and the residue was dissolved in diethylether (20
mL), washed with a saturated solution of NaHCO3 (1x 50 mL) and a
saturated solution of NaCI (1x 50 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. Chromatography of the residue (100 g
of silica gel, EtOAc- hexane, 1:10) afforded 0.18 g (38%) of the (4R,5R)-MOD-
DIOP as colorless oil which was recrystallized from methyl alcohol: 1H NMR
(300 MHz, CDCI3) 8 1.37 (s, 6H), 2.21
2.44 (m, 28 H), 3.67 - 3.78 (m, 13H),
3.79 - 3.88 (m, 1H), 7.11 (dd, J = 8, 11 Hz, 4H). MS (CI) m/z 730.3552 (calcd
for C43H5606P2: 730.3552).
.CO2Me
Me0
CO2H
OH
(3S)-3-(2-Bromo-5-hydroxy-4-methoxybenzyI)-4-methoxy-4oxobutanoic Acid. (73b). To a stirred solution of carboxylic acid 73 (2.5g,
9.3 mmol) in glacial acetic acid (50 mL), a solution of bromine (0.5 mL, 9.4
mmol) in acetic acid (10 mL) was added dropwise over a period of 30 min.
The mixture was stirred at room temperature for 10 min, and a 5 M aqueous
solution of sodium thiosulfate (5 mL) was added. The resulting mixture was
poured on ice and the product was extracted with EtOAc (4x 50 mL). The
combined organic extracts were washed with water and a saturated solution
of NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to afford 3.1 g (92 %) of crude 73b which was not further purified:
96
[423 -32.7 (c 1.48, Me0H); IR (neat) 3315, 3238, 2983, 1715, 1502, 1441,
1277, 1230, 1183, 1161 cm-1; 1HNMR(300 MHz, CDCI3) 8 2.48 (dd, J = 4, 17
Hz, 1H), 2.71 - 2.85 (m, 2H), 3.09 (dd, J = 6, 13 Hz, 1H), 3.14 - 3.23 (m, 1H),
3.70 (s, 3H), 3.87 (s, 3H), 6.76 (s, 1H), 7.00s, 1H); 13CNMR(100 MHz, CDCI3)
34.7, 37.0, 41.4, 52.1, 56.2, 113.5, 115.2, 116.7, 130.2, 145.0, 146.1, 174.4,
177.4; MS m/z 346 (M+), 269, 267, 216, 191, 159, 127, 118; HRMS m/z
346.0054 (calcd for C13H15O6Br: 346.0052).
,CO2Me
MeO
OH 0
Methyl
(2S)-8bromo-5-hydroxy-6-methoxy-4-oxo-1,2,3,4-
tetrahydro-2-naphthalenecarboxylate (86). To a solution of carboxylic
acid 73b (3.0 g, 8.61 mmol) in methanesulfonic acid (50 mL), P205 (ca 0.5g)
was added, and the resulting mixture was stirred for 10 h at ambient
temperature. Methyl alcohol (30 mL) was added, and the mixture was poured
on ice. The product was extracted with EtOAc (4x 100 mL), and the combined
organic extracts were washed with a saturated solution of NaHCO3 (3x 70
mL), a saturated solution of NaCI, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to afford 2.1 g (75 %) of tetralone 8 6
as yellow solid: [423 +22.6 (c 1.68, CHCI3); mp 95-96 °C; IR (neat) 2928,
1731, 1643, 1465, 1435, 1281, 1245, 1181 cm-1; 1H NMR(300 MHz, CDCI3)
8 2.85 - 3.30 (m, 5H), 3.74, (m, 3H), 3.87 (s, 3H), 7.20, (s, 1H), 12.7 (s, 1H);
13C NMR(CDCI3, 75 MHz) 8 31.8, 39.0, 39.9, 52.3, 56.3, 111.4, 116.9, 121.3,
97
131.3, 147.6, 152.7, 172.9, 202.9; MS m/z 328 (M+), 298, 296, 271, 269, 253,
239, 191, 189, 175, 119; HRMS m/z 327.9946 (calcd for C13F11305Br:
327.9946); Anal. Calcd for C13H1305Br: C, 47.44; H, 3.98. Found: C, 47.52; H,
3.76.
Me0
OH 0
Methyl
(2S)-5-hydroxy-6-methoxy-4-oxo-1,2,3,4-tetrahydro-2-
naphthalenecarboxylate (89). A mixture of bromotetralone 86 (1.3g, 3.4
mmol), Me0H (100 mL), NaHCO3 (1.6g) and (10%)Pd/C catalyst (40 mg) was
intensively stirred for 45 min under hydrogen atmosphere at ambient
temperature. The mixture was filtered, and the resultant solution was
concentrated under reduced pressure. The residue was treated with an
aqueous solution of HCI (5%, 10 mL), and the product was extracted with
EtOAc (3x 100 mL). The obtained solution was washed with water and a
saturated solution of NaCI, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to afford 1.0 g (100%) of a crude product as yellow
oil which was not further purified. [0],23 +42.5 (c 1.04, CHCI3); IR (neat) 2960,
1733, 1645, 1422, 1263 cm-1; 1H NMR(300 MHz, CDCI3) 8 2.85 - 2.90 (m,
2H), 3.04 - 3.17 (m, 3H), 3.69 (s, 3H), 3.84 (s, 3H), 6.65 (d, J = 8 Hz, 1H), 6.97
(d, J = 8 Hz, 1H), 12.50 (s, 1H); 13C NMR(75 MHz, CDCI3) 8 31.8, 40.2, 40.6,
52.4, 56.5, 116.5, 118.1, 118.3, 133.2, 147.3, 153.2, 173.6, 203.2; MS m/z
250 (M+), 191, 159, 147, 131, 103, 91, 85, 83; HRMS m/z 250.0840 (calcd for
98
C13F11405: 250.0841); Anal. Calcd for C13H1405: C, 62.39; H, 5.64. Found: C,
62.07; H, 5.57.
Me0
OH 0
(2S)-5-Hydroxy-6-methoxy-4-oxo-1,2,3,4-tetrahydro-2naphthalenecarboxylic Acid (90). To a solution of ester 89 (400 mg,
1.70 mmol) in a THF-H20 mixture (1:1, 10 mL), Li0H-H20 (360 mg, 8.6 mmol)
was added, and the mixture was stirred for 12 h at ambient temperature. The
reaction was acidified with an aqueous solution of HCI (5%), and the product
was extracted with EtOAc (3 x 100 mL). The combined organic extracts were
washed with water and a saturated solution of NaCI, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to afford 402 mg (100 %)
of 90 as yellow crystalline solid: [423 +38.4 (c 0.66, THF); m.p. >203 °C dec.;
IR(neat) 3047, 2969, 1728, 1611, 1445, 1347, 12 59, 1195, 1039 cm-1; 1H
NMR (300 MHz, d8-THF) 8 2.81 - 2.85 (m, 2H), 3.01 - 3.18 (m, 3H), 3.78 (s,
3H), 6.65 (d, J = 8 Hz, 1H), 7.04 (d, J = 8 Hz, 1H), 12.5 (s, 1H); 13C NMR (75
MHz, d8-THF) 8 35.1, 43.3, 44.0, 59.3, 120.0, 120.9, 122.4, 137.4, 150.8,
157.3, 177.1, 207.3; MS m/z 236 (M+), 191, 159, 131, 80, 78, 69; HRMS m/z
236.0684 (calcd for C12H1205: 236.0685).
99
Me0
OH 0
(2S)-5-Hydroxy-3-[(E)-hydroxymethylidene]-6-methoxy-4-oxo1,2,3,4-tetrahydro-2-naphthalenecarboxylic
Acid
(91)
To
a
suspension of KH (35 w.t. % suspension in mineral oil, 540 mg, 4.6 mmol) in
THF (15 mL), a solution of tetralonecarboxylic acid 90 (110 mg, 0.46 mmol)
in dry THF (15 mL) was added, and the mixture was stirred for 4 h at ambient
temperature. To the mixture, freshly distilled methyl formate (1 mL, 16 mmol)
was added dropwise over a period of 40 min. (The reaction apparatus must
be equipped with an outlet of an appropriate size, able to accommodate
large volume of gas produced during the addition!) Stirring was continued for
another 3 h at ambient temperature. The reaction was quenched with a
saturated solution of NH4CI and was acidified with an aqueous solution of
HCI (5%). The product was extracted with EtOAc (3x 50 mL), and the
combined organic extracts were washed with water and a saturated solution
of NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was washed with hexane to afford a crude product
which was not further purified. IR (neat) 3218 (br), 2954, 1709, 1626, 1450,
1254, 1025 cm-1; 1H NMR (300 MHz, CDCI3) 8 3.09 (dd, J = 7, 15 Hz, 1H),
3.22 (dd, J = 3, 15 Hz, 1H), 3.52 (m, 1H), 3.87 (s, 3H), 6.65 (d, J = 8 Hz, 1H),
6.96 (d, J = 8 Hz, 1H), 11.91 (s, 1H); MS 171/Z 264 (M +), 220, 204, 191, 159,
131, 97, 71; HRMS m/z 264.0633 (calcd for C13H1206: 264.0634).
100
Me0
(3R,3aR,9aS)-3,5-Dihydroxy-6-methoxy-3a-(3-oxobutyI)3,3a,9,9a- tetrahydronaphtho[2,3-c]furan-1,4-dione (92). A mixture
of /3-ketoaldehyde 91 (130 mg, 0.49 mmol), methyl vinyl ketone (0.4 mL, 4.90
mmol), triethylamine (0.15 mL, 1.0 mmol) and CH2Cl2 (30 mL) was stirred for
12 h at ambient temperature. The mixture was concentrated under reduced
pressure, and the residue was chromatographed (40 g of silica gel, EtOAchexane-HCO2H, 1:1:0.005) to afford 161 mg (80 %) of 92 as yellow oil: IR
(neat) 3418, 3022, 2944, 1782, 1718, 1635, 1435, 1254 cm-1; 1HNMR (300
MHz, CDCI3) 8 2.08-2.30 (m, 5H), 2.55
2.72 (m, 2H), 3.09 - 3.22 (m, 2H),
3.34 (d, J = 15 Hz, 1H), 3.85 (s, 3H), 6.04 (s br, 1H), 6.70 (d, J = 8 Hz, 1H),
7.05 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 23.6, 25.7, 30.1, 38.2,
42.1, 55.8, 56.6, 99.7, 116.0, 118.9, 120.0, 131.3, 147.3, 154.1, 176.1, 202.9,
208.6; MS m/z 334 (M+), 316, 288, 260, 242, 203, 191, 175, 163, 159, 131,
98; HRMS m/z 334.1051 (calcd for Ci7H1807: 334.1053).
101
Me0
(8aR,9S)-4-Hydroxy-3-Methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-9phenanthrenecarboxylic Acid (93). To a stirred solution of 92 (420 mg,
1.25 mmol) in a THE -H20 mixture (1:1, 30 mL), NaOH (250 mg, 6.3 mmol)
was added, and the reaction was stirred for 10 h at ambient temperature. The
mixture was acidified with an aqueous solution of HO (5%), and the solid
precipitate was filtered and washed with Me0H to afford 253 mg (70%) of 93
as a yiellow crystalline compound. (Additional 20 - 25% of 93 could be
obtained by extraction of the filtrate and chromatography of the residue)
[a]D23
+235.0 (c 0.31, DMSO); IR (neat) 3325, 2925, 1718, 1620, 1567, 1484, 1294
cm-1; 1H NMR(300 MHz, d6 -DMSO) 8 1.70 - 1.81 (m, 1H), 2.02
1H), 2.38 - 2.46 (m, 3H), 2.79
2.16 (m,
2.86 (m, 1H), 2.92 (d, J = 7 Hz, 2H), 3.80 (s,
3H), 6.67 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 7.35 (d, J = 2 Hz, 1H), 9.50
(s, 1H), 12.58 (br s, 1H); 13CNMR (75 MHz, d6 -DMSO) 6 33.2, 38.2, 41.9,
50.9, 61.4, 118.3, 123.4, 123.7, 131.8, 135.7, 151.4, 151.9, 159.3, 191.8, 207;
MS m/z 288 (M±), 243, 215, 187, 183; HRMS m/z 288.0998 (calcd for
C16H1605: 288.0998). Anal. Calcd for C16H1605: C, 66.66; H, 5.59. Found: C,
66.61; H, 5.45.
102
Me0
Methyl
(8aR,9S)-4-Hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-
hexahydro-9-phenanthrenecarboxylate (98). To a suspension of the
carboxylic acid 93 (1.0 g, 3.47 mmol) in EtOAc (30 mL), a 0.7 M solution of
diazomethane in diethylether (10 mL) was added and the mixture was stirred
at ambient temperature until a homogeneous solution was obtained. Acetic
acid (0.5 mL) was added and stirring was continued for 10 min. The mixture
was
concentrated
under
reduced
pressure,
and
the
residue
chromatographed (60 g of silica gel, CH2Cl2- EtOAc- hexane, 1:2:1) to afford
0.94 g (90%) of 98 as white crystalline compound:
[a]D23 +176.0 (c 1.27,
CHCI3); mp 178 - 179 0C; IR (neat) 2940, 2846, 1729, 1650, 1480, 1289 cm1; 1H NMR(300 MHz, CDCI3) 8 1.80 - 1.90 ( m, 1H), 2.04
2.16 (m, 1H), 2.42
- 2.65 (m, 3H), 2.87 3.00 (m, 2H), 3.10 (dd, J = 12, 15 Hz, 1H), 3.76 (s, 3H),
3.91 (s, 3H), 6.69 (d, J = 8 Hz, 1H), 6.79 (s, 1H), 6.84 (d, J = 8 Hz, 1H); 13C
NMR(75 MHz, CDCI3) 8 28.5, 34.0, 37.3, 39.9, 46.7, 52.2, 56.7, 112.2, 118.2,
119.4, 128.2, 131.0, 145.6, 146.7, 153.6, 175.0, 201.0; MS rn/z 303 (M+),
243, 193, 183, 113; HRMS m/z 303.1238 (calcd for C17F11905 303.1233).
Anal. Calcd for C17H1905: C, 67.54; H, 6.00. Found: C, 67.25; H, 5.57.
103
MeO
Methyl
(8aR,9S)-1,5-Dibromo-4-hydroxy-3-methoxy-6-oxo-
6,7,8,8a,9,10-hexahydro-9-phenenthrenecarboxylate
(99).
To a
mixture of the enone 98 (0.10 g, 0.31 mmol), CHCI3 (30 mL), and NaHCO3
(0.29 g, 3.31 mmol), maintained at 0°C, a solution of bromine in CHCI3 (10%,
3.40 mL, 0.62 mmol) was added dropwise over a period of 30 min. Stirring
was continued for
1
h, and the mixture was filtered over celite and
concentrated under reduced pressure. A chromatography of the residue
(CH2Cl2- EtOAc- hexane, 1:2:1) afforded 0.11 g (70%) of the product as
yellow crystalline solid: [a]D23 +39.7 (c 0.35, CHCI3); mp > 129 0C dec.; IR
(neat) 3394, 3301, 2939, 1429, 1682, 1481, 1439, 1268, 1129 cm-1; 1H NMR
(300 MHz, CDCI3) 5 1.91
2.05 (m, 1H), 2.25
15 Hz, 1H), 2.65 - 2.88 (m, 3H), 3.49
2.34 (m, 1H), 2.54 (dd, J = 5,
3.42 (m, 1H), 3.57 (dd, J = 3, 15 Hz,
1H), 3.61 (s, 3H), 3.91 (s, 3H), 6.13 (s, 1H), 7.06 (s, 1H); 13C NMR (75 MHz,
CDCI3) 8 28.8, 29.9, 37.2, 41.0,45.6, 56.2, 111.2, 115.2, 123.5, 124.3, 129.0,
141.1, 145.0, 153.0, 173.3, 190.8; MS (CI) m/z 461 (M+ + 1), 383, 303, 229,
221, 213, 135(100); HRMS (CI) m/z 458.9440 (calcd for Ci7F11705Br2
458.9443). Anal. Calcd for C17H1605Br2: C, 44.37; H, 3.51. Found: C, 44.12;
H, 3.43.
104
Me0
Methyl
(7aR,8S)-1-Bromo-3-methoxy-5-oxo-5,6,7,7a,8,9-
hexahydrophenanthro[4,5,-bcd]furan-8-carboxylate
(100). To a
solution of 99 (235 mg, 0.51 mmol) in benzene (50 mL), DBU (0.23 mL, 1.53
mmol) was added, and the mixture was stirred for 4 h at 68 °C. The mixture
was cooled to room temperature and filtered through a short column of silica
gel, which was subsequently rinsed with a hexane -EtOAc mixture (2:1). The
obtained solution was concentrated under reduced pressure to afford 174 mg
(90 %) of 100 as a white crystalline compound which was not further purified.
[a]p23 +140.8 (c 0.70, CH2Cl2); mp > 172 °C dec.; IR (neat) 2949, 1728, 1674,
1503, 1269, 1171, 1103 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.80 - 1.94 (m,
1H), 2.50 - 2.88 (m, 4H), 3.03 (dd, J = 12, 17 Hz, 1H), 3.31 (dd, J = 4, 17 Hz,
1H), 3.51
3.42 (m, 1H), 3.83 (s, 3H), 4.06 (s, 3H), 7.05 (s, 1H); 13C NMR (75
MHz, CDCI3) 8 31.1, 31.6, 32.6, 33.8, 39.9, 48.4, 52.5, 57.7, 115.1, 117.5,
123.6, 128.0, 137.7, 142.9, 145.5, 145.7, 173.6, 186.3;
MS (CI) m/z 381
(100), 380 (M+ + 1), 301, 243, 239, 95; HRMS (CI) m/z 379.0181 (calcd for
C171-11605Br 3798.0181).
105
Me0
Methy
(2S*,8aR*,991-1-Bromo-4-hydroxy-3-methoxy-6-oxo-
2,5,6,7,8,8a,9,10-octahydro-9-phenanthrenecarboxylate
(105). A
suspension of enone 100 (100 mg, 0.275 mmol) in a 0.3 M solution of NaOH
(20 mL) was stirred at room temperature until a homogeneous solution was
obtained. To the mixture, Hg-(10%)Na was added, and stirring was continued
for 1 h at room temperature. The aqueous solution was separated and
acidified with an aqueous solution of HCI (5%). The product was extracted
with CH2Cl2 (4x 10 mL) and the combined organic extracts were washed
with a saturated solution of NaCI and dried over anhydrous Na2SO4. The
mixture was treated with a 0.6 M diazomethane solution in diethylether and
concentrated under reduced pressure. Chromatography of the residue (10 g
of silica gel, EtOAc- hexane, 2:1) afforded 88 mg (85%) of the product as
colorless oil: 1H NMR (300 MHz, CDCI3) 8 1.95 - 2.07 (m, 2H), 2.13 - 2.39 (m,
3H), 2.47 2.62 (m, 1H), 2.81 - 2.95 (m, 2H), 3.04 - 3.27 (m, 2H), 3.50 - 3.63
(m, 1H), 3.78 (s, 3H), 3.87 (s, 3H), 5.70 (s, 1H), 7.00 )s, 1H);
106
MeO
Methyl
(7aW,8S1-Bromo-3-methoxy-5,6,7,7a,8,9-
hexahydrophenanthro[4,5-bcc]furan-8-carboxylate
(106).
To a
solution of enone 100 (50 mg, 0.110 mmol) in CH2Cl2 (5 mL), triethylsilane
(50 mL, 0.31 mmol) and a 1 M solution of TiCI4 in CH2Cl2 (0.543 mL, 0.543
mmol) were added, and the mixture was stirred for 4 h at room temperature.
The mixture was poured on ice and extracted with EtOAc (3x 20 mL). The
combined organic extracts were washed with a saturated solution of NaCI,
dried over anhydrous Na2SO4, and concentrated under reduced pressure.
Chromatography of the residue (3 g of silica gel, EtOAc- hexane, 1:3) afforded
38 mg (90 %) of 106 as a colorless oil: IR (neat) 2925, 2832, 1743, 1494,
1440, 1279, 1157, 1108, 1020 cm-1 ; 1H NMR (300 MHz, CDCI3) 8 1.01 1.17 (m, 1H), 1.88 - 2.08 (m, 1), 2.14 - 2.26 (m, 1H), 2.32 (d t, J = 5, 9 Hz, 1H),
2.59 - 2.75 (m, 1H), 2.78 - 2.90 (m, 1H), 2.92 - 3.11 (m, 3H), 3.19 (dd, J = 5, 16
Hz, 1H), 3.80 (s, 3H), 4.01 (s, 1H), 6.79 (s, 1H); 13C NMR (75 MHz, CDCI3) 8
23.4, 23.5, 28.1, 31.4, 33.6, 48.9, 52.1, 57.1, 111.1, 113.8, 116.4, 121.1,
130.1, 141.1, 144.5, 154.2, 174.9; MS (CI) m/z 365 (M++1), 335, 314, 307,
285, 217, 205, 189, 159, 123, 115, 103; HRMS (CI) m/z 365.0373 (calcd for
Ci7H1804Br: 365.0388).
107
MeO
Methyl
(4aS*,7aS*,8S*,9cR1-3-methoxy-4a,5,6,7,7a,8,9,9c-
octahydrophenanthro[4,5-bcc]furan-8-carboxylate. (107). A mixture
of enone 100 (12.8 mg, 0.0337 mmol), a (10%)Pd/C catalyst (ca 5 mg), and
Me0H (5 mL) was stirred for 9 h under hydrogen atmosphere at room
temperature. The mixture was filtered through a short column of silica gel,
and the resultant solution was concentrated under reduced pressure.
Chromatography of the residue (5 g of silica gel, EtOAc- hexane, 1:3)
afforeded 9.8 mg (68 %) of 107 as colorless oil: IR (neat) 2930, 2858, 1733,
1507, 1440, 1277, 1200, 1161, 1104, 1065 cm-1 ; 1H NMR (300 MHz, CDCI3)
8 0.92
1.05 (m, 1H), 1.06 - 1.24 (m, 2H), 1.50 - 1.68 (m, 2H), 1.93
2.03 (m,
1H), 2.64 - 2.73 (m, 2H), 2.85 - 2.91 (m, 1H), 3.20 (d, J = 17 Hz, 1H), 3.37 (t, J
= 6 Hz, 1H), 3.68 (s, 3H), 3.68 (s, 3H), 3.86 (s, 3H), 4.96 - 5.04 (m, 2H), 6.66
(d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 21.7,
23.5, 26.3, 27.9, 34.6, 37.8, 44.4, 52.2, 56.9, 85.9, 113.8, 119.9, 124.8,
127.0,143.6, 145.6, 175.4; MS (CI) rniz 288 (M +), 257, 229, 197, 97, 84, 69;
HRMS (CI) m/z 288.1363 (calcd for C1 7H2004: 288.1362);
There was also obtained 2.3 mg of Methyl (4aS*,5R*,7aS*,8S*,9cR1-
3,5-dimethoxy-4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5bcd]furan-8-carboxylate (108). IR (neat) 3366, 2923, 1724, 1508, 1445,
1281, 1152, 1089 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.25 - 1.47 (m, 2H),
1.52 - 1.61 (m, 1H), 1.82 - 1.92 (m, 1H), 2.63 - 2.85 (m, 3H), 3.09 (d, J = 14
Hz, 1H), 3.28 (s, 3H), 3.50 (t br, J = 6 Hz, 1H), 3.58 (t br, J = 4 Hz, 1H), 3.69 (s,
108
3H), 3.87 (s, 3H), 5.02 (dd, J 5, 9 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.72 (d, J = 8
Hz, 1H); 13C NMR (100 MHz, CDCI3) 8 20.2, 24.7, 26.4, 33.7, 37.0, 45.1,
52.2, 57.1, 59.1, 76.1, 86.4, 114.1, 119.4, 124.3, 127.7, 142.1, 148.1, 175.6;
MS (CI) m/z 318 (M+), 287, 259, 247, 227, 195, 187, 123, 97, 83; HRMS (CI)
m/z 318.1471 (calcd for C181-12205: 318.1467);
There was also obtained 2 mg of Methyl (4aS*,5R*,7aS*,8S*,9cR*)-5-
hydroxy-3-methoxy-4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5bcd]furan-8-carboxylate (109). IR (neat) 3443, 2928,1 734, 1503, 1435,
1277, 1147, 1060, 940 cm-1; 1H NMR (300 MHz, CDCI3) 6 1.36 - 1.49 (m,
1H), 1.51
1.63 (m, 1H), 1.85 - 1.97 (m, 2H), 2.63 2.87 (m, 3H), 3.10 (dd, J =
1, 16 Hz, 1H), 3.51 (t, J = 8 Hz, 1H), 3.69 (s, 3H), 3.87 (s, 3H), 4.08 - 4.11 (m,
1H), 4.97 (dd, J = 5, 9 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.71 (d, J = 9 Hz, 1H);
13C NMR (75 MHz, CDCI3) 6 19.6, 24.6, 28.2, 33.9, 36.6, 48.1, 52.3, 56.7,
66.2, 86.0, 113.5, 120.3, 124.4, 127.6, 141.7, 147.0, 175.5; MS (CI) m/z 304
(M+), 287, 273, 245, 227, 215, 187; HRMS (CI) m/z 304.1306 (calcd for
C17H2005: 304.1311).
Me0
OH
Methyl
(5S,7aR,8S)-1-Bromo-5-hydroxy-3-methoxy-5,6,7,7a,8,9-
hexahydrophenanthro[4,5-bccifuran-8-carboxylate
(111).
To a
solution of 100 (0.34g, 0.90 mmol) in a CH2C12-i-PrOH mixture (3:1, 40 mL),
sodium borohydrate (0.34g, 9.01 mmol) was added, and the reaction was
109
stirred for 12 h at ambient temperature. The reaction was quenched with an
aqueous solution of HCI (5%), and the organic layer was separated, washed
with a saturated solution of NaHCO3 and a saturated solution of NaCI, and
dried over anhydrous Na2SO4. Removal of the solvent under reduced
pressure furnished 0.35g (99%) of the alcohol 111 as white crystalline
product, which was not further purified: [a]D23 + 105.8 (c 1.15, CHCI3); mg >
171 °C dec.; IR(neat) 3400, 2947, 2834, 1729, 1493, 1432, 1272, 1164 cm-1;
1H NMR (300 MHz, CDCI3) 6 1.26 - 1.38 (m, 1H), 1.85 - 1.99 (m, 1H), 2.21 -
2.37 (m, 2H), 2.45 - 2.53 (m, 111), 2.94 (dd, J = 12, 16 Hz, 1H), 3.10 - 3.21 (m,
1H), 3.18 (dd, J = 4, 16 Hz, 1H), 3.80 (s, 1H), 4.02 (s, 3H), 4.94 - 4.99 (m, 1H),
6.85(s, 1H); 13H NMR (75 MHz, CDCI3) 8 29.8, 31.2, 33.7, 34.2, 48.7, 52.3,
57.2, 65.4, 112.4, 114.1, 120.0, 122.0, 129.2, 141.7, 144.7, 153.2, 174.5; MS
m/z 381(M±), 365, 303, 285, 278, 224, 149; HRMS m/z 380.0260 (calcd for
Ci7H1705Br 380.0259); Anal. Calcd for Ci7H1705Br: C, 53.56; H, 4.49. Found:
C, 53.75; H, 4.62.
Me0
OH
Methyl
(4aS,5S,7aS,8S,9cR)-5-Hydroxy-3-methoxy-
4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8carboxylate (112). A mixture of the allylic alcohol 111 (0.35 g, 0.91
mmol), Me0H (20 mL), NaHCO3 (75 mg, 091 mmol) and a (10%)Pd/C
catalyst (30 mg) was stirred for 1 h under a hydrogen atmosphere at
110
room temperature. The mixture was filtered over a short column of silica
gel,
and the obtained solution was concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed
with water and a saturated solution of NaCI. The solvent was removed
under reduced pressure, and the residue was dissolved in Me0H (15
mL). To the solution a (10%)Pd/C catalyst (20 mg) was added, and the
mixture was stirred for 24 h under hydrogen atmosphere at ambient
temperature. The mixture was filtered over a short column of silica gel
and concentrated under reduced pressure. Chromatography of the
residue.(300 g of silica gel, EtOAc- hexane, 1:1.5) afforded 0.21 g (75 %)
of 112 as colorless oil: [a]D23 4.1 (c 1.02, CHCI3); IR (neat) 3428, 2939,
2861, 1729, 1503, 1440, 1279, 1064
cm-1; 1H NMR(300 MHz, CDCI3)
8 1.05 - 1.18 (m, 1H), 1.29 - 1.43 (m, 1H), 1.66 - 1.72 (m, 1H), 1.78 - 1.85
(m, 1H), 2.65 - 2.75 (m, 2H), 2.90 - 2.91 (m, 1H), 3.18 (d, J = 17 Hz, 1H),
3.37 3.49 (m, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 4.67 - 4.72 (m, 1H), 6.65 (d,
J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 23.5,
25.1, 29.8, 34.2, 38.4, 43.7, 52.3, 56.8, 71.7, 93.2, 113.9, 120.3, 124.1,
127.2, 143.5, 145.4, 175.2; MS m/z 304(M+, 100), 287, 273, 245, 227,
187, 149, 119, 107, 102; HRMS m/z 304.1309 (calcd for C17H2005
304.1307);
There was also obtained 9.5 mg of 113: IR (neat) 3511, 2954, 1733,
1513, 1445, 1284, 1205, 1176, 1054 cm-1; 1H NMR (300 MHz, CDCI3) 8
1.37 - 1.47 (m, 2H), 1.88 - 2.00 (m, 2H), 2.66 - 2.85 (m, 3H), 3.07 - 3.13
(m, 1H), 3.51 - 3.60 (m, 1H), 3.70 (s, 3H), 3.87 (s, 3H), 4.10 - 4.14 (m, 1H),
4.95
5.00 (m, 1H), 6.66 (d, J = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 1H); 13C
NMR (75 MHz, CDCI3) 8 19.6, 24.5, 28.1, 33.8, 36.5, 45.1, 52.2, 56.7,
111
66.2, 86.0, 113.4, 120.2, 124.4, 127.6, 141.7, 147.0, 175.5; MS m/z 304
(M+), 244, 227, 215, 201, 199, 195, 187, 121, 119, 115, 86, 84; HRMS
m/z 304.1309 (calcd for C17H2005 304.1311).
Me0
OMOM
Methyl
(4aS,7aS,8S,9cR)-3-Methoxy-5-(methoxymethoxy)-
4a,5,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8-
carboxylate (116). A mixture of alcohol 112 (130 mg, 0.43 mmol),
CH2(OMe)2 (1.9 mL, 21.3 mmol), dry CHCI3 (30 mL), and of P205 (30 mg)
was stirred for 4 h at room temperature. The solution was separated from the
solid residue and neutralized with solid NaHCO3 (200 mg). The mixture was
filtered,
and the filtrate was concentrated under reduced pressure.
Chromatography of the residue (30 g of silica gel, hexane- EtOAc, 2:1)
afforded 129 mg (86%) of 116 as a colorless oil: [423 -9.2 (c 0.78, CHCI3);
IR (neat) 2939, 1733, 1503, 1445, 1108, 1054 cm-1; 1HNMR (300 MHz,
CDCI3) 5 1.05 - 1.19 (m, 1H), 1.25 - 1.38 (m, 1H), 1.63 - 1.70 (m, 1H), 1.85 1.93 (m, 1H), 2.65 - 2.74 (m, 2H), 2.89 - 2.91 (m, 1H), 3.18 (d, J = 18 Hz, 1H),
3.34 - 3.42 (m, 1H), 3.37 (s, 3H), 3.48 (t, J = 7 Hz, 1H), 3.68 (s, 3H), 3.87 (s,
3H), 4.69 (d, J = 7 Hz, 1H), 4.75 (d, J = 7 Hz, 1H), 4.77 (t, J = 8 Hz, 1H), 6.64
(d, J = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 23.5,
24.9, 28.5, 29.9, 34.2, 38.6, 43.7, 52.3, 55.4, 57.2, 76.1, 91.3, 95.6, 115.0,
120.2, 124.2, 127.2, 143.6, 145.7, 175.1, 181.9; MS m/z 348 (M+), 302, 243,
112
227, 215, 199, 183, 161, 115, 86, 84 69; HRMS m/z 348.1574 (calcd for
C19H2406: 348.1573).
Me0
OMOM
(4a8,58,7a8,88,9cR)-3-Methoxy-5-(methoxymethoxy)4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8carboxylic Acid (117). To a solution of ester 116 (100 mg, 0.29 mmol) in
THE (15 mL), H2O (15 mL) and LiOH -H20 (50 mg, 1.2 mmol) were added,
and the mixture was stirred for 20 h at ambient temperature. The reaction was
acidified with an aqueous solution of HCI (10%), and the product was
extracted with EtOAc (3x 30 mL). The combined organic extracts were
washed with a saturated solution of NaCI, dried over anhydrous Na2SO4,
and concentrated under reduced pressure to afford 100 mg (100 %) of acid
117 which was not further purified. [423 8.5 (c 1.55 CHCI3); IR (neat) 3174
(br), 2930, 1733, 1708, 1508, 1445, 1283, 1156, 1103, 1049 cm-1; 1H
NMR(300 MHz, CDCI3) 8 1.05 - 1.18 (m, 1H), 1.25 - 1.38 (m, 1H), 1.62 - 1.71
(m, 1H), 1.87 - 1.92 (m, 1H), 2.64 - 2.75 (m, 2H), 2.91
2.96 (m, 1H), 3.16 (d, J
= 17 Hz, 1H), 3.34 - 3.42 (m, 1H), 3.38 (s, 3H), 3.54 (t, J = 7 Hz, 1H), 3.86 (s,
3H), 4.69 (d, J = 7 Hz, 1H), 4.75 (d, J = 7 Hz, 1H), 4.78 (t, J = 8 Hz, 1H), 6.63
(d, J = 8 Hz, 1H), 6.72 (d, J = 8Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 23.2,
24.9, 28.4, 34.0, 38.5, 43.5, 55.3, 57.2, 76.0, 91.2, 95.5, 115.0, 120.2, 123.9,
127.0, 143.7, 145.7, 180.7; MS m/z 334 (M+), 304, 289, 271, 260, 243, 227,
113
215, 199, 183, 161, 115; HRMS m/z 334.1415 (calcd for C18F12206:
334.1417).
Me0
OMOM
1-[4aS,5S,7aS,8S,9cR)-3-Methoxy-5-(methoxymethoxy)4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8-y1]-2diazo-1-ethanone (118). To a solution of 117 (90 mg, 0.27 mmol) in dry
benzene (30 mL), oxalyl chloride (0.2 mL, 2.2 mmol) was added, and the
mixture was stirred for 18 h at room temperature. The solvent and excess
oxalyl chloride were removed under reduced pressure. The residue was
dissolved in benzene (25 mL) and added dropwise to a 0.6 M solution of
diazomethane in ether (30 mL). The mixture was stirred at ambient
temperature for 1 h, and nitrogen gas was passed through the solution for 2 h
to remove the excess diazomethane. The solvent was removed under
reduced pressure and the residue was chromatographed (30 g of silica gel,
EtOAc- hexane, 1:1) to afford 61 g (63%) of diazoketone 118 as a yellow oil:
[a]D23 -36.7 (c 0.95, CHCI3); IR(neat) 3091, 2930, 2099, 1630, 1503, 1445,
1362, 1152, 1112, 1054 cm-1; 1H NMR(300 MHz, CDCI3) 8 1.05 - 1.39 (m,
2H), 1.63 - 1.70 (m, 1H), 1.85 - 1.92 (m, 1H), 2.52
2.58 (m, 1H), 2.69 -
2.81(m, 2H), 2.93(d, J = 17, 1H), 3.35 - 3.41 (m,1H), 3.36 (s, 3H), 3.51 (t, J = 7
Hz, 1H), 3.87 (s, 3H), 4.67 (d, J = 7Hz, 1H), 4.73 (d, J = 7Hz, 1H), 4.76 (t, J = 8
114
Hz, 1H), 5.31 (s, 1H), 6.64 (d, J = 8 Hz, 1H), 6.73 (dd, J = 1, 8 Hz, 1H); 13C
NMR(75MHz, CDCI3) 8 23.5, 25.3, 28.5, 35.3, 38.4, 49.3, 54.3, 55.3, 57.2,
76.1, 91.3, 95.5, 115.1, 120.2, 123.6, 127.6, 143.8, 145.8, 197.2.
Me0
OMOM
(1R,4S,12S,13S,16R)-9-Methoxy-13-(methoxymethoxy)-11oxapentacyclo[8.6.1.01 02.04,16.06,17 Theptadeca-6(17),7,9trien-3-one (119). To a solution of diazoketone 118 (47 mg, 0.13 mmol) in
CH2Cl2 (50 mL) under argon atmosphere, Rh2(OAc)4 (1 mg) was added,
and the mixture was stirred for 1 h at ambient temperature. The mixture was
concentrated
under
reduced
pressure,
and
the
residue
was
chromatographed (10g of silica gel, EtOAc- hexane, 1:2) to afford 22 mg
(51%) of pentacyclic ketone 119 as colorless oil: [a]D23 +12.0 (c 0.44, CHCI3);
IR (neat) 2941, 1755, 1509, 1447, 1283, 1262, 1041 cm-1; 1H NMR(300MHz,
CDCI3) 8 1.21 - 1.31 (m, 1H), 1.34 - 1.57 (m, 1H), 1.73
1.83 (m, 1H), 1.86 -
1.95 (m, 1H), 2.47 - 2.55 (m, 1H), 2.72 - 2.76 (m, 1H), 2.85 - 2.93 (m, 2H), 3.40
(s, 3H), 3.57 - 3.64 (m, 1H), 3.87 (s, 3H), 4.72 (d, J = 7 Hz, 1H), 4.75 (d, J = 6
Hz, 1H), 4.79 (d, J = 7 Hz, 1H), 6.58 (d, J = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 1H);
13C NMR (75 MHz, CDCI3) 8 19.7, 27.5, 28.4, 42.2, 49.1, 50.1, 53.9, 55.5,
57.0, 77.9, 90.9, 95.9, 115.3, 120.7, 122.4, 133.1, 144.0, 144.2, 217.9; MS
m/z 330 (M+), 285, 257, 243, 199, 113, 83, 69, 55, 49, 45; HRMS m/z
330.1469 (calcd for C1 9H2205: 330.1467);
115
There was also obtained 5.6 mg (15 %) of (3S,3aS,9aR,9bR)-5-
Methoxy-3-(methoxymethoxy)-1,2,3,3a,9a,9b-
hexahydrophenanthro[4,5-bcd]furan (121):
IR (neat) 2931, 1723,
1639, 1505, 1460, 1440, 1280, 1157, 1107, 1037, 923 cm-1; 1H NMR (300
MHz, CDCI3) 8 1.00 - 1.28 (m, 2H), 1.70 - 1.86 (m, 2H), 2.52 - 2.63 (m, 1H),
3.41 (s, 3H), 3.50 - 3.59 (m, 1H), 3.74 (t, J = 9 Hz, 1H), 3.90 (s, 3H), 4.74 (d, J
= 7 Hz, 1H), 4.83 (d, J = 7 Hz, 1H), 4.91 (dd, J = 8, 9 Hz, 1H), 5.68 (dd, J = 6,
10, 1H), 6.42 (d, J = 10 Hz, 1H), 6.64 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H);
13C NMR (75 MHz, CDCI3) 8 26.6, 27.3, 33.9, 39.6, 55.4, 56.9, 91.7, 95.7,
113.6, 117.5, 124.1, 124.2, 125.7, 130.5, 145.0, 145.2; MS m/z 288 (M+),
258, 243, 227, 211, 199, 187, 171, 149, 128, 115; FIRMS m/z 288.1363
(calcd for C17H2004: 288.1362);
There
was
also
obtained
7.5
mg
(17
%)
of
1
[(4aS,5S,7aS,8R,9cR)-3-Methoxy-5-(methoxymethoxy)-
4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8-y1]-1ethanone (120): IR (neat) 2930, 1719, 1513, 1279, 1259, 1162, 1103,
1039 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.17 - 1.30 (m, 1H), 2.00 - 2.16 (m,
1H), 2.17 - 2.22 (m, 1H), 2.28 (s, 3H), 2.42 - 2.54 (m, 2H), 2.98 - 3.01 (m, 2H),
3.20
3.50 (m, 1H), 3.50 (s, 3H), 4.05 (s, 3H), 4.86 (d, J = 7 Hz, 1H), 4.39 -
4.84 (m, 1H), 5.07 (d, J = 7 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz,
1H); 13C NMR (75 MHz, CDCI3) 8 29.8, 30.3, 30.9, 32.1, 33.2, 55.8, 56.8,
57.1, 70.3, 96.2, 102.6, 120.9, 121.2, 122.4, 128.5, 142.7, 144.2, 151.3,
210.2; MS m/z 330 (M+), 288, 243, 225, 199, 187, 183, 115; HRMS m/z
330.1468 (calcd for C19H2205: 330.1467);
There was also obtained 5 % of the (4aS,5S,7aS,7bR,9aR,9dR)-
3-Methoxy-5-(methoxymethoxy)-4a,6,7,7a,7b,9,9a,9d-
116
octahydrocyclobuta[9,10]phenanthro[4,5-bcd]furan-8(5H)-one
(122). IR (neat) 2936, 1784, 1511, 1444, 1282, 1158, 1100, 1057 cm-1; 1H
NMR (300 MHz, CDCI3) 8 0.95 - 1.11 (m, 1H), 1.21 - 1.35 (m, 1H), 1.48
(m, 1H), 1.82 - 1.90 (m, 1H), 2.60 -2.68 (m, 2H), 3.34
3H), 3.51
1.62
3.42 (m, 1H), 3.39 (s,
3.69 (m, 4H), 3.74 - 3.79 (m, 1H), 3.84 (s, 3H), 4.50 (d, J = 7 Hz,
1H), 4.77 (d, J = 7 Hz, 1H), 4.80 (dd, J = 7, 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H),
6.78 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 24.7, 25.1, 28.3, 31.2,
39.3, 53.2, 55.4, 57.1, 65.1, 76.5, 90.4, 95.6, 115.0, 120.5, 126.3, 127.9,
144.3, 145.9, 210.6; MS (CI) m/z 330 (M++1), 288, 258, 243, 225, 211, 199,
187, 128, 115, 101, 86, 77, 69; HRMS (CI) m/z 330.1468 (calcd for C19H2206:
330.1467);
NOH
OMOM
(1R,4S,12S,13S,16R)-9-Methoxy-13-(methoxymethoxy)-11-
oxapentacyclo[8.6.1.01,12.04,16.06,17ijheptadeca-6(17),7,9trien-one Oxime (136). NH2OH-HCI (6.3 mg, 0.091 mmol) and NaOAc
(16.5 mg, 0.12 mmol) were added to a stirred solution of ketone 119 (20 mg,
0.062 mmol) in Me0H (10 mL). After stirring for 6 h at ambient temperature,
the mixture was concentrated under reduced pressure, and the residue was
dissolved in CHCI3 (15 mL). The obtained solution was washed with water
and a saturated solution of NaCl, dried over anhydrous Na2SO4, and
117
concentrated under reduced pressure. Chromatography of the residue (20 g
of silica gel, EtOAc- hexane 1:1) afforded 18.8 mg (90%) of oxime 136 as
colorless oil: IR (neat) 1073, 1284, 1440, 1507, 1606, 1640, 1552, 2935,
3374 cm-1 ; 1H NMR (300 Mz, CDCI3) 6 1.16
1.24 (m, 1H), 1.39 - 1.51 (m,
1H), 1.66 - 1.75 (m, 1H), 1.73 1.91 (m, 1H), 2.12
2.26 (m, 1H), 1.87 (d, J =
13 Hz, 1H), 2.73 3.10 (m, 3H), 3.40 (s, 3H), 3.51-3.58 (m, 1H), 3.87 (s, 3H),
4.69 - 4.81 (m, 3H), 6.58 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H); MS (El) m/z
345(M+), 241, 199, 167, 149, 115; HRMS m/z 345.1575 (calcd for C19H23 05N
345.1576).
Me0
&nom
(1R,5S,13S,14S,17S)-10-Methoxy-14-(methoxymethoxy)-12-oxa4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10tien-3-one (138). A mixture of oxime 136 (25 mg, 0.072 mmol), pbromobenzenesulphonyl chloride (28 mg, 0.11 mmol), triethylamine (16
0.12 mmol), catalytic amount of DMAP, and CH2Cl2 (5 mL) was stirred for 1 h
at ambient temperature. The solvent was removed under reduced pressure,
and the residue was dissolved in acetic acid (2 mL). The resulting solution
was stirred for 1 h at room temperature and was neutralized with a saturated
solution of NaHCO3. The product was extracted with CH2Cl2 (5x 10mL), and
the combined organic extracts were washed with a saturated solution of
NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
118
pressure. Chromatography of the residue (6g of silica gel, EtOAc -MeOH,
12:1) afforded 17 mg (69%) of lactam 138 as colorless oil: [a]D23 + 114.2 (c
1.47, CHCI3); IR (neat) 3271, 2932, 1673, 1509, 1437, 1288, 1119, 1037,
1021 cm-1; 1H NMR (300 MHz, CDCI3) 8 0.92 - 1.05 (m, 1H), 1.25 - 1.41 (m,
1H), 1.69
1.80 (m, 1H), 1.92 - 2.01 (m, 1H), 2.29 (dt, J = 4, 13 Hz, 1H), 2.52
(d, J = 17 Hz, 1H), 2.68 (d, J = 17 Hz, 1H), 2.75 (br s, 2H), 3.38 (s, 3H), 3.35 3.39 (m, 1H), 3.83 (br s, 1H), 3.88 (s, 3H), 4.41 (d, J = 7 Hz, 1H), 4.68 (d, J = 7
Hz, 1H), 4.75 (d, J = 7 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.76 (d, J = 8 Hz, 1H),
6.78 (br s, 1H); 13C NMR (75 MHz, CDCI3) 8 11.4, 23.0, 28.0, 28.3, 31.1,
38.2, 42.6, 43.8, 51.3, 55.4, 57.1, 76.4, 95.3, 95.6, 115.7, 121.5, 130.3, 144.6,
144.9, 170.9; MS (CI) m/z 346 (M++1), 339, 323, 284, 246, 185, 169, 141,
125, 89, 86, 84, 78, 75, 73; HRMS m/z 345.1575 (calcd for C19H2305N:
345.1576).
0
Me0
(1 R,5S,13S,14S,178)-10-Methoxy-14-(methoxymethoxy)-4methy1-12-oxa-4-
azapentacyclo[9.6.1.01 03.05,1 7.07,18]octadeca-7(18),8,10trien-3-one (142). To a solution of 138 (24 mg, 0.069 mmol) in dry
benzene (3 mL), NaH (55 wt % suspension in mineral oil, 12 mg, 0.28 mmol)
and CH3I (43 gL, 0.69 mmol) were added, and the mixture was refluxed for 5
h. The reaction was quenched with EtOH (401AL) followed by H2O (2 mL). The
119
organic solution was separated, and the aqueous layer was extracted with
CH2Cl2 (4x 5mL). The combined organic extracts were washed with a
saturated solution of NaCI, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. Chromatography of the residue (4g of silica gel,
EtOAc -MeOH, 12:1) afforded 24 mg (95%) of 142 as colorless oil: [a]p'
+148.9 (c 0.092, CHCI3); IR (neat) 2935, 1655, 1636, 1509, 1440, 1284,
1108, 1054, 1005 cm-1; 1H NMR (300 MHz, CDCI3) 8 0.98 - 1.26 (m, 1H),
1.28
1.38 (m, 1H), 1.68 - 1.78 (m, 111), 1.91 - 1.97 (m, 1H), 2.34 (dt, J = 4, 13
Hz, 1H), 2.56 (d, J = 17 Hz, 1H), 2.95 (d, J = 18 Hz, 1H), 3.00 (s, 3H), 3.31 3.38 (m, 1H), 3.38 (s, 3H), 3.69 - 3.72 (m, 1H), 3.88 (s, 3H), 4.41 (d, J = 7 Hz,
1H), 4.68 (d, J = 7 Hz, 1H), 4.75 (d, J = 7 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.75
(d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 5 23.0, 26.8, 28.0, 34.2, 39.2,
43.1, 44.9, 55.4, 57.2, 59.0, 76.4, 95.1, 95.6, 115.7, 121.2, 121.5, 130.4,
144.6, 144.9, 168.4; MS m/z 359 (M+), 329; 314, 298, 286, 256, 243, 225,
211, 199, 185; HRMS m/z 359.1733 (calcd for C20H2505N: 359.1733).
0
Me0
OH
(1R,5S,13S,14S,17S)-14-Hydroxy-10-methoxy-4-methy1-12-oxa-
4-azapentacyclo[9.6.1.01,1 3.05,17.07,18]octadeca-7(18),8,10trien-3-one. (143). To a solution of MOMether 142 (22 mg, 0.061 mmol)
in acetonitrile (2 mL), an aqueous solution of HBr (36%, 10 AL) was added,
and the mixture was stirred for 2 h at ambient temperature. The reaction was
120
quenched with solid NaHCO3 (30 mg), filtered, and concentrated under
reduced pressure. Chromatography of the residue (3 g of silica gel, Et0AcMe0H, 9:1) afforded 18 mg (95%) of 143 as a colorless oil: [a]D23 +130.1 (c
0.092, CHCI3); IR (neat) 3394, 2936, 1620, 1509, 1440, 1280, 1097 cm-1; 1H
NMR (300 MHz, CDCI3) 5 1.00
(m, 1H), 1.84
1.10 (m, 1H), 1.28 - 1.48 (m, 1H), 1.73 - 1.80
1.90 (m, 1H), 2.36 (dt, J = 4, 13 Hz, 1H), 2.56 (d, J = 17 Hz,
1H), 2.65 (dd, J = 4, 18 Hz, 1H), 2.70 (d, J = 17 Hz, 1H), 2.95 (d, J =18 Hz,
1H),3.01 (s, 1H), 3.33 3.43 (m, 1H), 3.70 - 3.73 (m, 1H), 3.87 (s, 3H), 4.34 (d,
J = 7 Hz, 1H), 6.63 (d, J = 8 Hz, 1H), 6.76 (d, J = 8 Hz, 1H); 13C NMR (75
MHz, CDCI3) 5 23.2, 26.8, 29.4, 34.2, 39.2, 42.9, 44.9, 56.8, 59.0, 72.3, 97.0,
114.8, 121.3, 121.5, 130.5, 144.4, 144.7, 168.4; MS m/z 315 (M+), 301, 286,
258, 243, 229, 213, 199, 185, 178; HRMS m/z 315.1472 (calcd for
C18H2104N: 315.1471).
0
Me0
(1R,5S,13S,17S)-10-Methoxy-4-methy1-12-oxa-4azapentacyclo[9.6.1.01 ,13.05,17.07,18]octadeca-7(18),8,10triene3,14-dione (144). A mixture of secondary alcohol 143 (16 mg,
0.051 mmol), Dess-Martin periodinane (26 mg, 0.061 mmol) and CHCI3 (3
mL) was stirred for 1 h at ambient temperature. The suspension was treated
with a Na2S203/NaHCO3 solution (4 mL, 50 g of Na2S203 in 200 mL of a
saturated solution of NaHCO3), and the chloroform layer was separated,
121
washed with a saturated solution of NaCI, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Chromatography of the residue
(4g of silica gel, EtOAc -MeOH, 11:1) afforded 15 mg (96 %) of ketone 144 as
a colorless oil: [4023 +181.3 (c 0.71, CHCI3); IR (neat) 2935, 1738, 1636,
1504, 1440, 1284, 1101, 771 cm-1; 1H NMR (300 MHz, CDCI3) 5 1.26 - 1.39
(m, 1H), 2.01 - 2.08 (m, 1H), 2.40 - 2.48 (m, 2H), 2.62 (dd, J = 4, 18 Hz, 1H),
2.76 2.80 (m, 3H), 2.98 (d, J = 18 Hz, 1H), 3.04 (s, 3H), 3.78 - 3.80 (m, 1H),
3.91 (s, 3H), 4.70 (s, 1H), 6.64 (d, J = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 1H); 13C
NMR (75 MHz, CDCI3) 5 25.3, 26.9, 34.3, 39.1, 39.2, 44.5, 46.9, 57.2, 58.7,
91.6, 111.2, 116.2, 121.2, 122.1, 127.3, 143.9, 146.2, 167.7, 206.0; MS m/z
313 (M+), 256, 241, 231, 212, 198, 181, 131, 121, 97, 83, 71; FIRMS m/z
313.1314 (calcd for C1 8F11904N: 313.1341).
0
MeO
(1R,5S,13S,17S)-10-Methoxy-4-methy1-12-oxa-4-
azapentacyclo[9.6.1.01,1 3.05,17.07,18]octadeca-7(18),8,10,15tetraene-3,14-dione (135). To a mixture of ketone 144 (35 mg, 0.11
mmol) and THF (5 mL) at 0°C, under argon atmosphere, a 1 M solution of
KOt-Bu in t-BuOH (130 !IL, 0.13 mmol) was added, and the mixture was
stirred for 30 min at 0 °C. A solution of PhSeCI (28.7 mg, 0.15 mmol) in THF
(0.4 mL) was added, and the mixture was allowed to warm to room
122
temperature over a period of 1 h. The mixture was treated with a saturated
aqueous solution of NH4CI (0.5 mL), and the product was extracted with
CHCI3 (4x 5 mL). The combined organic extracts were washed with a
saturated solution of NaCI, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. To a solution of the residue in a THE -H20 mixture
(1:1, 4 mL), Na104 (180 mg, 0.88 mmol) was added, and the mixture was
stirred for 30h at room temperature. The product was extracted with CHCI3
(5x 3mL), and the combined organic extracts were washed with a saturated
solution of NaCI, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Chromatography of the residue (3g of silica gel, EtOAcEtOH, 11:1) afforded 22 mg (64 %) of 135 as colorless oil: [a]D23 = + 106.6 (c
1.37, CHCI3); IR (neat) 1159, 1287, 1449, 1505, 1634, 1681, 2859, 2929 cm1; 1H NMR (300 MHz, CDCI3) 8 2.56 (dd, J = 4, 18 Hz, 1H), 2.78 - 2.81 (d, J =
17 Hz, 1H), 3.05 - 3.12 (m, 4H), 3.42 (br s, 1H), 3.87 (s, 3H), 4.04 - 4.07 (m,
1H), 4.71 (s, 1H), 6.19 (dd, J = 3, 10 Hz, 1H), 6.63 (d, J = 8 Hz, 1H), 6.69 6.74 (m, 2H); 13C NMR (100 MHz, CDCI3) 8 29.9, 34.4, 38.4, 43.2, 57.3, 58.5,
87.7, 118.2, 121.0, 122.3, 129.0, 134.1, 143.9, 144.2, 145.2, 167.6, 193.7;
MS (CI) m/z 321 (M++H), 201, 130, 121, 115, 111, 102, 97 86, 83, 69; HRMS
(CI) m/z 312.1235 (calcd for C181-I1804N: 312.1236).
me0
OH
123
-(+)-Codeine (76). To a suspension of LiAIH4 (6.1 g, 0.16 mmol) in dry THF
(0.5 mL), a solution of 135 (5 mg, 0.0196 mmol) in THF (1 mL) was added,
and the mixture was refluxed for 6 h. The mixture was cooled to room
temperature and treated with a saturated solution of Rochelle's salt (1 mL).
The product was extracted with CH2Cl2 (5x 1 mL), and the combined organic
extracts were washed with a saturated solution of NaCI, dried over
anhydrous
Na2SO4,
and
concentrated
under
reduced
pressure.
Chromatography of the residue (2g of silica gel, CHCI3- (5 %)diethylamine)
afforded 4.1 mg (70 %) of the product as white solid: [a]023 +137.5 (c 0.16,
EtOH); 1HNMR (400 MHz,CDCI3) 8 1.90 (d, J = 12 Hz, CDC13), 2.11 - 2.17
(m, 1H), 2.36 (dd, J = 6, 18 Hz, 1H), 2.44 - 2.47 (m, 1H), 2.49 (s, 3H), 2.65 2.68 (m, 1H), 2.78 (br s, 1H), 3.05 (d, J = 18 Hz, 1H), 3.41 (br s, 1H), 3.84 (s,
3H), 4.17 - 4.19 (m, 1H), 4.90 (d, J = 6 Hz, 1H), 5.26 - 5.30 (m, 1H), 5.72 (d, J
= 10 Hz, 1H), 6.57 (d, J = 8Hz, 1H), 6.67 (d, J = 8 Hz, 1H); 13C NMR (100
MHz, CDCI3) 6 20.83, 35.6, 40.6, 43.0, 43.1, 46.8, 56.6, 59.3, 66.5, 91.3,
113.3, 119.9, 128.0, 131.0, 133.9, 139.6, 142.6, 146.5;
Me0
Methyl
(4aS*,7aS*,8S*,9cR1-3-Methoxy-5-oxo-
4a,5,6,7,7a,8,9,9c-octahydrophenanthro[4,5-bcd]furan-8-
124
carboxylate (130). A mixture of 112 (30 mg, 0.099 mmol) and Dess-Martin
periodinane (50 mg, 0.12 mmol), and CHCI3 (5 mL) was stirred for 1 h at
room temperature. A solution of Na2S2O3/NaHCO3 (5 mL, 50 g of Na2S2O3 in
200 mL of a saturated solution of NaHCO3) was added, and stirring was
continued for another 20 min. The chloroform layer was separated, washed
with a saturated solution of NaCI, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. A chromatography of the residue (5 g
of silica gel, EtOAc- hexane, 1:2) afforded 27 mg (92 %) of 130 as a colorless
oil: IR (neat) 2946, 1733, 1684, 1504, 1435, 1271, 1206, 1167 cm-1; 1H NMR
(300 MHz, CDCI3) 8 1.37
1.50 (m, 1H), 1.92 - 1.99 (m, 1H), 2.38 - 2.43 (m,
2H), 2.67 (d, J =7, 18 Hz, 1H), 2.94
2.98 (m, 1H), 3.17 - 3.10 (m, 1H), 3,.22
(d, J = 18 Hz, 1H), 3.72 (s, 3H), 3.89 (s, 3H), 3.88 - 3.92 (m, 1H), 5.05 (d, J = 9
Hz, 1 H), 6.65 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H); 13C NMR (75 MHz,
CDCI3) 8 20.5, 23.5, 26.9, 30.3, 30.4, 34.0, 39.5, 41.8, 43.3, 52.5, 57.1, 87.3,
115.0, 121.0, 123.8, 124.1, 142.9, 146.8, 174.7, 207.8; MS rn/z 302 (M+), 248,
231, 214, 187, 161, 119, 86, 84; HRMS m/z 302.1154 (calcd for C171-11805:
302.1154).
MeO
(4aS*,7aS*,8S*,9cR1-3-Methoxy-5-oxo-4a,5,6,7,7a,8,9,9coctahydrophenanthro[4,5-bcd]furan-8-carboxylic Acid (131). To a
solution of 130 (50 mg, 0.165 mmol) in a THE -H20 mixture (1:1.3, 35 mL),
125
Li0H-H20 (28 mg, 0.66 mmol) was added, and the mixture was stirred for 18
h at room temperature. The reaction was acidified with an aqueous solution
of HCI (10%), and the product was extracted CH2Cl2 (3x 10 mL). The
combined organic extracts were washed with a saturated solution of NaCI,
dried over anhydrous Na2SO4, and concentrated under reduced pressure to
afford 47 mg (99 %) of 131 colorless oil which was not further purified: IR
(neat) 3209, 2945, 1728, 1509, 1450, 1284, 1196, 1167, 1108, 917 cm-1; 1H
NMR (300 MHz, CDCI3) 8 1.38 1.48 (m, 1H), 1.95 - 1.99 (m, 1H), 2.37 - 2.46
(m, 2H), 2.86 (dd, J = 7, 18 Hz, 1H), 3.00 (d, J = 8 Hz, 1H), 3.11 - 3.18 (m, 1H),
3.22 (d, J = 18 Hz, 1H), 3.90 (s, 3H), 3.97 (t, J = 7 Hz, 1H), 5.06 (d, J = 9 Hz,
1H), 6.66 (d, J = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3)
6 23.3, 26.9, 33.9, 39.5, 41.7, 43.2, 57.2, 87.2, 115.6, 121.0, 123.6, 124.2,
143.0, 146.9, 180.1, 207.7; MS m/z 288 (M+), 260, 232, 215, 187, 183, 161,
115; HRMS m/z 2888.0996 (calcd for C16H1605: 288.0998).
Me0
(3aS*,9R*,9aS*,9bR1-9-(2-Diazoacety1)-5-methoxy-
1,3a,8,9,9a,9b-hexahydrophenanthro[4,5-bcd]furan-3(2H)-one
(132). To a solution of 131 (210 mg, 0.73 mmol) in dry benzene (20 mL),
126
oxalyl chloride (325 pL, 3.72 mmol) was added, and the mixture was for
stirred 18 h at ambient temperature. The solvent and excess oxalyl chloride
were removed in under reduced pressure. The residue was dissolved in
benzene (25 mL) and added dropwise to a 0.6 M solution of diazomethane in
ether (100 mL). The mixture was stirred for 1 h, and nitrogen gas was passed
through the solution for 2 h to remove the excess diazomethane. The solvent
was
removed
under
reduced
pressure,
and
the
residue
was
chromatographed (18 g of silica gel, EtOAc- hexane, 1:1) to afford 190 mg (83
%) of diazoketone 132 as yellow oil: IR (neat) 3086, 2930, 2109, 1728, 1636,
1504, 1440, 1362, 1284, 1157, 113 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.37 -
1.51 (m, 1H), 1.94 - 1.99 (m, 1H), 2.36
2.48 (m, 2H), 2.72 (dd, J =6, 18 Hz,
1H), 2.84 - 2.88 (m, 1H), 2.96 (d, J = 18, 1H), 2.98 - 3.03 (m, 1H), 3.91 (s, 3H),
3.96 (t, J = 6 Hz, 1H), 5.05 (d, J = 9 Hz, 1H), 5.38 (s, 1H), 6.67 (d, J = 8 Hz,
1H), 6.74 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 23.8,27.4, 35.0,
39.6, 41.7, 48.8, 54.7, 57.1, 87.3, 115.3, 121.0, 123.3, 124.6, 143.2, 147.0,
196.7, 207.7;
O
MeO
(1 WO 2S*,16R1-9-Methoxy-11oxapentacyclo[8.6.1.01 ,1 2.04,14.06,17 ]heptadeca-6(17),7,9-
127
triene-3,13-dione (133). To a stirred solution of diazoketone 132 (0.19 g,
0.605 mmol) in dry CH2Cl2 (200 mL), under argone atmosphere, Rh2(OAc)4
(ca 2 mg) was added and the mixture was stirred for 1 h at room temperature.
The solvent was removed under reduced pressure, and the residue was
chromatographed (30 g of silica gel, EtOAc- hexane, 1:2) to afford 91 mg (53
%) of pentacyclic ketone 133 as colorless oil: IR (neat) 2941, 2839, 1740,
1721, 1503, 1442, 1283, 1088 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.48 - 1.63
(m, 1H), 2.03 2.11 (m, 1H), 2.39 2.50 (m, 1H), 2.55 - 2.64 (m, 2H), 2.72 (d, J
= 17 Hz, 1H), 2.84 - 2.92 (m, 4H), 3.90 (s, 3H), 4.92 (s, 1H), 6.62 (d, J = 8 Hz,
1H), 6.72 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 21.7, 27.5, 40.7,
42.6, 49.9, 52.0, 53.3, 56.9, 88.2, 115.5, 121.7, 121.9, 129.9, 143.5, 145.1,
207.3, 216.6; MS tn/z 284 (M+), 256, 242, 227, 213, 199, 185, 181, 128, 121,
115; HRMS m/z 284.1047 (calcd for C17H1604: 284.1048);
There was also obtained 8.6 mg (5%) of (3aS*,7bR*,9aR*,9bS*,9cR1-
5-Methoxy-1,2,3a,7b,8,9b,9c-
octahydrocyclobuta[9,10]phenanthro[4,5-bcd]furan-3,9-dione
(135a). IR (neat) 2931, 1776, 1729, 1503, 1447, 1283, 1103 cm-1; 1H NMR
(300 MHz, CDCI3) 8 1.30 -1.40 (m, 1H), 1.80
1.87 (m, 1H), 2.37 - 2.42 (m,
2H), 2.65 - 2.71 (m, 1H), 3.02 - 3.10 (m, 1H), 3.54 - 3.70 (m, 2H), 3.81 - 3.87
(m, 1H), 3.93 (s, 3H), 3.98 - 4.03 (m, 1H), 5.07 (d, J = 8 Hz, 1H), 6.66 - 6.67
(m, 2H); 13C NMR (75 MHz, CDCI3) 5 24.7, 27.1, 31.4, 39.6, 42.5, 53.3, 57.0,
64.5, 86.5, 115.2, 121.3, 123.3, 127.5, 143.7, 207.4, 209.9; MS rniz 284 (M+),
242, 199, 185, 174, 88, 86, 84; HRMS m/z 284.1047 (calcd for C17H1604:
284.1049);
There was also obtained 25 mg (17%) of the (3aS*,9aR*,9bR*)-5Methoxy-1,3a,9a9b-tetrahydrophenanthro[4,5-bcd]furan-3(2H)-
128
one (135b). IR (neat) 3032, 2939, 1728, 1508, 1450, 1435, 1279, 1098,
1069 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.34 - 1.49 (m, 1H), 1.98 - 2.07 (m,
1H), 2.33 - 2.41 (m, 2H), 2.91 - 3.02 (m, 1H), 3.92 (s, 3H), 4.19 (t, J = 9 Hz,
1H), 5.20 (d, J = 9 Hz, 1H), 5.88 (dd, J = 6, 10 Hz, 1H), 6.46 (d, J = 10 Hz, 1H),
6.63 (d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 5
27.0, 33.8, 38.6, 43.4, 56.7, 87.8, 113.8, 118.3, 122.9, 123.7, 125.1, 129.1,
144.7, 146.1, 208.0; MS rri/z 242 (M+), 211, 201, 199, 184, 171, 161, 143,
115, 86, 84; HRMS nilz 242.0944 (calcd for 015H1403: 242.0943).
O
Me0
(1R*,4S*,12S*,16R1-9-Methoxy-11oxapentacyclo[8.6.1.01,12.04,16.06,171jheptadeca-6(17),7,9,14tetraene-3,13-dione (134). To a stirred solution of 133 (48 mg, 0.17
mmol) in EtOAc (7 mL), PhSeCI (46 mg, 0.24 mmol) was added, followed by
an aqueous solution of HCI (36%, 5 drops), and the mixture was stirred for 5
h at ambient temperature. To the mixture, solid NaHCO3 (30 mg) was added,
and stirring was continued for another 30 min. The solution was filtered and
129
concentrated under reduced pressure. The residue was dissolved in a THF-
H20 mixture (1:1.5, 25 mL) and treated with Na104 (150.2 mg, 0.70 mmol).
The reaction was stirred for 30 h at room temperature. THE was removed
under reduced pressure, and the product was extracted with EtOAc (4x 5
mL). The combined organic extracts were washed with a saturated solution of
NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue (5 g of silica gel, EtOAc- hexane,
2:1) afforded 19 mg (46 %) of enone 134 as colorless oil: IR (neat) 2959,
2842, 1748, 1684, 1503, 1450, 1284, 1264, 1176, 1084, 927, 805 cm-1; 1H
NMR (300 MHz, CDCI3) 8 2.89 (dd, J = 5, 17 Hz, 1H), 3.02 (dd, J = 2, 17 Hz,
1H), 3.07 - 3.10 (m, 1H), 3.46 - 3.50 (m, 1H), 3.85 (s, 3H), 5.05 (s, 1H), 6.24
(d, J = 2, 10 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 6.95 (dd, J = 2, 10 Hz, 1H); 13C
NMR (75 MHz, CDCI3) 5 28.3, 41.0, 49.5, 49.6, 52.1, 56.9, 86.3, 115.6, 121.3,
122.0, 122.3, 132.3, 134.7, 143.1, 144.6, 145.3, 193.3, 215.3; MS m/z 282
(M+), 254, 226, 211, 201, 185, 85, 83; HRMS m/z
282.0891 (calcd for
Ci7H1404: 282.0892).
0
Me0
OMOM
(117*,5S*,135 *,14S*,17S1-10-Methyxy-14-(methoxymethoxy)-
4,12-dioxapentacyclo[9.6.1.01,1 3.05,17.07,18]octadeca7(18),8,10-trien-3-one (139). To a solution of pentacyclic ketone 1 1 9
(30 mg, 0.091 mmol) in CHCI3 (10 mL), m-chloroperbenzoic acid (84%, 37
130
mg, 0.18 mmol) and NaHCO3 (50 mg) were added, and the mixture was
stirred for 5 h at room temperature. Methyl sulfide (20 lit) was added to the
mixture, and stirring was continued for 20 min. The solution was washed with
a saturated solution of Na2CO3 and a saturated solution of NaCI, dried over
anhydrous
Na2SO4,
and
concentrated
under
reduced
pressure.
Chromatography of the residue (17 g of silica gel, EtOAc- hexane, 2:1)
afforded 26 mg (84 %) of 139 as colorless oil: IR (neat) 2940, 2891, 1738,
1503, 1440, 1279, 1220, 1147,
1039, 1010, 669 cm-1; 1H NMR (300 MHz,
CDCI3) 8 0.90 - 1.03 (m, 1H), 1.30 - 1.43 (m, 1H), 1.77 - 1.82 (m, 1H), 1.95
2.00 (m, 1H), 2.43 (dt, J = 4, 13 Hz, 1H), 2.67 (d, J = 18 Hz, 1H), 2.83 (dd, J =
18 Hz, 1H), 2.89 (d, J = 18 Hz, 1H), 3.16 (d, J =18 Hz, 1H), 3.43 - 3.35 (m,
4H), 3.88 (s, 3H), 4.41 (d, J = 7 Hz, 1H), 4.68 (d, J = 7 Hz, 1H), 4.75 (d, J = 7
Hz, 1H), 4.92 - 4.94 (m, 1H), 6.67 (d, J = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H); 13C
NMR (75 MHz, CDCI3) 8 22.1, 28.0, 30.0, 38.4, 42.1, 43.3, 55.4, 57.5, 76.3,
78.6, 94.4, 95.6, 116.1, 120.3, 121.5, 129.4, 144.5, 144.6, 169.1; MS m/z 346
(M+), 288, 243, 213, 199, 185; HRMS m/z 346.1416 (calcd for C191-12206:
346.1416).
0
MeO
OH
(1 R*,5S*,13S*,14S*,17S*)-14-Hydroxy-10-methoxy-4,12dioxapentacyclo[9.6.1.01 03.05,1 7.07,18]octadeca-7(18),8,10trien-3-one (145). To a solution of 139 (36 mg, 0.104 mmol) in acetonitrile
131
(10 mL), an aqueous solution of HBr (36%, 50 AL) was added, and the
solution was stirred for 30 min at room temperature. Solid NaHCO3 (100 mg)
was added, and stirring was continued for another 30 min. The solution was
filtered and concentrated under reduced pressure. Chromatography of the
residue (3 g of silica gel, EtOAc- hexane, 2:1) afforded 30 mg (95%) of 145 as
a colorless oil: IR (neat) 3399, 2940, 1733, 1714, 1504, 1445, 1284, 1030
cm-1; 1H NMR (300 MHz, CDCI3) 8 0.89 - 1.03 (m, 1H), 1.39 - 1.49 (m, 1H),
1.79
1.85 (m, 1H), 1.87 - 1.94 (m, 1H), 2.45 (dt, J = 4, 13 Hz, 1H), 2.67 (d, J =
18, 1H), 2.84 (dd, J = 4, 18 Hz, 1H), 2.88 (d, J = 18 Hz, 1H), 3.17 (dd, J = 2,
18 Hz, 1H), 3.46 - 3.39 (m, 1H), 3.88 (s, 3H), 4.35 (d, J = 8 Hz, 1H), 4.93 - 4.96
- (m, 1H), 6.69 (d, J = 8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H); 13C NMR (75 MHz,
CDCI3) 5 22.3, 29.4, 30.0, 38.4, 41.9, 43.4, 56.7, 72.2, 78.7, 96.2, 115.2,
120.3, 121.6, 129.4, 144.3, 144.5, 169.1;MS m/z 302 (M+), 242, 227, 213,
199, 183, 175, 115; HRMS m/z 302.1154 (calcd for C17H1805: 302.1154).
0
Me0
(1 R*,5S*,13S*,17S1-10-Methoxy-4,12dioxapentacyclo[9.6.1.01 ,13.05,17.07,18]octadeca-7(18),8,10triene-3,14-dione (146). A mixture of 145 (35 mg, 0.116 mmol), DessMartin periodinane (52.2 mg, 0.174 mmol), and CHCI3 (25 mL) was stirred
for 1 h at room temperature. The suspension was treated with an aqueous
solution of Na2S2O3/NaHCO3 (20 mL, 50 g of Na2S2O3 in 200 mL of
132
saturated solution of NaHCO3), and the chloroform layer was separated,
washed with a saturated solution of NaC1, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Chromatography of the residue (6
g of silica gel, EtOAc- hexane, 2:1) afforded 33 mg (95%) of 146 as colorless
oil: IR (neat) 2942, 1730, 1509, 1447, 1278, 1211, 1114, 1031, 995, 728 cm1; 1H NMR (300 MHz, CDCI3) 8 1.20 - 1.34 (m, 1H), 2.06 - 2.14 (m, 1H), 2.46-
2.54(m, 2H), 2.83 (dd, J = 4, 18 Hz, 1H), 2.88 - 2.96 (m, 3H), 3.21 (dd, J = 2,
18 Hz, 1H), 3.92 (s, 3H), 4.72 (s, 1H), 5.00 - 5.02 (m, 1H), 6.70 (d, J = 8 Hz,
1H), 6.80 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 24.1, 30.0, 38.0,
39.0, 42.8, 45.8, 56.9, 78.0, 90.7, 116.3, 119.9, 122.3, 126.3, 143.9, 145.7,
168.3, 205.5; MS m/z 300 (M+), 258, 248, 231, 203, 181, 169, 131, 119, 83,
76, 69; HRMS m/z 300.0998 (cacld for C17H1605: 300.0998).
0
Me0
(1R*,5S*,13S*,17S*)-10-Methoxy-4,12-
dioxapentacyclo[9.6.1.01,13.05,17.07.18]octadeca-7(18),8,10,15tetraene-3,14-dione (147). To a stirred solution of 146 (24 mg, 0.080
mmol) in EtOAc (10 mL), PhSeCI (23 mg, 0.12 mmol) and an aqueous
solution of HCI (36%, 2 drops) were added, and the mixture was stirred for 5
h at ambient temperature. Solid NaHCO3 (100 mg) was added and stirring
was continued for another 30 min. The solution was filtered and concentrated
under reduced pressure. The residue was dissolved in a THE -H20 mixture
133
(1:1.5, 10 mL) and treated with Na104 (75.1 mg, 0.35 mmol), and the reaction
was stirred for 30 h at room temperature. THE was removed under reduced
pressure and the product was extracted with EtOAc (4x 5 mL). The combined
organic extracts were washed with water and a saturated aqueous solution of
NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Chromatography of the residue (5 g of silica gel, EtOAc- hexane,
2:1) afforded 13 mg (56 %) of 147 as colorless oil: IR (neat) 2935, 1738,
1684, 1509, 1279, 1049, 1015 cm-1; 1H NMR (300 MHz, CDCI3) S 2.76 (dd, J
= 4, 18 Hz, 1H), 2.95 (d, J = 18 Hz, 1H), 3.08 (d, J = 18 Hz, 1H), 3.31 (d, J = 18
Hz, 1H), 3.52
3.55 (m, 1H), 3.88 (s, 3H), 4.73 (s, 1H), 5.23 - 5.26 (m, 1H),
6.24 (dd, J = 3, 10 Hz, 1H), 6.68 (dd, J = 2, 10 Hz, 1H), 6.69 (d, J = 8.2, 1H),
6.78 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 30.6, 37.5, 41.7, 42.1,
57.2, 86.9, 111.2, 112.3, 116.8, 119.8, 122.6, 128.0, 134.3, 141.2, 142.1,
143.8, 145.1, 167.6, 193.1; MS m/z 298 (Mt), 213, 174, 149, 135, 121, 107;
HRMS m/z 298.0841 (calcd for C17H1405 : 298.0841).
0
MeO
OH
(1 R*,5S*,13S*,14R*,17S1-14-Hydroxy-10-methoxy-4,12-
dioxapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10,15tetraen-3-one (148). To a stirred solution of 147 (50 mg, 0.24 mmol) in dry
THE (20 mL) at -78 °C, under argon atmosphere, a 1 M solution of L-selectride
(282 gL, 0.282 mmol) was added, and the mixture was stirred for 2 h at -78 °C.
134
To the solution, H2O (200 ML), EtOH (3001.4 a 6 M aqueous solution of NaOH
(350 AL), and a 30% aqueous solution of H202 (400 AL) were added in
succession, and product was extracted with EtOAc (4x 10 mL). The solvent was
removed under reduced pressure, and the residue was chromatographed (6g
of silica gel, EtOAc- hexane, 2:1) to afford 41 mg (81%) of 148 as colorless oil:
IR (neat) 3466, 2955, 1728, 1508, 1453, 1294, 1216, 1051, 1018 cm-1; 1H
NMR (300MHz, CDCI3) 8 2.79 (dd, J = 5, 19 Hz, 1H), 2.85 (d, J = 18, 1H), 2.97 3.00 (m, 1H), 3.08 (d, J = 18 Hz, 1H), 3.23 (d, J = 19 Hz, 1H), 3.85 (s, 3H), 4.23 -
4.27 (m, 1H), 4.92 (d, J = 7 Hz, 1H), 5.13 - 5.16 (m, 1H), 5.33 - 5.38 (m, 1H),
5.91
- 5.94 (m, 1H), 6.63 (d, J = 8 Hz, 1H), 6.74 (d, J = 8 Hz, 1H); 13C
NMR(75MHz, CDCI3) 8 30.9, 36.1, 41.6, 42.3, 56.5, 65.1, 89.7, 114.6, 120.9,
121.8, 122.9, 129.6, 136.3, 143.1, 146.1, 186.6; MS m/z 300 (M+), 291, 259,
240, 225, 213, 209, 199, 174, 85, 83; HRMS m/z 300.0999 (calcd for C,7H1605:
300.0998).
0
Me0
OMOM
(1 R*,5S*,13S*,14S*,17S1-10-Methoxy-14-(methoxymethoxy)-
4,12-dioxapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-trien-3-one
(160). A mixture of 148 (32 mg, 0.11 mmol),
dimethoxymethane (0.28 mL, 4.26 mmol), P205 (10 mg), and dry CHCI3 (12
mL) was stirred at room temperature until TLC analysis indicated quantitative
conversion (ca 3h). The solution was separated from the solid residue and
135
was neutralized with solid NaHCO3 (50 mg), filtered, and concentrated under
reduced pressure. Chromatography of the residue (4g of silica gel, EtOAc-
hexane, 1:1) afforded 33 mg (90%) of 160 as colorless oil: IR(neat) 2950,
1733, 1513, 1455, 1284, 1220, 1049, 1020, 966 cm-1; 1H NMR (300 MHz,
CDCI3) 8 3.09 (d, J = 18 Hz, 1H), 3.24 (d, J = 18 Hz, 1H), 3.46 (s, 3H), 3.85 (s,
3H), 4.24 - 4.33 (m, 1H), 4.74 (d, J = 7 Hz, 1H), 4.90 (d, J = 7 Hz, 1H), 4.97 (d,
J = 7 Hz, 1H), 5.14 - 5.16 (m, 1H), 5.40
5.44 (m, 1H), 5.92 - 5.96 (m, 1H),
6.58 (d, J = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8
31.1, 36.5, 42.0, 42.3, 56.1, 56.6, 69.5, 89.2, 95.8, 115.0, 120.7, 121.1, 123.9,
129.6, 133.9, 143.1, 147.3, 168.8; MS (CI) m/z 344(M+),315, 285, 283, 257,
241, 237, 224, 174, 83; HRMS (CI) m/z 344.1259 (calcd for Ci 012006:
314.1260).
MeO
OMOM
Methyl
(2S1-2-[13R*,3aS*,9aS1-5-Methoxy-3-
(methoxymethoxy)-9-oxo-3,8,9,9a-tetrahydrophenanthro[4,5bccifuran-9(3aH)-yliacetone (163). To a solution of 160 (28 mg, 0.081
mmol) in a THE -H20 mixture (1:1, 10 mL), Li0H-H20 (32 mg, 0.77 mmol) was
added, and the mixture was stirred for 20 h at ambient temperature. The
solution was cooled to 4 °C and neutralized with an aqueous solution of HCI
(5%). The product was extracted with CH2Cl2 (4x 5 mL), and the combined
organic extracts were washed with a saturated solution of NaCI and dried
136
over anhydrous Na2SO4. To the mixture, a 0.6 M solution of diazomethane in
diethylether (20 mL) was added, and the reaction was stirred for 15 min at
0°C. The excess diazomethane was reacted with AcOH, and the resultant
solution was washed with water and a saturated solution of NaCI, and dried
over anhydrous Na2SO4. All volatiles were removed under reduced pressure,
and the obtained residue was dissolved in CHCI3 (5 mL) and treated with
Dess-Martin periodinane (49 mg, 0.12 mmol). The mixture was stirred for 1 h
at room temperature and treated with of a solution of Na2S203/Nal-IC03 (5
mL, 50 g of Na2S2O3 in 200 mL of a saturated solution of NaHCO3). The
organic layer was separated, washed with a saturated solution of NaCI, dried
over anhydrous Na2SO4 and concentrated under reduced pressure. A
chromatography of the residue (7g of silica gel, EtOAc- hexane, 1:2) afforded
25 mg (82 %) of 163 as a colorless oil: IR (neat) 2953, 1737, 1710, 1508,
1455, 1205, 1052 cm-1, 1H NMR (300 MHz, CDCI3) 8 2.80 (d, J = 17 Hz, 1H),
2.95 (d, J = 17 Hz, 1H), 3.37.- 3.39 (m, 111), 3.43 (d, J = 21 Hz, 1H), 3.68 (d, J
= 20 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 4.46 - 4.50 (m, 1H), 4.80 (d, J = 7 Hz,
1H), 4.88 (d, J = 7 Hz, 1H), 5.34 (dt, J = 3, 10 Hz, 1H), 5.38 (d, J = 5 Hz, 1H),
5.90 - 5.94 (m, 1H), 6.57 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H); 13C NMR
(75 MHz, CDCI3) 8 40.6, 41.4, 47.1, 51.9, 52.1, 55.6, 56.1, 72.0, 89.8, 85.7,
113.7, 119.7, 121.1, 125.8, 129.2, 131.4, 143.2, 147.9, 170.0, 210.2; MS tn/z
374 (M+), 343, 301, 285, 281, 269, 253, 240, 225; HRMS m/z 374.1365 (calcd
for C20H2207: 374.1365).
137
me0
0 M OM
Methyl
(2S1-2-[(3R*,3aS1-5-Methoxy-3-(methoxymethoxy)-9-
oxo-3,3a,8,9-tetrahydrophenanthro[4,5-bccifuran-9(2H)yl]acetale (164). To a solution of 163 (10 mg, 0.028 mmol) in CH2Cl2 (2
mL), a 1 M solution of methylamine in THE (50 pt, 0.050 mmol) was added,
and the mixture was stirred for 2 h at ambient temperature. The solution was
washed with an aqueous solution of HCI (5%) and a saturated solution of
NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to afford 10 mg (100 %) of 164 as colorless oil: IR (neat) 2959,
1738, 1689, 1631, 1504, 1455, 1279, 1201, 1152, 1040 cm-1; 1H NMR(300
MHz, CDCI3) 8 2.51 - 2.57 (m, 2H), 2.66 (d, J = 16 Hz, 1H), 2.88 (d, J = 16 Hz,
1H), 3.19 (s, 1H), 3.51 (d, J = 21 Hz, 1H), 3.63 (s, 3H), 3.75 (d, J = 21 Hz, 1H),
3.88 (s, 311), 4.29 (d, J = 7 Hz, 1H), 4.36 - 4.32 (m, 1H), 4.67 (d, J = 7 Hz, 1H),
5.45 (d, J = 5 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.73 - 6.79 (m, 2H); 13C NMR
(75 MHz, CDCI3) 5 27.9, 41.4, 46.4, 51.6, 55.2, 56.5, 72.5, 88.6, 96.2, 113.8,
119.8, 121.2, 130.8, 133.4, 138.4, 142.9, 145.7, 170.5, 197.6; MS m/z 374
(M+), 343, 313, 301, 281, 269, 253, 241, 211; HRMS m/z 374.1365 (calcd for
C20H2207: 374.1366).
138
OMEM
(4aS*,5s*,7aS*,8S*,9cR1-3-Methoxy-5-[(2methoxyethoxy)methoxy)]-4a,5,6,7,7a,8,9,9c-
octahydrophenanthro[4,5-bcd]furan-8-carboxylate.
To
a
stirred
solution of 112 (35.2 mg, 0.12 mmol) in CH2Cl2 (5 mL), MEMCI (53.0 mL,
0.46 mmol) and N,N-diisopropilethylamine (90.6 mL, 0.52 mmol) were
added, and the mixture was stirred for 3 h at ambient temperature. The
solution was washed with water and a saturated solution of NaCI, dried over
anhydrous
Na2SO4,
and
concentrated
under
reduced
pressure.
Chromatography of the residue (25 g of silica gel, EtOAc- hexane, 1:1)
afforded 43 mg (95%) of the MEMether as colorless oil: IR (neat) 2932, 2894,
1733, 1507, 1458, 1293, 1210, 1172, 1139 cm-1; 1 HNMR (300 MHz, CDCI3)
8 1.03 1.32 (2H, m), 1.61 - 1.65 (1H, m), 1.81 - 1.91 (1H, m), 2.63 - 2.71 (2H,
m), 2.87 - 2.89 (1H, m), 3.15 (1H, d, J = 17 Hz), 3.34
3.58 (7H, m), 3.64 -
3.71 (4H, m), 3.84 - 3.78 (4H, m), 4.71 - 4.77 (3H, m), 6.62 (1H, d, J = 8 Hz),
6.69 (1H, d, J = 8 Hz); 13C NMR (75 MHz, CDCI3) 8 23.4, 24.8, 28.0, 34.1,
38.5, 43.6, 52.2, 56.7, 59.0, 66.6, 71.8, 75.6, 77.4, 91.0, 93.9, 114.3, 120.1,
124.0, 127.0, 143.5, 145.5, 175.0; MS m/z 392 (M+), 287, 227, 199, 195, 149,
123, 121, 119 (100), 117, 105, 93, 90; HRMS m/z 392.1835 (calcd for
C21H2807 392.1835).
139
OMEM
(4aS*,5S*,7aS*,8S*,9cR1-3-Met hoxy-5-[(2methoxyethoxy)methoxy]-4a,5,6,7,7a,8S,9coctahydrophenanthro[4,5-bcd]furan-8-carboxylic Acid. To a solution
of the ester (26.0 mg, 0.066 mmol) in a mixture of THE and water (2:1, 6 mL),
LiOH -H20 (13.9 mg, 0.331 mmol) was added, and the mixture was stirred at
ambient temperature for 20 h. The reaction was acidified with an aqueous
solution of HCI (5%), and the product was extracted with EtOAc (3x 4 mL).
The combined organic extracts were washed with a saturated solution of
NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to afford 24.8 mg (99%) of the carboxylic acid as colorless oil: IR
(neat) 3162, 2947, 1730, 1709, 1509, 1442, 1283, 1175, 1103, 1051 cm-1;
1H NMR (300 MHz, CDCI3) 8 1.05 - 1.36 (2H, m), 1.64
1.68 - (1H, m), 1.88
1.91 (11-I, m), 2.63 2.73 (2H, m), 2.90 2.93 (1H, m), 3.15 (1H, d, J = 18 Hz),
3.36 (3H, s), 3.37 - 3.60 (4H, m), 3.65 - 3.72 (1H, m), 3.80 - 3.84 (4H, m), 4.73
- 4.78 (3H, m), 6.63 (1H, d, J = 8 Hz), 6.70 (1H, d, J = 8 Hz); 13C NMR (75
MHz, CDCI3) 8 23.2, 24.8, 28.0, 34.0, 38.5, 43.5, 56.8, 59.1, 66.7, 71.9, 75.6,
91.0, 94.0, 114.4, 120.2, 123.8, 126.9, 143.6, 145.6, 180.5; MS m/z 378 (M+),
273, 227, 199, 195, 187, 161, 115; HRMS rn/z 378.1678 (calcd for C201-12607
378.1678).
140
OMEM
1-{(4aS*,5S*,7aS*,8S*,9cR1-3-Methoxy-5-[(2methoxyethoxy)methoxy]-4a,5,6,7,7a,9,9coctahydrophenanthro[4,5-bcd]furan-8-yI)-2-diazo-1-ethanone.
To
a solution of the carboxylic acid (50 mg, 0.13 mmol) in dry benzene (2 mL),
oxalyl chloride (46.5 mL, 0.53 mmol) was added, and the mixture was stirred
for 18 h at ambient temperature. The solvent and excess oxalyl chloride were
removed under reduced pressure, and the obtained residue was dissolved in
benzene (2 mL) and treated with a 0.6 M solution of diazomethane in
diethylether (5 mL). Through the solution was passed nitrogen gas for 2 h to
removed excess diazomethane, and the mixture was concentrated under
reduced pressure. Chromatography of the residue (12 g of silica gel, EtOAc-
hexane 2:1) afforded 37 mg (71%) of the diazoketone as colorless oil:
IR(neat) 2938, 2888, 2107, 1634, 1507, 1441, 1375, 1265, 1106, 1051 cm-1;
1H NMR(300 MHz, CDCI3) 8 1.05 - 1.28 (m, 2H), 1.64
1.70 (m,1H), 1.87 -
1.92 (m,1H), 2.04 - 2.56 (m, 1H), 2.69 - 2.79 (m, 2H), 2.93 (d, J = 17 Hz, 1H),
3.35 (s, 3H), 3.37 - 3.57 (m, 4H), 3.65 - 3.72 (m, 1H), 3.79 - 3.87 (m, 4H), 4.72
- 4.89 (m, 3H), 5.31 (s, 1H), 6.65 (d, J = 8 Hz, 1H), 6.72 (d, J = 8 Hz, 1H); 13C
NMR (75 MHz, CDCI3) 8 23.5, 25.3, 28.1, 35.3, 38.4, 49.3, 54.3, 56.8, 59.1,
66.7, 71.9, 75.7, 91.1, 94.0, 114.5, 120.2, 123.5, 127.5, 143.8, 145.8, 197.2.
141
0
MeO
6M EM
(1R*,4S*,12S*,13S*,16R1-9-Methoxy-13-[(2methoxyethoxy)methoxy]-11-
oxapentacyclo[8.6.1.01,1 2.04,16.06,17ijheptadeca-6(17),7,9trien-3-one. To a solution of the diazoketone (50 mg, 0.124 mmol) in
CH2Cl2 (100 mL) under argon atmosphere, Rh2(OAc)4 (ca 2 mg) was added,
and the mixture was stirred for 30 min at ambient temperature. The solution
was
concentrated
under
reduced
prsssure,
and
the
residue
was
chromatographed (12 g of silica gel, EtOAc- hexane, 1:1) to afford 21 mg
(46%) of the pentacyclic ketone as colorless oil: IR (neat) 2932, 2890, 1756,
1509, 1447, 1278, 1252, 1108, 1063 cm-1; 1H NMR (300 MHz, CDCI3) 5 1.21
- 1.34 (m, 1H), 1.41
1.54 (m, 1H), 1.76 - 1.82 (m, 1H), 1.88 - 1.97 (m, 1H),
2.46 - 2.52 (m, 3H), 2.73 - 2.76 (m, 1H), 2.86 - 2.88 (m, 2H), 3.38 (s, 3H), 3.52
3.76 (m, 4H), 3.80 - 3.84 (m, 1H), 3.86 (s, 3H), 4.75 (d, J = 6 Hz, 1H), 4.81 4.87 (m, 2H), 6.59 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H); 13C NMR (75 MHz,
CDCI3) 5 19.7, 27.5, 28.2, 42.3, 49.2, 50.1, 53.9, 56.7, 59.2, 67.0, 71.9, 90.9,
94.5, 114.7, 120.7, 122.3, 133.0, 144.0, 218.0; MS m/z 374 (M +), 285, 269,
243, 227, 199, 89; HRMS m/z 374.1729 (calcd for C21 H2406: 374.1729).
142
Me0
OMEM
(1 R*,5S*,13S*,14S*,17 S1-10-Methoxy-14-[(2-
methoxyethoxy)methoxy]-4,12dioxapentacyclo[9.6.1.01 ,1 3.050 7.07,18]octadeca-7-(18),8,10trien-3-one (139). To a solution of the pentacyclic ketone (8 mg, 0.021
mmol) in CH2Cl2 (3 mL), NaHCO3 (20 mg, 0.24 mmol) and m-CPBA (86 wt
%, 8.7 mg, 0.043 mmol) were added, and the mixture was stirred for 6 h at
ambient temperature. The solution was washed with a saturated solution of
Na2CO3 and a saturated solution of NaCI, dried over a anhydrous Na2SO4,
and concentrated under reduced pressure. Chromatography of the residue
(10g silica gel, EtOAc- hexane, 2:1) to afforded 6 mg (75%) of 139 as
colorless oil: IR (neat) 2937, 1737, 1508, 1445, 1275, 1211, 1115, 1030 cm1; 1H NMR (300 MHz, CDCI3) 8 0.88 - 1.02 (m, 1H), 1.25 - 1.39 (m, 1H), 1.74 -
1.86 (m, 1H), 1.94 - 2.02 (m, 1H), 2.42 (dt, J = 4, 12 Hz, 1H), 2.65 (d, J = 18
Hz, 1H), 2.82 (dd, J = 4, 18 Hz, 1H), 2.87 (d, J = 18 Hz, 1H), 3.15 (dd, J = 2, 18
Hz, 1H), 3.35 (s, 3H), 3.39 3.48 (m, 1H), 3.52 - 3.56 (m, 2H), 3.66 3.73 (m,
1H), 3.79
3.84 (m, 1H), 3.86 (s, 3H), 4.38 (d, J = 7 Hz, 111), 4.76 - 4.80 (m,
2H), 4.90 - 4.93 (m, 1H), 6.66 (d, J = 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H); 13C
NMR (75 MHz, CDCI3) 5 22.0, 27.5, 29.9, 38.4, 42.0, 43.3, 56.6, 59.1, 66.8,
71.8, 75.9, 78.6, 94.1, 94.2, 115.5, 120.2, 121.4, 129.3, 144.4, 144.5, 169.5;
MS tniz 390 (M+), 374, 285, 279, 213, 199, 167, 149 (100), 119; HRMS m/z
390.1680 (calcd for C21 H2607 390.1678).
143
NHCH3
,OH
Me0
OMEM
(2S1-21(3S*,3aS*,9S*,9aS1-9-Hydroxy-5-methoxy-31(2methoxyethoxy)methoxy]-1,3,3a,8,9,9a-
hexahydrophenanthro[4,5-bcd]furan-9(2H)-y1FN-methylacetamide
(151). A mixture of 139 (17 mg, 0.043 mmol) and a 1 M solution of CH3NH2
in Me0H (5 mL) was sealed in a tube and stirred for 10 h at 70 °C. All
volatiles were removed under reduced pressure, and the residue was
chromatographed (3 g of silica gel, EtOAc -MeOH, 96:4) to afford 18 mg (98%)
of 151 as colorless oil: IR (neat) 3379, 2931, 1658, 1644, 1509, 1280, 1107,
1047, 1012 cm-1; 1H NMR (300 MHz, CDCI3) 5 0.75 - 0.88 (m, 1H), 1.22 1.30 (m, 1H), 1.60 - 1.65 (m, 1H), 1.81
1.85 (m, 1H), 2.47 (d, J = 13 Hz, 1H),
2.57 - 2.63 (m, 1H), 2.73 - 2.86 (m, 6H), 2.88 - 3.34 (m, 1H), 3.36 (s, 3H), 3.52
- 3.55 (m, 2H), 3.66 - 3.75 (m, 1H), 3.79 - 3.82 (m, 1H), 3.86 (s, 3H), 4.76 (d, J
= 7 Hz, 1H), 4.78 (s, 2H), 6.11 - 6.13 (m, 1H), 6.65 (d, J = 8 Hz, 1H), 6.74 (d, J
= 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 24.5, 26.6, 27.4, 30.0, 31.4, 39.7,
43.6, 45.4, 56.6, 59.1, 66.7, 71.0, 71.9, 76.4, 94.1, 95.0, 114.5, 121.3, 123.1,
130.8, 143.8, 144.7, 172.5; MS m/z 421 (MI), 403, 391, 330, 316, 254, 241,
224, 213, 149, 89, 85, 83; HRMS m/z 421.2100 (calcd for C22H3107N:
421.2100).
144
Me0
OMEM
(2S*)-2-[(3S*,3aS*,9aS*)-5-methoxy-3-[(2methoxyethoxy)methoxy]-1,3,3a,9a-tetrahydrophenanthro[4,5bcd]furan-9(2H)-y1FN-methylacetamide
(152).
To a
solution
of
triphenyl phosphine (10 mg, 0.0372 mmol) in THF (1 mL), maintained at -78
°C, a 1 M solution of bromine in CCI4 (347 mL, 0.0347 mmol) was added,
and the mixture was stirred for 30 min at -78 °C. To the mixture, a solution of
secondary alcohol 151 (10 mg, 0.0248 mmol) in THF (0.5 mL) was added,
and the reaction was stirred for 1h at -78 °C, and for 16 h at
room
temperature. Me0H (0.5 mL) was added, and the mixture was filtered over a
short column of silica gel. The obtained solution was concentrated under
reduced pressure, and the residue was chromatographed (5g of silica gel,
EtOAc- hexane, 6:1) to afford 9 g (84%) of 152 as colorless oil: IR (neat)
3355, 2920, 1660, 1504, 1440, 1279, 1162, 1132, 1059, 1025 cm-1; 1H NMR
(400 MHz, CDCI3) 8 0.88 - 0.99 (m, 1H), 1.31 - 1.41 (m, 1H), 1.75 - 1.83 (m,
2H), 2.22 (d, J = 14 Hz, 1H), 2.35 (d, J = 14 Hz, 1H), 2.76 (d, J = 4 Hz, 3H),
2.85
2.91 (m, 1H), 3.37 (s, 3H), 3.47 - 3.61 (m, 3H), 3.70 - 3.75 (m, 1H), 3.84
3.89 (m, 1H), 3.87 (s, 3H), 4.81 - 4.85 (m, 2H), 5.10 (d, J = 7.4 Hz, 1H), 5.33
(br s, 1H), 5.82 (dd, J = 5, 9 Hz, 1H), 6.38 (d, J = 9Hz, 1H), 6.62 (d, J = 8 Hz,
1H), 6.69 (d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCI3) 8 26.1, 26.4, 26.9,
145
37.9, 40.9, 45.7, 56.4, 59.1, 66.7, 71.9, 94.1, 94.9, 113.3, 117.7, 123.0, 123.4,
128.9, 130.6, 133.2, 144.6, 145.4, 171.3;
OMEM
(1R*,5R*,13S*,14S*,17S1-5-Hydroxy-10-methoxy-14-[(2methoxyethoxy)methoxy]-4-methy1-12-oxa-4-
azapentacyclo[9.6.1.01,1 3.05,17.070 8]octadeca-7(18),8,10trien-3-one (155). A mixture of amide 151 (10 mg, 0.024 mmol), DessMartin periodinane (13 mg, 0.31 mmol), and CHCI3 (5mL) was stirred for 5 h
at ambient temperature. To the mixture, a solution of Na2S203/NaHCO3 (5
mL, 50 g of Na2S2O3 in 200 mL of a saturated solution of NaHCO3) was
added, and stirring was continued for 15 min. The organic layer was
separated, washed with a saturated solution of NaCI, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Chromatography of the
residue (5g of silica gel, EtOAc -MeOH, 96:4) afforded 8 mg (78 %) of 155 as
a colorless oil: IR (neat) 3327, 2927, 1637, 1509, 1447, 1283, 1108, 1072,
1026 cm-1; 1H NMR (300 MHz, CDCI3) 5 0.92 - 1.05 (m, 1H), 1.18
1.33 (m,
1H), 1.97 - 2.02 (m, 2H), 2.10 (dd, J = 4, 12 Hz, 1H), 2.59 (d, J = 17 Hz, 1H),
2.67 (d, J = 17 Hz, 1H), 2.75 (d, J = 17 Hz, 1H), 2.95 (s, 3H), 3.08 (d, J = 17
Hz, 1H), 3.24 (s, 1H), 3.37 (s, 3H), 3.49 - 3.38 (m, 1H), 3.56 - 3.53 (m, 2H),
3.72 - 3.66 (m, 1H), 3.85
3.83 (m, 1H), 3.86 (s, 3H), 4.37 (d, J = 7 Hz, 1H),
3.86 (s, 3H), 4.37 (d, J = 7 Hz, 1H), 4.79 (s, 2H), 6.60 (d, J = 8 Hz, 1H), 6.74
146
(d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 5 14.4, 21.4, 24.7, 26.8, 27.2,
30.6, 33.1, 44.3, 44.9, 47.0, 56.8, 59.1, 60.6, 66.8, 71.9, 76.1, 88.7, 94.1, 94.6,
115.3, 120.9, 122.3, 129.6, 144.7, 144.9, 168.5; MS rn/z 419 (M +), 346, 314,
270, 257, 240, 229, 213, 89; HRMS m/z 419.1944 (calcd for C22H2907N:
419.1944).
MeO
OMEM
Methyl
(2S1-2-[(3S*,3aS*,9aS1-5-Methoxy-3-[(2-
methoxyethoxy)methoxy]-9-oxo-1,3,3a,8,9,9ahexahydrophenanthro[4,5-bcd]furan-9(2H)-yl]acetate (159). To a
solution of 139 (30 mg, 0.077 mmol) in a THE -H20 mixture (1:1, 10 mL),
LiOH -H20 (32 mg, 0.77 mmol) was added, and the mixture was stirred for 20
h at ambient temperature. The solution was cooled to 4 °C and neutralized
with an aqueous solution of HCI (5%). The product was extracted with
CH2Cl2 (4x 5 mL), and the combined organic extracts were washed with
water and a saturated solution of NaCI, and dried over anhydrous Na2SO4.
To the obtained solution maintained at 4°C, a 0.6 M solution of diazomethane
in diethylether (0.6 M, 5 mL) was added. The mixture was stirred for 15 min
and nitrogen gas was passed through the solution to remove excess
diazomethane. All volatiles were removed under reduced pressure, and the
obtained residue was dissolved in CHCI3 (10 mL) and treated with Dess-
147
Martin periodinane (49 mg, 0.12 mmol). The mixture was stirred for 1 h at
ambient temperature, and a solution of Na2S203/NaHCO3 (10 mL, 50 g of
Na2S2O3 in 200 mL of saturated NaHCO3) was added. Stirring was
continued for 20 min, and the organic layer was separated, washed with a
saturated solution of NaCI, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. Chromatography of the residue (7g of silica gel,
EtOAc- hexane, 1:2) afforded 26 mg (80 %) of 159 as a colorless oil: IR (neat)
2932, 2891, 1735, 1704, 1509, 1447, 1283, 1088, 1052, 1016 cm-1 ; 1H NMR
(300 MHz, CDCI3) 6 1.16 - 1.29 (m, 1H), 1.38 - 1.50 (m, 1H), 1.86
1.95 (m,
1H), 2.34 (d, J = 16 Hz, 1H), 2.71 (d, J = 16 Hz, 1H), 3.00 (dd, J = 6, 13 Hz,
1H), 3.37 (s, 3H), 3.58 - 3.46 (m, 5H), 3.77 - 3.67 (m, 4H), 3.87 - 3.81 (m, 1H),
3.89 (s, 3H), 4.85 - 4.80 (m, 2H), 4.90 (d, J = 7 Hz, 1H), 6.66 (d, J = 8 Hz, 1H),
6.80 (d, J = 8 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 24.7, 26.9, 38.4, 41.7,
47.7, 52.0, 52.4, 56.6, 59.1, 66.9, 71.9, 93.6, 94.3, 114.9, 120.3, 121.9, 128.7,
144.6, 145.2, 170.8, 210.9; MS m/z 420 (M+), 244, 315, 271, 241,213, 89;
HRMS tn/z 420.1782 (calcd for C22H2808: 420.1784).
148
A Unified Asymmetric Approach Toward Synthesis of
Polyhydroxylated Pyrrolizidine Alkaloids, Australine and
Alexine
Chapter V. Introduction
Castanospermum australe, a rainforest tree found
in
Queensland,
Australia, and Alexa leiopetala, a leguminous tree indigineous to Guyana,
Surinam, French Guiana, Venezuela, and the Amazon basin, are rich
sources of polyhydroxylated pyrrolizidine and indolizidine alkaloids. The
major alkaloidal component of these species is castanospermine (1),1,2 a
member of a family of powerful glycosidase inhibitors which includes
swainsonine (2), deoxynojirimycin (3), and DMDP(4).3
OHH
OH
HO
OH
H OH
-OH
HO,, ANN
N
HOHC
HO
OH
OH
1
2
3
,.CHOH
4
Castanospermine is a strong inhibitor of several glucosidases,4 including
mammalian intestinal sucrosidase and the glucosidase involved in lysomal
glycoprotein procession.5 In addition, the alkaloid has potential utility as an
inhibitor of replication of human immunodeficiency virus (HIV) and other
retroviruses. It is also reported to be efficient for suppression of tumor growth
and for treatment of malaria and diabetes.6
149
The wide variety of biological activities described for castanospermine
has drawn considerable interest toward other alkaloids present in the pods
and seeds of Castanospermum australe and Alexa leiopetala. Alexine (5),
isolated in 1987 from Alexa leiopetala,7 was the
first example of a
polyhydroxylated pyrrolizidine alkaloid with a C3 hydroxymethyl branch.
Subsequently, several structurally related alkaloids were isolated from
Castanospermum australe. These included 3,7a-diepialexine (6),8 7aepialexine (australine) (7),9 7,7a-diepialexine (8),10 and 1,7a-diepialexine
(9).10, 11 Recently, this family of compounds was enriched with a naturally
occurring pentahydroxy pyrrolizidine alkaloid, casuarine (10).12
HO H OH
HO
H
OH
HO
OH
H
...iOH
HO
....OH
HO
HO
6
5
7
HO H OH
HOHO
8
HO
9
10
Like castanospermine, the alexines are potent glycosidase inhibitors
although they appear to be more selective
in
their binding to specific
enzymes. For example, while alexine and 3,7a-diepialexine are only poor
inhibitors
of
mammalian
glucosidases,8
they
display
powerful
amyloglucosidase inhibition similar to castanospermine.10 Alexine was also
shown to be an effective thioglucosidase inhibitor.13 Australine is a specific
150
inhibitor
of
fungal
amyloglucosidase
and
glycoprotein
processing
glucosidase I. On the other hand, no significant inhibition of p-glucosidase, a-
and 13-mannosidase, or a- and 13-galactosidase was observed for this
compound.14 1,7a-Diepialexine showed only modest glucosidase
I,
0-
glucosidase, and a-mannosidase inhibition but, like 7,7a-diepialexine, it
displayed strong activity in a mouse gut digestive a-glucosidase assay.11
Recently,
it
has been shown that australine, 1,7a-diepialexine, 7,7a-
diepialexine and casuarine all inhibit HIV-induced synostia formation in JM
cels.10, 11 This promising lead in AIDS research is being actively pursued.
Structural assignments to alexine,7 australine,9 3,7a-diepialexine8 and
casuarine12 were made by X-ray crystallographic analysis. Comparison of
3JH,H coupling constants in most of these structures showed characteristic
patterns which could be correlated with the configuration and conformation of
these molecules. However, the NMR data for australine as reported by
Molyneux, did not fit these spectral trends and thus prevented the formulation
of more general rules which could be used for structural assignments to other
members of this class of compounds. Although the anomalies were originally
explained by a conformational change in australine, further evaluation cast
doubt on the authenticity of the published data for this alkaloid.15
This
placed the structural assignments to 1,7a-diepialexine and 7,7a-diepialexine
in question since these were made exclusively on the basis of NMR data.
Thus the configuration of 8 and 9 necesarily awaited further confirmation. It
was these structural ambiguities which, in part, motivated synthetic research
in
this area and which resulted
compounds.
in
several total syntheses of these
151
The first synthetic approach towards australine was reported
by
Pearson.16 The underlying strategy involved intramolecular opening of
epoxide followed by intramolecular alkylation, and readily afforded the
pyrrolizidine framework (Scheme 1).
TsCc
EtOH
K2CO3, Me0H
C-N H2
H
Scheme 1
Application
of this
strategy to synthesis
of the polyhydroxylated
pyrrolizidine australine required preparation of a more oxygenated precursor
(Scheme 2). This was accomplished by utilization of 2,3,5-tri-O-benzyl-Lxylofuranose (11), prepared in three steps from L-xylose. Wittig reaction of
11 afforded the olefin 12, which was transformed to the azide 13 with
configurational inversion. Oxidative truncation of the terminal olefin 13
followed by Wittig reaction of the resultant aldehyde 14 gave the desired cis
olefin 15. Epoxidation of 15 afforded a 1:1 mixture of the epoxides 16 which
was inseparable.
152
Ph3P=CH2
Bn0
BnO,
Tf2O; Bu4N N3
66 %
75 %
B
BnO
11
BnQ
BnO "'
N3
Bn0
12
13
03
OH
OH
BnQ,,
BnQ
m-CPBA
Ph3P(CH2)30H
BnO
Bn0
KHMDS
65 %
Bn0--1
35 %
from 13
Bn02
14
15
Scheme 2
Tosylation of the primary alcohol and reduction of the azide functionality
set the stage for the tandem cyclization, which was found to give a mixture of
two isomeric pyrrolizidines 17 and 18. It was expected that, after cleavage of
the benzyl protecting groups, the NMR data of one of these compounds
should match the spectral data for authentic australine (7). However, data
supplied to Pearson for material believed to be the natural australine did not
match those of either of the two products. In fact, Pearson's spectra of
compounds obtained from 17 and 18 after cleavage of the benzyl groups
were identical to those of 7-epialexine (19) and 7,7a-diepyalexine (8). In
view of the fact that the australine structure had been determined by X-ray
crystallographic analysis,
Pearson concluded
that an
unprecedented
epimerization had occurred in the course of the final steps of the synthesis,
thus thwarting his planned approach to australine. As subsequent events
153
have shown, Pearson's synthesis did indeed lead to australine. The mistaken
identities of 7 and 8 by the Oxford group resulted in an unfortunate set of
circumstances which misled not only Pearson but others as well.
OH
1. TsCI
2. Pd/C, H2
3. K2CO3, EtOH
16
17
18
Pd/C, H2, 87 %
HO H OH
HO H OH
'"OH
HO
7
--OH
HO
8
19
Scheme 3
A synthesis of 1,7a-diepialexine (9) has been accomplished by Fleet
starting from bisacetonide 20 (Scheme 4).17 The latter is available in
several steps from L-gluconolactone. The lactone 20 was transformed into
nitrile 21 in several straightforward steps, and the latter was advanced to the
tricyclic lactam 22 by hydrolysis of the cyano group and subsequent
cylization. At this point, the configuration of the C7 hydroxyl group was
inverted by an oxidation-reduction sequence to afford the stereoisomeric
alcohol 23. Lactam 23 was reduced and deprotected to furnish 1,7a-
154
diepialexine (9), which in every respect matched an authentic sample of this
compound.
H PH
NH4CI
NH3,EtOH
60 %
20
TBDPSO---
21
22.
1. PCC
2. NaPH4
CF3CO2H
BH3
-4(
43 %
94 %
TBDPSO----
9
TBDPSO--23
Scheme 4
Subsequent to Pearson's work, a short sequence transforming natural
castanospermine (1) to australine (7) was developed by Tyler (Scheme
5).18 The route involved an unusual ring contraction of an indolizidine
skeleton to 3-hydroxymethylpyrrolizidine. This process possibly mimics
interconversion of castanospermine and its derivatives to the corresponding
C3-branched polyhydroxylated pyrrolizidines.
In Tyler's synthesis of australine, castanospermine was first transformed
into its triacetate 24. Exposure of 24 to trifluoromethanesulfonic anhydride
gave initially an aziridine, which upon exposure to benzyl alcohol produced
the pyrrolizidine 25. Deprotection of 25 gave australine, which according to
155
the author matched an authentic sample, although it must be pointed out that
the NMR data for the synthetic material were reported for the trifluoromethane
sulfonate salt.
OH
HO
OH
OH
1. Bu3Sn)20
BnOCOCI
2. Ac20
3. Pd/C
64%
1
OAc
AcO
,,OAc
NOH
24
1. Tf20
2. BnOH
AcO H
OAc
1. H2, Pd/C
OAc
2. liq. NH3
35%
from 24
7
B
25
Scheme 5
Very recently, Denmark accomplished a synthesis of 7,7a-diepialexine
(8).19 Athough the experimental details of this synthesis await publication,
Denmark concluded that his material was not identical with the sample of
7,7a-diepialexine described by Nash.
The synthetic studies outlined above suggest that while the structure of
1,7a-diepialexine is assigned correctly, that of 7,7a-diepialexine is not.
It
could be surmised, based on the results of Pearson, that the data assigned to
7,7a-diepialexine belong to australine, but unfortunately, the nature of
Pearson's synthesis does not allow unambiguous structural interpretation.
156
This leaves the X-ray crystal structure of australine and the synthetic
correlation with castanospermine reported by Tyler as the only firm
indications of the structure of this pyrrolizidine alkaloid.
157
Chapter VI. Results and Discussion
6.1. Retrosynthetic Analysis
The primary goal of our study directed toward asymmetric synthesis of
alexine (5) and 7-epialexine (australine 7) was to develop a sequence which
would afford these compounds in a concise and flexible manner and would
be adaptable to the synthesis of other members of this class of compounds. A
very important aspect of the present research was to prepare these alkaloids
without
structural
ambiguity
in
order
to
permit
verification
of
the
stereochemical assignments described in the literature.1 -12
HO
11.1
OH
HO H OH
-OH
-OH
HO
5
7
The transannular cyclization of cyclooctane derivatives has excellent
synthetic potential as a strategy for assembling a bicyclo[3,3,0]octane
framework.20 Most of the examples of this reaction described in the literature
are based upon an acid-catalyzed transannular electrophilic addition to a
conveniently situated double bond or to some other structural moiety that is
able to accommodate electrophilic attack. These reactions are usually
initiated by exposure of an electron rich double bond or epoxide to a
Bronsted or Lewis acid. The major complication which often arises in these
reactions is the low stability of the initially formed bicylic carbocation which
158
can undergo a variety of transformations, including 1,2-hydride shift, Wagner-
-Meerwein rearrangement, elimination, or nucleophilic attack to form a wide
spectrum of structurally diverse compounds (Scheme 6).
W-M
Nu"
elimination
1,2-shift
H
101.
Scheme 6
From the viewpoint of a synthesis of australine and alexine, an
electrophilic transannular cyclization would be prohibited by the strong
basicity of the nitrogen atom. However, nucleophilic transannular opening of
an epoxide by the nitrogen atom of a cyclooctane affords an attractive entry to
the pyrrolizidine nucleus since this would, in a single synthetic step, establish
the configuration of the bridging C7a carbon and the adjacent carbon
bearing the newly formed hydroxyl group (Scheme 7).21 In addition, the
nucleophilic modification of this reaction
would exclude formation of
undesired sideproducts. This dramatically increases the predictability of the
transformation.
159
0
/L\
1)N
26
Scheme 7
For successful application of the transannular cyclization strategy, a
reliable means for control of the epoxide configuration is necessary. In
addition, the epoxidation step requires that the nitrogen atom be protected
with a functional group subsequently removable without destroying the labile
oxirane ring. Another prerequisite for success in this approach would be
sufficient conformational freedom of the eight-membered cycle to allow
effective transannular orbital interaction. In this respect, the epoxide 26
would not impose a higher conformational rigidity than, for example, olefin
27. The latter has been shown to undergo facile transannular cyclization
(Scheme 8).22
Na2CO3
aq. dioxane
OMs
12h, 60 °C
75%
C9OH
27
Scheme 8
Utilization of this strategy for the synthesis of australine (7) and alexine
(5) required preparation of the more highly functionalized precursors 28 and
160
29. These were expected to arise from the corresponding olefins by
stereoselective epoxidation.
H OH
HO
-OH
HO
7
HO H OH
...OH
HO
29
5
Scheme 9
A cursory inspection of cyclooctene shows that the eight-membered ring
presents a significant steric bias towards one of the two faces of a double
bond inscribed within the ring (Scheme 10).
oxidation
Scheme 10
Therefore, it could be anticipated that a. cyclooctene derivative which exists
as a single stable conformer should allow for a highly stereoselective
epoxidation in a predictive manner. Although it would be difficult to apply
161
such a strategy to stereocontrolled epoxidation of an unsubstituted
azacycloctene, the substitution needed in synthetic precursors to australine
and alexine, 30 and 31 respectively, could exist in a preferred conformation
and thus could afford a stereoselective substrate-controlled epoxidation. An
analogous approach to prediction of the stereoselectivity in epoxidation of
larger cycles was developed by Still23 and was later utilized in several
synthetic studies.24
R04/"\,s0R
RiN
NRi
RO
30
OR
31
Comprehensive molecular modeling was conducted to determine the
most suitable combination of protecting groups in 30 and 31 in order to
obtain substrates of a single conformation which would result in epoxidation
from the desired face. Clearly, an axially oriented substituent on the eight-
membered ring encounters a severe steric interaction, causing a large
increase of energy for such a conformation. An apparent advantage
possessed by the australine and alexine precursors is that their substitution
pattern allows all the substituents attached to the ring to adopt an equatorial
orientation. To reinforce this orientation, the nitrogen atom and the adjacent
hydroxymethyl functionality were linked as cyclic carbamates 30a and 31a.
The optimized geometries of these structures indicated that the equatorial
disposition of the allylic hydroxyl groups exposes the opposite face of the
adjacent double bond to electrophilic attack by the oxidizing agent (Figure
162
6.1, Figure 6.2). In both 30a and 31a this would result in epoxidation from
the desired face.
30a
Figure 6.1. AM1-Optimized Geometry for Carbamate 30a
RO,/=\ ,OR
Figure 6.1. AM1-Optimized Geometry for Carbamate 31a
163
Ring-closing metathesis (RCM)25 has been established as a powerful
tool for synthesis of cyclic olefins of various sizes, although application of this
strategy to the constriction of eight-membered rings has met with only
moderate success.26 According to studies published by Grubbs, RCM can be
employed for the synthesis of eight-membered rings if a satisfactory
conformational restriction is introduced into the acyclic precursor. The best
results were achieved when the pair of terminal olefins were attached
through a tether of an appropriate size to a cyclohexene ring in a trans
fashion. For example, RCM of the cyclohexene derivative 32 proceeded
rapidly and gave 75 % of the desired epoxide 33 (Scheme 11).
PCy3
CI
I ___
/Ph
'Ru--
CI'
TESO
PCy3
benzene, r.t.
75 %
32
33
Scheme 11
It was hoped that the cyclic carbamates 34 and 35, would adopt
prefered conformations which would facilitate RCM. Although deprotection of
these oxazolidinones without destruction of an epoxide could pose a
complication, the sequences envisioned could be easily modified by
exchange of the protecting groups at a later stage of the synthesis.
164
RO) ILOR
35)r°
0
34
A further attribute of 34 and 35 is that utilization of these cyclic carbamates
provides a very convenient link to a pathway developed by Kishi for
construction of various 1,2-amino alcohols.27 Kishi's approach is based
upon intramolecular epoxide opening by an anion of carbamate 36 to afford
the
oxazolidone 37.
The advantage
of this
strategy
that
is
the
stereochemistry of the resulting 1,2-aminol is controlled by the configuration
of the epoxide. The latter
is established
by
Sharpless
epoxidation28 at an initial stage of the synthesis.
It
asymmetric
clear that
is
straightforward modification of the sequence would provide access to other
stereoisomers of 34 and 35 and hence to other members of the alexine
family.
H
O
OH
37
N Bn
42
Scheme 12
165
Based on the above considerations, a scheme was designed for a
unified approach towards australine and the alexine alkaloids. In the initial
version, it was planned that the carbamate 37 obtained by application of
Kishi's methodology would be transformed into the primary alcohol 38,
which, in turn, would be a convenient precursor to each individual alkaloid.
Construction of 38, and
its further transformation
to the pyrrolizidine
alkaloids, australine and deoxyalexine, are described in the following
chapters
.0H
HO
5
HO H OH
"OH
HO
7
Scheme 13
166
6.2. Synthesis of Carbamate 38, the Precursor to Alexine and
Australine Alkaloids.
The strategy for synthesis of alexine and australine envisioned primary
alcohol 38 as the key intermediate. This structure was expected to arise from
carbamate 37, which in turn was to originate from acyclic carbamate 36.
The synthesis of 37 started from 1,2:5,6-di-O-isopropylidene-D-
mannitol (39), which was oxidatively truncated with sodium periodate
(Scheme 14). The resulting isopropylidene-D-glycerol was subjected to a
Horner-Emmons reaction to give the desired E olefin 40 along with the Z
isomer in a 48:1 ratio. Diisobutylaluminum hydride (DIBAL) reduction of 4 0
gave the allylic alcohol 4029 which was transformed to the corresponding
epoxide 41 by Sharpless asymmetric epoxidation.27
/
1. Na104
0
2. K2CO3,
(EtO)2P(0)CH2CO2Et
89 %
40
DIBAL, CH2Cl2,
-78 °C, 88 %
0
°JL1>\°H
41
DIPT, TBHP, Ti(Oi -Pr)4
-30 °C, CH2Cl2
61%
Scheme 14
/00H
0
167
The resulting epoxy alcohol was treated with benzyl isocyanate to yield
the carbamate 42, exposure of which to potassium tert-butoxide triggered
intramolecular epoxide opening and gave the secondary alcohol 3 7
(Scheme 15).
t-BuOK
THE
84 %
42
Scheme 15
Further transformation of 37 to the primary alcohol 38 required
cleavage of the acetonide and differentiation of the primary from the two
secondary hydroxyl groups. To circumvent excessive protective group
manipulation,
an acid-catalyzed
isomerization
of acetonide
37
was
employed to liberate the corresponding primary alcohol in a single synthetic
step. The driving force for this isomerization is believed to be formation of a
more substituted five-membered ring; it proceeds only in the case where the
two secondary hydroxyl groups have a 1,2-syn-relationship. For example,
exposure of 43 to an acidic catalyst results in fast isomerization to the
primary alcohol 44, whereas the isomeric structure 45 does not undergo a
chemical change under analogous conditions (Scheme 16).30
168
OH
OH
H+
43
OH
44
H+
OH
0-7c
45
Scheme 16
The carbamate 37 possesses the required 1,2-syn configuration of the
two internal secondary hydroxyl groups, and therefore appeared to be a
suitable substrate for the isomerization process. Indeed, when the acetonide
46a (37) was exposed to Amberlyst resin in dry acetone, rapid equilibration
occurred and resulted in a mixture of the desired primary alcohol 47a and
the starting carbamate in a 2:1 ratio (Scheme 17). These two compounds
were readily separated by column chromatography, and the recovered
starting material was reequilibrated.
OH
Amberlyst 15
acetone
47a-c
Scheme 17
169
R in 46
46 : 47
Benzyl (a)
1 :
2
Ally' (b)
1 :
2
H (c)
1 :
7
Table 6.1: The Influence of the R Substituent on the Ratio of
Carbamates 46 and 47
In order to optimize the proportion of the primary alcohol 47 in the
equilibration step, we investigated replacement of the benzyl group with a
sterically less demanding ally' substituent. This was accomplished by
exposure of epoxy alcohol 41 to commercially available allyl isocyanate to
afford the corresponding carbamate 48 (Scheme 18). Unfortunately, this
change of protecting group did not improve the ratio of 46:47 and again
produced only a 2 : 1 mixture of the product and starting material.
0
NCO
°J4>\C)H
41
i-Pr2NEt, 60 °C
98 %
0
OjLi>0y0
48
t-BuOK, THF, 92 %
46b
Scheme 18
170
Apparently, the substituent attached to the nitrogen atom must tolerate
steric interaction with the neighboring hydroxymethyl group, and on this basis
it was surmised that complete removal of the protecting group from nitrogen
would result in a more favorable ratio from the equilibration process.
Treatment of the N-benzyl carbamate with sodium metal in liquid ammonia31
gave the deprotected carbamate 49, and as expected, exposure of 49 to
Amberlyst resin in dry acetone produced a mixture of the primary alcohol and
the starting compound in a much improved 7:1 ratio, respectively. The two
isomeric carbamates were not separable by column chromatography,
however, and it was therefore decided ito proceed with the readily purified
benzylcarbamate 47a.
Na, NH3
0
-78 °C
85 %
49
Scheme 19
171
6.3. Approach toward Australine
In the synthetic approach towards australine, the cyclooctene derivative
51 was expected to originate from the diene 50, which, in turn, was to arise
from the primary alcohol 47a (Scheme 20). It was predicted on the basis of
molecular modeling that formation of epoxide 52 should proceed with the
desired stereoselectivity. In the key step, we anticipated that removal of the
carbamate protecting group would liberate the secondary amine without
destruction of the epoxide which would then trigger an instantaneous
transannular cyclization. In the event that selective removal of the carbamate
presented a complication, an exchange of the protecting group could be
incorporated into the plan.
HO H OH
P.
\OR
CNfOR
000
-OH
HO
7
52
OH
c0\/
0
Bnsrc'0
0
0
47a
,01(
50
Scheme 20
51
172
The sequence began with transformation of the primary alcohol 47a to the
terminal olefin 53 (Scheme 21). This was accomplished by oxidation of the
primary alcohol under Swern conditions32 and Wittig olefination of the
resulting aldehyde with triphenylphosphonium methylide, generated from
methyltriphenyl-phosphonium
bis(trimethylsilyl)amide.33
bromide
The
next
and
transformation
potassium
required
selective
removal of a benzyl group and its replacement with a 3-butenyl substituent.
Reductive removal of the benzyl group was accomplished under Birch
conditions, but cleavage of the acetonide with concomitant migration of the
double bond also occurred, resulting in allylic alcohol 54 as the major
product of the reaction.31
OH
0
NO
DMSO, (COCI)2; Et3N
74 %
47a
Bn,
0
00
Ph3P=CH2, THF,
64%
Na, NH3
-78 °C
66 %
Scheme 21
173
This outcome prompted us to attempt removal of the benzyl substituent prior
to installment of the terminal olefin, a transformation which was accomplished
by treatment of the carbamate 47a with sodium in liquid ammonia (Scheme
22). However, oxidation of the resulting primary alcohol 55 proved to be
surprisingly difficult and none of the desired aldehyde 56 was produced.
OH
c0
Bn,
0
OH
O
Na, NH3
oxidation
-78 °C
00
47a
76%
HN
00
55
00
56
Scheme 22
It was clear from these results that the butenyl substituent had to be
incorporated prior to any manipulation of the primary alcohol. The most
attractive means for accomplishing this was to replace benzyl isocyanate with
3-butenylisocyanate in the reaction with epoxide 41 (Scheme 23). That
modification of the sequence would have the advantage of eliminating the
two steps required for the benzyl group exchange. 3-Butenylisocyanate was
prepared from 4-pentenoic acid (57) by Curtius rearrangement of the
corresponding acyl azide, which was prepared by treatment of 57 with
diphenylphosphoryl azide (DPPA). The resulting 3-butenylisocyanate was
trapped in situ with the epoxy alcohol 41 to give the carbamate 58. The
latter, upon exposure to potassium tent-butoxide, yielded the cyclic carbamate
59.
174
1. DPPA, Et3N; A
CO2H
57
240
0 .)Q-0
-4-0
0
.,OH
41
92 %
1200
0_
\/'\NH
KOt-Bu
89 %
0
58
Scheme 23
Acid-catalyzed equilibration
of carbamate 59
using
Amberlyst
resin
produced the desired primary alcohol 60, again as a 2:1 mixture with the
starting acetonide (Scheme 24). The isomers were readily separated by
column chromatography, and oxidation of the primary alcohol under Swern
conditions gave the corresponding aldehyde 61. The latter, after purification
was immediately subjected to conditions of a Wittig olefination with
triphenylphosphonium methylide to afford the desired diene 50.
175
NOH
Amberlyst 15
62 %
59
DMSO, (COCI)2;
Et3N, 90
Ph3P=CH2
74%
50
61
Scheme 24
Molecular modeling had suggested that the cyclic acetal and the
carbamate attached to 50 would impose sufficient conformational restriction
to facilitate the RCM.26 Indeed, RCM of 50, using Grubbs' catalyst 102,
proceeded rapidly and afforded the desired eight-membered cycle 51 in
virtually quantitative yield (Scheme 25). This result further supports the
observations of Grubbs regarding
immobilization of RCM precursors.
the
importance
of conformational
176
CI , CY3 Ph
Ru
<0
CI
PCy3
102
,
HC 2C12
97 %
0
0
50
51
Scheme 25
With the cyclic olefin 51 in hand, we began considering its final
elaboration to australine. First, we needed to verify whether our predictions
about the selectivity of epoxidation were correct. In fact, when the azacyclooctene 51 was treated with meta-chloroperbenzoic acid (m-CPBA)36 it
afforded the epoxide 62 as a single isomer (Scheme 26). An X-ray
crystallographic analysis of 62 confirmed the expected configuration of the
oxirane ring (Figure 6.3.).
m-CPBA
82 %
51
62
Scheme 26
177
Figure 6.3. ORTEP Representation From X-Ray Structure of 62.
It was concluded from these results that cleavage of the 1,3-dioxolane would
be mandatory prior to transannular cyclization. However, the acetonide
proved to be more stable than expected, and initial efforts for its selective
removal in the presence of the oxirane ring failed. In fact, the only condition
found for its cleavage was exposure to concentrated aqueous hydrobromic
acid, and application of these conditions to olefin 51 gave the desired diol
63. Upon exposure to m-CPBA 63 gave epoxide 64 as a single isomer
(Scheme 27). Although it was impossible to obtain crystals of 64 suitable
for X-ray analysis, molecular modeling confirmed that removal of the
acetonide should not result in a change of conformation of the eight-
178
membered cycle. For this reason, the configuration of the epoxide in 64 was
assigned in analogy to that of 62.
HBr
CH3CN
99 %
63
m-CPBA, CH2Cl2,
82%
O
EtONa
Et OH, A
7
\N_,'""OH
64
Scheme 27
Unfortunately, carbamate 64 was unreactive towards hydrolysis under a
variety of conditions, including treatment with sodium ethoxide, sodium
hydroxide, and sodium thiopropoxyde. On the other hand, carbamate 51 was
readly cleaved when treated with sodium ethoxide in ethyl alcohol at an
elevated temperature (Scheme 28).
179
0
/-------7N...0
Na0Et
\N---(°
Et0H, A
0)
--7---\...0v
1\-IN-07\
95 %
HO
51
Scheme 28
It appeared likely that the presence of alkyl substituents on the
secondary hydroxyl groups would indirectly facilitate cleavage of the
carbamate. It was therefore decided to modify the eight-membered epoxide
by attaching benzyl substituents to the pair of vicinal hydroxyl groups in the
belief that this would afford a substrate more amenable to carbamate
cleavage and subsequent transannular reaction.
Benzyl substituents were introduced by deprotonation of diol 63 with
sodium hydride and subsequent treatment with benzyl bromide in the
presence of tetra-n-butylammonium iodide (Scheme 29).37 Epoxidation of
the resulting dibenzyl ether afforded epoxide 66 as a single isomer with the
correct configuration as established by X-ray crystallographic analysis
(Figure 6.4.).
OH
OBn
NaH, BnBr
TBAI, THF, A
m-CPBA
75%
84%
63
65
Scheme 29
66
180
Figure 6.4. ORTEP Representation From X-Ray Structure of 66.
Exposure of epoxide 66 to sodium ethoxide at elevated temperature resulted
in cleavage of the carbamate and produced a mixture of two principal
components of increased polarity (Scheme 30). Neither of these
compounds contained an epoxide ring, and in each case it was inferred by
determining the exact mass of the two isomers that intramolecular
displacement had occured. It was observed that the relative ratio of these two
181
compounds was directly proportional to the concentration of base used for
cleavage of the carbamate. The component favored by lower concentration of
the base was assigned as the di-O-benzyl australine (67) and the isomeric
compound was presumed to be derived by deprotonation of the newly
formed primary alcohol and transannular attack by the alkoxide on the
epoxide ring. The structure of the side product was assigned as 68, based on
1H COSY spectra and correlation of observed proton chemical shifts with
estimated shifts of the critical hydrogen atoms.
OH
EtONa
EtOH, A
62%
66
67
68
Scheme 30
It was clear from this result that a milder base would be required to suppress
formation of the undesired side product 68 from its precursor 66. Indeed,
when epoxide 66 was treated with aqueous lithium hydroxide, di-O-benzyl
australine (67) was produced as a single isomer in quantitative yield
(Scheme 31). Final removal of the benzyl groups was achieved cleanly by
catalytic hydrogenolysis using hydrogen gas over Pearlman's catalyst, and
resulted in a quantitative yield of australine alkaloid. The synthesized
alkaloid matched the authentic sample by comparison of optical rotation, and
1H and 13C NMR spectra.
182
O
i-\..-0Bn
\N___"'"OBn
0'0
66
HO H OBn
LiOH
HO H OH
Pd(OH)2/C, H2
...0Bn
EtOH -H20
100%
100 %
67
Scheme 31
....OH
Me0H, r.t.
HO
7
183
6.4. Approach Toward Alexine
In the approach towards alexine 5, the key intermediate was azacyclooctene 69, which was expected to arise by coupling of fragments 7 0
and 71, with subsequent RCM of the resultant diene (Scheme 32).
Epoxidation of 69 was predicted to occur from the front face, and it was
assumed that the resultant epoxide would undergo transannular cyclization
after cleavage of the cyclic carbamate along lines analogous to those
employed successfully in the australine synthesis.
RO,,/7K,OR
RO,,
....OH
HN
0
70
5
71
Scheme 32
The plan for preparation of 71 was patterned on the reductive
fragmentation
of
13-alkoxy
halides
developed
by
Ireland.38
This
transformation involves reductive cleavage of a halide to generate a
carbanion which triggers elimination of an alkoxide from the adjacent carbon
to produce an olefin. With this approach in mind, the primary alcohol 47a
was transformed to the corresponding chloride 72
by exposure to the
hexamethylphosphorous triamide-carbon tetrachloride complex (Scheme
33).39
184
CI
HMPT-CCI4
-78 -> 60°C
83%
47a
72
Na, NH3
-78 °C
6'1 0/0
HN_,cOH
0
74
73
Scheme 33
It was hoped that under Birch conditions, reductive elimination of the
acetonide and removal of the benzyl substituent could be accomplished in a
single step and in fact, treatment of 72 with sodium in liquid ammonia
produced the desired carbamate 73 in 61 % yield. The only competing
process that occurred during this transformation was transfer of the benzyl
substituent from the nitrogen atom to the newly formed carboanion prior to
the fragmentation process to afford acetonide 74 in 25 % yield. The ratio of
73 to 74 very likely corresponds to the relative rates at which the benzyl
group and the chlorine atom are removed. When the carbanion is generated
with the benzyl group still present on the nitrogen atom, intramolecular
benzyl transfer is a faster process than extrusion of acetone (Scheme 34).
185
73
74
Scheme 34
The remaining step in the construction of fragment 71 was selective
protection of the allylic secondary alcohol in the presence of the carbamate
moiety. Initial attempts to introduce a protecting group at the secondary
hydroxyl group led to competitive substitution at the nitrogen atom. For
example,
treatment
of
73
with
tert-butyldimethylsilyl
trifluoromethanesulfonate in the presence of 2,6-lutidine,40 acylation with an
equimolar amount of benzoyl chloride,
trichloroacetimidate
under
acidic
treatment with benzyl 2,2,2-
conditions,41
and
alkylation
with
chloromethyl methoxymethyl ether in the presence of a Hunig base were all
unsuccessful.42
Finally,
we
found
that
treatment
of
73
with
dimethoxymethane in the presence of phosphorous pentoxide43 introduced
the methoxymethyl protecting group on the hydroxyl substituent at a
significantly faster rate and afforded 85% of the desired MOM-ether 75
(Scheme 35).
186
"OH
(MeO)2CH2
HN
P205
75 %
'OMOM
)'"
OHO
73
75
Scheme 35
For construction of fragment 70, natural L-malic acid 76 was selected
as a suitable precursor. The transformation of 76 to 4-pentene-1,3-diol with a
benzyloxymethyl (BOM) protecting group on the secondary alcohol has been
described previously in the literature.44, 45 For our purposes, a different
protecting group was required such as a para-methoxybenzyl (PMB), tetbutyl-dimethylsilyl (TBDMS), or methoxymethyl (MOM) substituent, in order to
facilitate removal at a late stage of the synthesis.
L-Malic acid was first protected as
its isopropylidene
acetal 7 7
(Scheme 36). This was accomplished with 2,2-dimethoxypropane in the
presence of camphorsulphonic acid (CSA). Selective reduction of the free
carboxyl group in 77 was carried out with borane-tetrahydrofuran (BH3-THF)
complex according to Brown's procedure46 to afford the primary alcohol 78.
Upon exposure to CSA 78 cyclized to the desired 2-hydroxybutyrolactone
(79).
187
0
OH
HO
O
6F1
(MeO)2CMe2
CSA
85 %
76
BH3-THF
0
HO,
TsOH
OH
0
CHCI3
72%
79
from 77
78
Scheme 36
The butyrolactone 79 was protected as its TBDMS ether 80, by treatment
with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of 2,6-
lutidine (Scheme 37) and subsequent transformation of 80 to the lactol 81
was accomplished by reduction with diisobutylaluminum hydride (DIBAL) at
low temperature. However, attempts to carry out a Wittig reaction with 81
resulted in rapid cleavage of the TBDMS group. This can be explained by
migration of the silyl group to the newly formed primary alkoxide and its
subsequent cleavage.
188
0
ff
HO,
TBSTf
2,6-lutidine
TBSO,
OH
DIBAL
0
\sos
99%
79
0
63 %
80
81
n-BuLi
HO,
OH
TBDMS0,
TBDMS0
)
'
0
Scheme 37
Fortunately, the methoxymethyl protected lactone 82 prepared by treatment
of 79 with dimethoxymethane in the presence of phosphorous pentoxide,
proved to be a more compliant substrate for synthesis of fragment 7 0
(Scheme 38). Lactone 82 was readily transformed to 3-0-methoxymethy1-
4-pentene-1,3-diol (84) by DIBAL reduction and Wittig olefination of the
resulting lactol 83. Finally, the primary alcohol was transformed to the
corresponding toluenesulfonate 85 for the purpose of coupling with 71.
189
HO
(MeO)2CH2
P2O5
79
96 %
82
DIBAL, CH2Cl2,
76%
MOMO,,/
Ph3P=CH2
60%
\OH
83
84 = H
TsCI,
Et3N, DMAP
92%
85 = 02S061-140H3(P)
Scheme 38
The coupling of fragments 75 and 85 was accomplished in the
presence of sodium hydride and a catalytic amount of tetra-n-butylammonium
iodide (TBAI) in benzene at elevated temperature and afforded the diene 86
in good yield (Scheme 39).
MOMO,,/
MOTs
85
NaH, TBAI
0()
84 %
75
MOMO,,)
sOMOM
\--N
86
0
Scheme 39
However, diene 86 failed to produce any trace of the desired eightmembered ring upon exposure to Grubbs' catalyst 102 either at room
190
temperature or upon heating. Equally unsuccessful were attempts to carry out
RCM of the diol 87.
I
HBr, CH3CN
HO.,,,/
I
\.0F1
96%
0
87
Scheme 40
There are several factors that have a critical impact on the outcome of
the RCM. According to Grubbs' observations, the cyclization is a reversible
process, and the degree of conversion in this reaction depends on the
thermodynamic stability of the cyclic product.26 It was also sudgested that
functional groups capable of complexing the metal in the vicinity of the
double bond can retard the methatesis process.47 To assess whether either
of these factors is responsible for failure of RCM in the case of 86 and 87, a
modified diene 88 was constructed which possessed greater conformational
restriction than the previous substrates. In analogy to RCM of 50 we
supposed that the cyclic acetal present in 88 could enhance the prospects
for ring closure.
191
,Ph
88
The synthesis of 88 started from carbamate 73, which was transformed
to the diol 89 by treatment with di-O-tert-butylcarbonate and subsequent
hydrolysis with sodium ethoxide at room temperature. The resulting diol was
then protected as a benzylidene acetal 90.
,OBoc
(BocO)2C =O
Et3N
H
0
c
BocN
--.0
93 %
0
73
EtONa,
EtOH, 72 %
PhCH(OMe)2
BocN°
96 %a
1
H
\ s.OH
BocNOH
HI
90
89
Scheme 41
The construction of 88 began from 3-0-para-methoxybenzy1-4-pentene-1,3diol 91, which was prepared from L-malic acid by an analogous sequence to
192
that used for 84. For the coupling of fragments it was necessary to convert 91
to the corresponding trifluoromethanesulfonate 92 in order to achieve
reaction with the bulky carbamate 90 (Scheme 42). In spite of the structural
modification made to 93, however this substrate proved to be equally
unreactive when exposed to Grubbs' catalyst (Scheme 43).
NH
PMB'OACC13,
92%
O v0
CSA
PMBO'
79
PMBOJ
)
FOR
04-26
Tf20,
Et3N
95 %
R=H
91
R = Tf
92
Scheme 42
NaH, TBAI, 92
PMBO
\N
O
BOON
Ph
82 %
90
93
s's
0
BOO
102
PMBO
Scheme 43
This result leaves open the possibility that the ally' substituents adjacent to
the double bond retard the metathesis either by steric interaction with the
193
catalyst or, more likely, by complexation with the metal atom. To test this
hypothesis, a diene analogous to 86 was prepared with only one allylic
substituent. This substituent was placed on the carbamate side of the diene.
Replacing 84 with comercially available 4-pentenol 94, provided rapid
access to this substrate. The alcohol 94 was transformed to tosylate 94a
which was coupled with 75 in the presence of sodium hydride and
tetrabutylammonium iodide. The resulting diene 95 in the presence of a
Grubbs
catalyst
at elevated
temperature
afforded
the
correspondig
azacyclooctene 96 in a good 75% yield (Scheme 44).
\--OR
TsCI, Et3N,
DMAP
99%
94
94a
°MOM
0
75
R=H
R = Ts
NaH, TBAI
THF, A
70 %
sOMOM
PCy3ph
CI, Flu=x
CI- PCy3
0
75%
96
95
Scheme 44
It can be concluded from the foregoing results that for initation of RCM at least
one of the terminal olefins must be without an allylic alkoxy or hydroxy
substituent. Presumably, the metathesis process starts, at this double bond
194
and is not significantly influenced by the character of substitution in the
vicinity of the second olefin.
With the azacyclooctene 96 in hand, it become feasible to carry out a
synthesis of 7-deoxyalexine 97. This substance is believed to be a naturally
occurring alkaloid of Castanospermum australe and Alexa leiopetala.48 For
this purpose, the methoxymethyl protecting group in 96 was removed with
aqueous hydrobromic acid in acetonitrile to afford the secondary alcohol 98.
Epoxidation
98
of
with
meta-chloroperbenzoic
acid
afforded
the
corresponding epoxide 99 as a single isomer. It was not possible to obtain
suitable crystals of this compound for X-ray analysis, and therefore the
configuration of the epoxide was initially assumed to be as shown on the
basis of molecular modeling. As with 64, however, exposure of epoxide 99
to aqueous lithium hydroxide at elevated temperature produced no reaction.
98
96
m-CPBA, CH2Cl2,
78 %
LiOH
""OH
N
HO
97
0
99
195
,,OMOM
HBr
CH3CN
N1
--o
100 %
O
96
m-CPBA, CH2Cl2,
78 %
H OH
1
N-OH
H
LiOH
-I--)e--
HO
97
99
Scheme 45
Our experience with the australine synthesis suggested that protection of the
secondary alcohol as a benzyl ether should facilitate cleavage of the
carbamate and promote the subsequent transannular reaction. Conversion
of 99 to its crystalline benzyl ether 100 was accomplished by deprotonation
with sodium hydride and subsequent treatment with benzyl bromide
(Scheme 46), conditions which were fully compatible with the epoxide ring.
As expected, carbamate hydrolysis and transannular cyclization of 100
proceeded smoothly in the presence of lithium hydroxide and afforded 2-0benzyldeoxyalexine (101).
99
100
0/../
/Lip
C1/141 0
9s
0/y
ni
Aio
101
48
"047
197
6.5. References
1.
Hohenschutz,L.D; Bell, E.A.; Jewess, P.J.; Leworthy, D.P.; Price, R.J.;
Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811.
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Nash, R.J.; Fellows, L.E.; Dring, J.V.; Striton, C.H.; Carter, D.; Hegarty,
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3.
Fellows, L.E.; Fleet, G.W.J. in J. Chrom. Library, "Natural Products
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4.
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Tetrahedron Lett. 1989, 30, 5685.
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Simmonds, M.S.J.; Blaney, W.M.; Fellows, L.E. J. Chem. Ecol. 1990,
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a) Fellows, L.; Nash, R. Chem. Abs. 1990, 114, 143777s.
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12.
Nash, R.J.; Thomas, P.I.; Waigh, R.D.; Fleet, G.W.J.; Wormald, M.R.;
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b) Tropea, J.E.; Molyneux, R.J.; Kaushal, C.P.; Pan, Y.T.; Mitchell, M.;
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Fleet, G.W.J.; Haraldsson, M.; Nash. R.J.; Fellows, L.E. Tetrahedron
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Wormald, M.R.; Nash, R.J.; Hmciar, P.; White, J.D.; Molyneux, R.J.;
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19.
Private communication from Prof. S.E. Dennmark
20.
Harrowven, D.C.; Pattenden, G. in Comprehensive Organic Synthesis,
Trost, B.M. Ed.; Pergamon: Oxford, U.K. 1991, vol. 3, pp 379-411.
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2965.
199
22.
Matthews, R.S.; Whitesell, J.K. J. Org. Chem. 1975, 40, 3312.
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Still, W.C.; Romeo, A.G. J. Am. Chem. Soc. 1986, 108, 2105.
24.
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b) Vedejs, E.; Gapinski, D.M. J. Am. Chem. Soc. 1983, 105, 5058.
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Soc. 1995, 117, 3448.
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26.
Grubbs, R.M.; Pine, S.H. in Comprehensive Organic Synthesis, Trost,
B.M., Ed.; Pergamon: New York 1991, Vol 5, Chapter 9.3.
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1995, 117, 2108.
27.
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29.
Marshall, J.A.; Trometer, J.D.; Cleary, D.G. Tetrahedron 1989, 45,
391.
30.
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1986, 1152.
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Kim, D.; Weinreb, S.M. J. Org. Chem. 1978, 43, 125.
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200
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Czemecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett.
1976, 3535.
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Ireland, R.E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C.S. J. Org. Chem.
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201
Chapter VII. Experimental Section
General experimental techniques and instrumentation used in this work are
outlined in part I chapter
4-o
0-.)LCO2Et
Ethyl (E)-3-[(4S)-2,2-Dimethy1-1,3-dioxolan-4-y1]-2-propenoate
(39). To a slurry of 1,2:5,6-di-O-isopropylidene-D-mannitol in an aqueous
solution of NaHCO3 (5%, 8.3 mL) maintained at 0°C, a solution of Na104
(1.05 g, 4.91 mmol) in H2O (8.3 mL) was added dropwise over a period of 20
min. The cooling bath was removed, and the mixture was stirred for 1 h at
room temperature. The mixture was cooled to 0°C, and diisopropyl(ethoxycabonylmethyl)phosphonate (4.0 mL, 16.4 mmol) and a 6 M solution
of K2CO3 (25 mL) were added. The reaction was stirred for 24 h at room
temperature and the product was extracted with CH2Cl2 (3x 10 mL). The
combined organic extracts were dried over anhydrous MgSO4, and
concentrated under reduced pressure. Chromatography of the residue (150
g of silica gel, Hexane-Et20, 4:1) afforded 1.37 g (89 %) of the product as a
colorless oil: [a]D23 + 38.2 (c 2.34, CHCI3); IR (neat) 2983, 1723, 1664, 1376,
1308, 1274, 1191, 1069 cm-1; 1H NMR (300 MHz, CDCI3) 5 1.27 (t, J = 7 Hz,
3H), 1.38 (s, 3H), 1.42 (s, 3H), 3.65 (t, J = 8 Hz, 1H), 4.13 - 4.21 (m, 3H), 4.64
202
(q, J = 6Hz, 1H), 6.07 (d, J = 15 Hz, 1H), 6.85 (dd, J = 6, 15 Hz, 1H); 13C NMR
(75 MHz, CDCI3) 8 14.4, 25.9, 26.6, 60.7, 69.0, 75.1, 110.3, 122.6, 144.8,
166.1; MS (CI) m/z 201 (M++1), 185, 155, 143, 115, 101, 97; HRMS (CI) m/z
201.1126 (calcd for C10H1704: 201.1127).
4-o
(E)-31(4S)-2,2-Dimethy1-1,3-dioxolan-4-y1]-2-propen-1-ol
(40). To
a solution of 39 (1.37g, 6.84 mmol) maintained at -78°C, a 1 M solution of
DIBAL in hexanes (17.1 mL, 17.1 mmol) was added, and the mixture was
stirred for 2 h at -78°C. The reaction was quenched with water (1mL) and
worked up with a saturated solution of Rochelle's salt. The CH2Cl2 solution
was separated, washed with a saturated solution of NaCI, dried over
anhydrous Na2S 04, and concentrated under reduced pressure.
Chromatography of the residue (80 g of silica gel, EtOAc- Hexane, 2:1)
afforded 0.96 g (89%) of 40 as colorless oil: [aJD23 +34.1 (c 3.20, CHCI3); IR
(neat) 3415, 2992, 2868, 1461, 1391, 1222, 1158 1058 cm-1; 1H NMR (300
MHz, CDCI3) 6 1.39 (s, 3H), 1.43 (s, 3H), 3.60 (t, J = 8 Hz, 1H), 4.10 (dd, J = 6,
8 Hz, 1H), 4.17 (dd, J = 1, 5 Hz, 1H), 4.54 (q, J = 7 Hz, 1H), 5.68 - 5.76 (m,
1H), 5.92 - 6.00 (m, 1H); 13C NMR (75 MHz, CDCI3) 8 26.1, 28.9, 62.8, 69.6,
76.6, 109.6, 128.7, 133.7; MS (CI) m/z 159, 157, 143, 141, 111, 83, 72;
HRMS (CI) m/z 159.1022 (calcd for C8111503: 159.1022).
203
-4-0
0
OH
{(2S,3R)-3-[(4R)-2,2-Dimethy1-1,3-dioxolan-4yl]oxiranyl}methanol (41). To a mixture of dry CH2Cl2 (20 mL), ground
molecular sieves (4A), and titanium(IV) isopropoxide (0.84 mL, 2.84 mmol)
maintained at -30 °C, diisopropil-L-tartarate (0.72 mL, 3.41 mmol) was
added, and the mixture was stirred for 20 min at -30 °C, tertButylhydroperoxyde (1.20 mL, 10.76 mmol) was added, and stirring was
continued for 30 min at -30 °C. To the mixture, allylic alcohol 40 (0.90g, 5.69
mmol) was added and the reaction was allowed to stand for 3 days at -30 °C.
The mixture was treated with an aqueous solution of tartaric acid (10%, 10
mL), and the resulting slurry was stirred at for 30 min at -30 °C and for 1 h at
room temperature. The organic phase was separated, and the aqueous
solution was extracted with CH2Cl2 (4x 10mL). The combined organic
extracts were washed with a saturated solution of NaCI, dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
Chromatography of the residue (100g of silica gel, Et20-hexane, 2:1)
afforded 0.60 g (61 %) of epoxide 41 as colorless oil: [a]D23 -22.4 (c 1.88,
CHCI3); IR (neat) 3453 (br), 2984, 2935, 1455, 1382, 1259, 1220, 1157,
1064, 844 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.36 (s, 3H), 1.42 (s, 3H), 2.13
(s br, 1H), 3.10 - 3.15 (m, 2H), 3.64 - 3.68 (m, 1H), 3.81 - 3.89 (m, 1H), 3.92 -
3.96 (m, 1H), 4.05 - 4.17 (m, 2H); 13C NMR (75 MHz, CDCI3) 8 25.7, 26.5,
55.2, 55.6, 61.0, 66.2, 75.4, 110.2; MS (Cl) m/z 175 (M#4-1), 159, 145, 117,
204
101, 99, 87, 73, 71, 69; HRMS (CI) m/z 175.0971 (calcd for C8I-11504:
175.0970).
0
{(2S,3R)-3-[(4R)-2,2-Dimethy1-1,3-dioxolan-4-yl]oxiranyl}methyl
Benzylcarbamate (42). To a solution of alcohol 41 (27.3 mg, 0.157
mmol) in dry benzene (2 mL), N,N-diisopropylethylamine (50 mL, 0.310
mmol) and benzylisocianate (40 mL, 0.324 mmol) were added, and the
mixture was stirred for 16 h at 60 °C. The mixture was concentrated under
reduced pressure, and the residue was chromatographed (15 g of silica gel,
EtOAc- hexane, 1:3) to afford 44.3 mg (92 %) of 42 as colorless oil: [0E])23
-18.9 (c 1.06, CHCI3); IR (neat) 3335 (br), 2984, 1728, 1548, 1250, 1147,
1069 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.36 (s, 3H), 1.42 (s, 3H), 2.98 (s br,
1H), 3.19 - 3.22 (m, 1H), 3.81 - 3.88 (m, 1H), 4.00 - 4.12 (m, 3H), 4.37 - 4.44
(m, 3H), 5.13 (s br, 1H), 7.28 - 7. 38 (m, 5H); 13C NMR (75 MHz, CDCI3) 8
25.7, 26.5, 45.4, 53.0, 56.0, 64.5, 66.2, 75.1, 110.3, 127.7, 127.8, 128.9,
138.4, 156.1; MS (CI) m/z 308 (M++1), 292, 250, 235, 221, 151, 129, 117,
114, 101, 99, 91, 88, 74, 71; HRMS (CI) m/z 308.1500 (calcd for
Ci6H2205N: 308.1498).
205
(4R)-3-Benzy1-4-[(2R)-[(4R)-2,2-dimethy1-1,3-dioxolan-4-
y1](hydroxy)methyl]-1,3-oxazolidin-2-one
(37). To a solution of
lactone 42 (41.8 mg, 0.136 mmol) in dry THE (10 mL) maintained at -10 °C, a
1 M solution of KOt-Bu in t-BuOH (272 mL, 0.272 mmol) was added, and the
mixture was stirred for 2 h at 0°C. The reaction was quenched with a
saturated solution of NH4CI (1mL), and the product was extracted with EtOAc
(4x 10mL). The combined organic extracts were washed with a saturated
solution of NaCI, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Chromatography of the residue (4g of silica gel, EtOAcHexane, 2:1) afforded 53.1 mg (84 %) of 37 as yellow oil: [a]D23 -14.6 (c 4.55,
CHCI3); IR (neat) 3433, 2994, 1738, 1445, 1382, 1269, 1220, 1147, 1069
cm-1; 1H NMR (300 MHz, CDCI3) 8 1.33 (s, 3H), 1.43 (s, 3H), 2.45 (d, J = 6
Hz, 1H), 3.62 - 3.68 (m, 1H), 3.75 - 3.86 (m, 2H), 3.94 - 3.99 (m, 2H), 4.18 -
4.28 (m, 2H), 4.51 (dd, J = 7, 9 Hz, 1H), 4.84 (d, J = 15 Hz, 1H), 7.29 - 7.42
(m, 5H); 13C NMR (75 MHz, CDCI3) 8 25.3, 26.3, 46.6, 58.0, 63.1, 66.0, 67.5,
75.7, 110.3, 128.2, 128.3, 129.2, 136.0, 159.2; MS (CI) m/z 308 (M++1), 278,
250, 176, 151, 129, 91; HRMS (CI) m/z 308.1500 (calcd for Ci 6H2205N:
308.1498).
206
{(2S,3R)-3-[(4R)-2,2-dimethy1-1,3-dioxolan-4-yl]oxiranyl}methyl
Allylcarbamate (48). To the solution of 41 (30.0 mg, 0.17 mmol) in dry
benzene (2 mL), N,N-diisopropylethylamine (93 mL, 0.51 mmol) and ally!
isocyanate (46 mL, 51 mmol) were added, and the mixture was stirred for 24
h at 60 °C. The mixture was concentrated under reduced pressure, and the
residue was chromatographed (12 g of silica gel, EtOAc-Hexane, 1:3) to
afford 43.4 mg (98 %) of carbamate 48 as colorless oil: [a]023 -17.6 (c 3.90,
CHCI3); IR (neat) 3341, 2993, 1717, 1553, 1377, 1253, 1167, 1066 cm-1 ; 1H
NMR (300 MHz, CDCI3) 6 1.34 (s, 3H), 1.41 (s, 3H), 2.96 - 2.98 (m, 1H), 3.17
- 3.20 (m, 1H), 3.77 3.89 (m, 3H), 3.95 - 4.11 (m, 3H), 4.38 (dd, J = 3, 12 Hz,
1H), 4.98 (s br, 1H), 5.13 (dd, J = 1, 15 Hz, 1H), 5.18 (dd, J = 1, 22 Hz, 1H),
5.76 - 5.91 (m, 1H); 13C NMR (75 MHz, CDCI3) 8 25.7, 26.5, 43.6, 53.0, 55.9,
64.4, 66.1, 75.1, 110.2, 116.4, 134.4, 156.0; MS (CI) m/z 258 (M++1), 242,
224, 200, 185, 169, 141, 117, 99; HRMS (CI) m/z 258.1341 (calcd for
Ci 2H2005N: 258.1341).
207
OH
(4R)-3-Ally1-4-[(2R)-[(4R)-2,2-dimethy1-1,3-dioxolan-4-
A(hydroxymethy1]-1,3-oxazolidin-2-one (46b). To a solution of the
lactam 48 (40 mg, 0.16 mmol) in dry THE (15 mL) maintained at -10 °C, a 1
M solution of KOt-Bu in t-BuOH (280 mL, 0.28 mmol) was added, and the
resulting mixture was stirred for 2 h at 0°C. The reaction was quenched with
a saturated solution of NH4CI, and the product was extracted with EtOAc (3x
8 mL). The combined organic extracts were washed with a saturated solution
of NaCI, dried over anhydrous Na2SO4, and concentrated under reduced.
Chromatography of the residue (6g of silica gel, EtOAc- hexane, 2:1) afforded
the 36.8 g (92 %) of 46b as colorless oil: [4,23 -18.6 (2.12 CHCI3); IR (neat)
3438, 2989, 2935, 1733, 1450, 1367, 1264, 1230, 1147, 1069 cm-1; 1H NMR
(300 MHz, CDCI3) 5 1.34 (s, 3H), 1.44 (s, 3H), 2.81 (d, J = 6 Hz, 1H), 3.67
(dd, J = 8, 19 Hz, 1H), 3.78 - 3.85 (m, 2H), 3.87 - 3.96 (m, 1H), 4.02 - 4.06 (m,
2H), 4.14 4.23 (m, 1H), 4.28 (t, J = 9 Hz, 1H), 5.23 (s, 1H), 5.26 - 5.28 (m,
1H), 5.72 5.85 (m, 1H); 13C NMR (75 MHz, CDCI3) 5 25.4, 26.3, 45.2, 58.3,
63.1, 66.1, 67.3, 75.9, 110.2, 119.0, 132.4, 158.8; MS (CI) m/z 258, 228, 199,
170, 140, 125; HRMS (CI) m/z 258.1340 (calcd for C12H2005N: 258.1341).
208
OH
(4R)-4-[(2R)1(4R)-2,2-Dimethy1-1,3-dioxolan-4y1Rhydroxy)methy1]-1,3-oxazolidin-2-one (49). Anhydrous ammonia
(100 ml) was condesed into a 250 mL two-necked flask containing a solution
of the benzyl carbamate (1.14 g, 3.71 mmol) in THE (7 mL) maintained at -78
°C. To the mixture, sodium metal was added until the blue color persisted.
The reaction was stirred for additional 2 h at -78 °C and was quenched with
solid NH4CI. The ammonia was evaporated, and the residue was extracted
with a EtOAc- (5 %)MeOH mixture (3x 10 mL). The obtained solution was
filtered over celite and concentrated under reduced pressure. A
chromatography of the residue (40 g of silica gel, EtOAc- hexane, 2:1)
afforded 0.69 (85 %) of 49 as colorless oil: [a]D23 -2.5 (c 1.96, CHC13); IR
(neat) 3198, 2983, 1772, 1440, 1381, 1244, 1059, 946 cm-1; 1H NMR (300
MHz, CDCI3) 8 1.35 (s, 3H), 1.44 (s, 3H), 3.20 (d, J = 7 Hz, 1H), 3.58 - 3.64
(m, 1H), 3.92 - 3.97 (m, 2H), 4.06 (t, J = 7 Hz, 1H), 4.14 - 4.19 (m, 1H), 4.45 (t,
J = 9 Hz, 1H), 4.48 - 4.59 (m, 1H), 6.81 (s, 1H); 13C NMR (75 MHz, CDCI3) 8
25.2, 26.3, 55.3, 65.8, 67.3, 71.3, 75.5, 110.0, 160.9; MS (CI) m/z 218 (M++1),
202, 188, 160, 142, 116, 109, 98, 88, 86, 84, 73; HRMS (CI) m/z 218.1029
(calcd for CgH1605N: 218.1028).
209
(4R)-3-Ally1-4-[(4R,5R)-5-(hydroxymethyl)-2,2-dimethy1-1,3-
dioxolan-4-yI]-1,3-oxazolidin-2-one
(47b).
To a solution of the
isopropylidene acetal 46b (35.0 mg, 0.136 mmol) in dry acetone (20 mL),
Amberlyst 15 resin (ca 10 mg) was added, and the mixture was stirred for 18
h at room temperature. The mixture was filtered, and the resulting solution
was neutralized with solid NaHCO3 (20 mg). The mixture was filtered over a
short column of silica gel, and the obtained solution was concentrated under
reduced pressure. Chromatography of the residue (5g of silica gel, EtOAcHexane, 1:1) afforded 22.4 mg (64 %) of the product as colorless oil: [a]D23
-13.9 (c 1.10, CHCI3); IR (neat) 3443, 2989, 2925, 1738, 1450, 1377, 1259,
1084, 1044, 1000 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.41 (s, 3H), 1.45 (s,
3H), 3.65
3.84 (m, 4H), 3.97 - 4.02 (m, 1H), 4.18 - 4.24 (m, 2H), 4.29 - 4.38
(m, 2H), 5.24 - 5.32 (m, 2H), 5.73 5.93 (m, 1H); 13C NMR (75 MHz, CDCI3)
8 27.0, 27.2, 45.4, 54.8, 62.3, 62.7, 75.1, 110.1, 119.0, 132.2, 158.2; MS (CI)
m/z 258 (M++1), 242, 228, 200, 182, 156, 141, 131, 126; HRMS (CI) m/z
258.1341 (calcd for C12H2005N: 258.1341).
210
(4S)-3-Benzy1-41(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolan-4-y11-1,3-oxazolidin-2-one
(47a). To a solution of the
isopropilidene acetal 37 (1.19 g, 3.87 mmol) in dry acetone (80 mL),
Amber list 15 molecular resin (c.a. 100 mg) was added, and the mixture was
stirred for 18 h at room temperature. The mixture was filtered and neutralized
with solid NaHCO3 (2g). The obtained solution was concentrated, and the
residue was chromatographed (160 g of silica gel, EtOAc- Hexane, 1:1) to
afford 761 mg (64 %) of 47a as colorless oil: [a]D23 -6.30 (c 1.73, CHCI3); IR
(neat) 3438, 2984, 1743, 1440, 1250, 1098, 1030 cm-1; 1H NMR (400 MHz,
CDCI3) 8 1.35 (s, 3H), 1.44 (s, 3H), 3.57 - 3.62 (m, 1H), 3.62 - 3.73 (m, 2H),
3.78 - 3.83 (m, 1H), 4.18 (dd, J = 2, 8 Hz, 1H), 4.25 (d, J = 17 Hz, 1H), 4.27 (d,
J = 15 Hz, 1H), 4.34 (dd, J = 6, 9 Hz, 1H), 4.83 (d, J = 15 Hz, 1H), 7.28 - 7.37
(m, 5H); 13C NMR (100 MHz, CDCI3) 8 27.0, 27.2, 46.9, 54.5, 62.3, 62.7,
75.2, 110.1, 128.2, 128.5, 129.0, 135.0, 158.6; MS (CI) m/z 308 (M++1), 250,
176, 151, 129, 114, 91, 84; HRMS (CI) m/z 308.1500 (calcd for C16H2205N:
308.1498).
211
(4S)-4-[(4R,5R)-5-(hydroxymethyl)-2,2-dimethy1-1,3-dioxolan-4-
y1]-1,3-oxazolidin-2-one (num). Anhydrous ammonia (25 ml) was
condesed into a 50 mL, two-necked flask containing a solution of the benzyl
carbamate (130 mg, 0.423 mmol) in THE (2 mL) maintained at -78 °C. To the
mixture, sodium metal was added until the blue color persisted. The reaction
was stirred for additional 2 h at -78 °C and quenched with solid NH4CI. The
ammonia was evaporated, and the residue was extracted with a EtOAc(5%)MeOH mixture (3x 5 mL). The obtained solution was filtered over celite
and concentrated under reduced pressure. A chromatography of the residue
(10 g of silica gel, EtOAc- hexane, 2:1) afforded 75 mg (82 %) of 49 as
colorless oil: [4023 -1.0 (c 1.50, CHCI3); IR (neat) 3365, 2984, 2984, 2940,
1793, 1255, 1044 cm-1; 1H NMR (300 MHz, CDCI3) 6 11.38 (s, 6H), 3.68 3.71 (m, 1H), 3.79 - 3.94 (m, 4H), 4.41 (dd, J = 5, 9 Hz, 1H), 4.52 (t, J = 8 Hz,
1H), 6.85 (br s, 1H), 13C NMR (75 MHz, CDCI3) 8 27.0, 54.8, 62.7, 68.3, 79.9,
81.1, 109.8, 160.5;
212
(4S,5R)-5-[4S)-3-Benzy1-2-oxo-1,3-oxazolidin-4-y1]-2,2-dimethyl1,3-dioxolane-4-carbaldehyde (55). To a solution of oxalyl chloride
(22.0 mL, 0.252 mmol) in CH2Cl2 (0.5 mL) maintained at -78 °C, a solution of
DMSO (32.8 mL, 0.462 mmol) in CH2Cl2 (0.5 mL) was added, followed after
2 min by a solution of alcohol 47a (64.5 mg, 0.210 mmol) in CH2Cl2 (0.1
mL). The mixture was stirred for 30 min at -78 °C, and triethylamine (0.146,
0.0105 mmol) was added. The stirring was continued for 2 h at -78 °C, and
the mixture was concentrated under reduced pressure. The mixture was
dilluted with EtOAc (15 mL) and filtered over a short column of silica gel. The
obtained solution was concentrated under reduced pressure, and the
residue was chromatographed (12 g of silica gel, EtOAc- hexane, 1:1) to
afford 47.4 mg (74 %) of 55 as colorless oil: [a]D23 -27.0 (c 2.52, CHCI3); IR
(neat) 2988, 2935, 1752, 1435, 1264, 1220., 1103, 712 cm-1; 1H NMR (400
MHz, CDCI3) 8 1.35 (s, 3H), 1.61 (s, 3H), 3.94
3.98 (m, 1H), 4.06 (d, J = 6
Hz, 1H), 4.28 4.36 (m, 4H), 4.90 (d, J = 15Hz, 1H), 7.31 - 7.50 (m, 5H); 13C
NMR (75 MHz, CDCI3) 8 25.3, 26.4, 47.1, 54.8, 62.6, 76.1, 80.6, 111.9, 128.1,
128.9, 129.1, 135.7, 158.7, 202.3; MS (CI) m/z 306 (M++1), 304, 248, 178,
176, 95, 91, 89, 83, 73; HRMS (CI) m/z 306.1343 (calcd for C1 6H2005N:
306.1341).
213
(4S)-3-Benzy1-4-[(4R,5R)-2,2-dimethy1-5-vinyl-1,3-dioxolan-4-ylj1,3-oxazolidin-2-one (53). To a suspension of Ph3P(CH3)Br (83.6 mg,
0.178 mmol) in THF (15 mL), a 1.6 M solution of n-BuLi in hexanes (0.11 mL,
0.18 mmol) was added, and the resulting solution was stirred for 30 min at 0
°C. The mixture was cooled to -78 °C, and a solution of aldehyde 55 (27.2
mg, 0.089 mmol) in THF (0.1 mL) was added. The reaction was gradually
warmed to 60 °C and stirred for another 18 h. The mixture was dilluted with
EtOAc (20 mL) and filtered over a short column of silica gel. The obtained
solution was concentrated under reduced pressure and the residue was
chromatographed (5g of silica gel, EtOAc- Hexane, 1:7) to afford 17.2 mg (64
%) of olefin 53 as coloress oil: [a]D23 -22.7 (c 2.37, CHCI3); IR (neat) 2979,
1762, 1430, 1235, 1083, 717 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.37 (s,
3H), 1.46 (s, 3H), 3.77 - 3.82 (m, 1H), 3.90 (dd, J = 2, 8 Hz, 1H), 4.01 (t, J = 8
Hz, 1H), 4.20 - 4.31 (m, 3H), 4.84 (d, J = 15 Hz, 1H), 5.27 (d, J = 16 Hz, 1H),
5.31 (d, J = 23 Hz, 1H), 5.69 - 5.80 (m, 1H), 7.29 - 7.38 (m, 5H); 13C NMR (75
MHz, CDCI3) 8 26.8, 27.0, 47.0, 53.6, 62.5, 78.4, 78.5, 110.0, 120.2, 128.2,
128.4, 130.0, 134.7, 135.9, 158.5; MS (CI) m/z 304 (M++1), 246, 176, 127,
61; HRMS (CI) m/z 304.1549 (calcd for Ci 7H2204N: 304.1549).
214
Me
\==\ ,,.OH
HN'7
)1,0
Of
(4R)-4-[(1S,2E)-1-Hydroxy-2-butenyI]-1,3-oxazolidin-2-one
(54).
Anhydrous NH3 (7 mL) was condensed into a 25 mL two-necked flask
containing a solution of carbamate 53 (44.0 g, 0.145 mmol) in THE (0.5 mL)
maintained at -78 °C. Sodium metal was added to the solution until the blue
color persisted. The reaction was stirred for another 2 h at -78 °C and was
quenched with solid NH4CI. The ammonia was evaporated, and the residue
was extracted with a EtOAc- (5 %)MeOH mixture (3x 5 mL). The obtained
solution was filtered over short column of silica gel and concentrated under
reduced pressure. A chromatography of the residue (2g of silica gel, EtOAchexane, 1:1) afforded 15.1 mg (66 %) of the product as colorless oil: [a]D23 =
+0.1 (c 0.90, CHCI3); IR (neat) 3326, 2925, 1748, 1421, 1250, 1157, 1044
cm-1; 1H NMR (300 MHz, CDCI3) 8 1.73 (d, 3H), 3.14 (br s, 1H), 3.84
3.90
(m, 1H), 4.12 (br s, 1H), 4.31 - 4.44 (m, 2H), 5.40 (ddd, J = 2, 7, 8 Hz, 1H),
5.79 - 5.91 (m, 1H), 6.23 (br s, 1H); 13C NMR (75 MHz, CDCI3) 8 18.1, 56.5,
66.6, 73.3, 128.1, 131.2, 160.7; MS (CI) m/z 158 (M++1), 140, 128, 114, 96,
86, 71; HRMS (CI) m/z 158.0817 (calcd for C7H1203N: 158.0817).
215
--)o
1),,o
V,
lor
{(2S,3R)-3-[(4R)-2,2-dimethy1-1,3-dioxolan-4-yl]oxiranyl}methyl
3-butenylcarbamate (58). To asolution of 4-pentenoic acid (1.03 mL,
10.0 mmol) in benzene (20 mL), DPPA (1.85 mL, 8.6 mmol) and triethylamine
(2.4 mL, 17.2 mmol) were added, and the mixture was stirred for 2 h at
ambient temperature. The mixture was filtered over a short column of silica
gel (6 g) which was subsequently rinsed with dry benzene (20 mL). The
mixture was warmed to 90 °C and stirred for 1.5 h. The temperature was
lowered to 60 °C and alcohol 41 (0.50 g, 2.87 mmol) was added followed by
triethylamine (1 mL). The mixture was the stirred for 18 h at 60 °C and
concentrated under reduced pressure. Chromatography of the residue (40 g
of silica gel, EtOAc- hexane, 1:1) to afford 0.72g (92 %) of the product as
colorless oil: [4)23 -20.3 (c 0.69, CHCI3); IR (neat) 3345, 2989, 1723, 1548,
1377, 1255, 1230, 1152, 1065 cm-1; 1H NMR(300 MHz, CDCI3) 5 1.34 (s,
3H), 1.40 (s, 3H), 2.21 - 2.28 (m, 2H), 2.94 - 2.96 (m, 1H), 3.16 - 3.18 (m, 1H),
3.21 - 3.27 (m, 2H), 3.79 - 3.86 (m, 1H), 3.96 (dd, J = 6, 12 Hz, 1H), 4.02 -
4.11 (m, 2H), 4.35 (dd, J = 3, 12 Hz, 1H), 4.90 (br s, 1H), 5.06 - 5.12 (m, 2H),
5.66 - 5.80 (m, 1H); 13C NMR (75 MHz, CDCI3) 5 25.7, 26.4, 34.2, 40.2, 53.0,
55.9, 64.2, 66.1, 75.1, 110.2, 117.2, 135.1, 156.0; MS (CI) miz 272 (M++1),
256, 230, 214, 154, 117, 112, 99, 83; HRMS (CI) m/z 272.1497 (calcd for
Ci 3H2205N: 272.1498).
216
(4R)-3-(3-Buteny1)-4-[(2R)-[(4R)-2,2-dimethy1-1,3-dioxolan-4-
Mhydroxy)methyl)-1,3-oxazolidin-2-one (59). To a solution of the
lactam 58 (0.72 g, 2.65 mmol) in dry THE (100 mL), a 1 M solution of t-BuOK
in t-BuOH (4.23 mL, 0.42 mmol) was added, and the mixture was stirred for 2
h at -10 °C. The reaction was quenched with a saturated NH4CI solution (10
mL), and the product was extracted with EtOAc (3 x 30 mL). The combined
organic extracts were washed with a saturated solution of NaCI, dried over
anhydrous Na2S0 4 , and concentrated under reduced pressure.
Chromatography of the residue (40 g of silica gel, EtOAc- hexane, 2:1)
afforded 0.45 g (62 %) of the product as yellow oil: [a]D23 +10.1 (c 1.12,
CHCI3); IR (neat) 3399, 2984, 2930, 1738, 1445, 1377, 1264, 1226, 1167,
1074 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.36 (s, 3H), 1.45 (s, 3H), 2.29 2.42 (m, 2H), 2.72 (d, J = 6 Hz, 1H), 3.11 - 3.23 (m, 1H), 3.54 - 3.64 (m, 1H),
3.76
3.86 (m, 2H), 3.93 - 4.03 (m, 1H), 4.05 - 4.13 (m, 2H), 4.27 (t, J = 9Hz,
1H), 4.49 (dd, J = 6, 9 Hz, 1H), 5.09 (dd, J = 1, 6 Hz, 1H), 5.14 (dd, J =1, 6 Hz,
1H), 5.72
5.85 (m, 1H); 13C NMR (75 MHz, CDCI3) a 25.4, 26.3, 32.0, 41.7,
58.6, 63.3, 66.5, 67.8, 75.8, 110.3, 117.8, 135.0, 159.0; MS (CI) m/z 272
(M++1), 242, 230, 214, 199, 153, 139, 127; HRMS (CI) m/z 272.1997 (calcd
for C13H2205: 272.1999).
217
(4R)-3-(3-Buteny1)-4-[(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-
1,3-dioxolan-4-y11-1,3-oxazolidin-2-one
(60).
To a solution of
isopropylidene acetal 59 (230 mg, 0.85 mmol) in dry acetone (25 mL),
Amber list 15 molecular resin (ca 20 mg) was added, and the mixture was
stirred for 18 h at room temperature. The mixture was filtered and quenched
with solid NaHCO3 (50 mg). Stirring was continued for 1 h, and the solution
was filtered and concentrated under reduced pressure. Chromatography of
the residue (40 g of silica gel, EtOAc- Hexane, 1:1) afforded 143 mg (62 %) of
the product as colorless oil: [a]023 +10.1 (c 1.12, CHCI3); IR (neat) 3428,
2994, 1738, 1450, 1377, 1250 cm-1; 1H NMJR (300 MHz, CDCI3) 6 1.42 (s,
3H), 1.43 (s, 3H), 2.28 - 2.44 (m, 2H), 3.19 - 3.28 (m, 1H), 3.57 - 3.83 (m, 4H),
4.05 (t, J = 8 Hz, 1H), 4.21 (d, J = 8 Hz, 1H), 4.29 (d, J = 7 Hz, 2H), 5.06 5.15
(m, 2H), 5.72
5.82 (m, 1H), 13C NMR (75 MHz, CDCI3) 8 27.0, 27.2, 31.9,
41.9, 55.1, 62.5, 62.7, 75.7, 77.0, 110.0, 117.6, 134.9, 158.4; MS (CI) m/z 272
(M++1), 230, 214, 167, 149, 137, 113, 95, 89; HRMS (CI) m/z 272.1497
(calcd for Ci 3H2205N: 272.1498).
218
(4R,5R)-51(4R)-3-(3-Buteny1)-2-oxo-1,3-oxazolidin-4-y1]-2,2dimethyl-1,3-dioxolane-4-carbaldehyde (61). To a solution of oxalyl
chloride (0.10 mL, 1.15 mmol) in CH2Cl2 (3.0 mL) maintained at -78 °C, a
solution of DMSO (0.15 mL, 2.11 mmol) in of CH2Cl2 (0.75 mL) was added,
followed after 3 min by a solution of alcohol 60 (216 mg, 0.80 mmol) in
CH2Cl2 (1 mL). The mixture was stirred for 30 min at -78 °C, and
triethylamine (0.146 mL, 0.0105 mmol) was added. Stirring was continued for
2 h at -78 °C, and the mixture was concentrated under reduced pressure.
The residue was dissolved in dry EtOAc (15 mL) and filtered over a short
column of silica gel. The obtained solution was concentrated under reduced
pressure, and the residue was chromatographed (20 g of silica gel, EtOAc-
hexane, 1:1) to afford 47.4 mg (59 %) of the aldehyde 61 as colorless oil:
[a]D23 -15.7 (c 1.15, CHCI3); IR (neat) 2979, 2925, 1748, 1435, 1367, 1264,
1215 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.35 (s, 3H), 1.,54 (s, 3H), 2.29 2.46 (m, 2H), 3.20 - 3.29 (m, 1H), 3.62 - 3.71 (m, 1H), 4.06 (d, J = 6 Hz, 1H),
4.10 - 4.16 (m, 1H), 4.16 - 4.36 (m, 4H), 5.07 - 5.17 (m, 2H), 5.73 - 5.82 (m,
1H), 9.88 (s, 1H); 13C NMR (75 MHz, CDCI3) 8 25.3, 26.3, 31.7, 42.2, 55.3,
62.5, 76.4, 80.4, 111.9, 117.7, 134.7, 158.5, 202.7; MS (CI) m/z 270 (M1--F1),
228, 21, 170, 140, 129, 100; HRMS (CI) m/z 270.1340 (calcd for
Ci3H2005N: 270.1341).
219
(4R)-3-(3-Buteny1)-4-[(4R,5R)-2,2-dimethyl-5-viny1-1,3-dioxolan4-y1]1,3-oxazolidin-2-one (50). To a suspension of Ph3P(CH3)Br (443
mg, 1.24 mmol) in dry THF (5mL), a 0.5 M solution of KHMDS in toluene
(2.34 mL, 1.17 mmol) was added, and the mixture was stirred for 30 min at
0°C. The mixture was cooled to -78 °C, and a solution of aldehyde 61 (0.167
g, 0.620 mmol) in THF (1 mL) was added. The reaction was then gradualy
warmed up to room temperature and was stirred for additional 18 h. EtOAc
(30 mL) was added, and the obtained solution was filtered over a short
column of silica gel and concentrated under reduced pressure.
Chromatography of the rsidue (5g of silica gel, EtOAc- hexane, 1:1) afforded
323 mg (74%) of olefin 50 as colorless oil: [a]D23 +2.4 (c 1.51, CHCI3); IR
(neat) 2981, 1748, 1425, 1370, 1221, 1082, 1037 cm-1; 1H NMR (300 MHz,
CDCI3) 8 1.42 (s, 3H), 1.44 (s, 3H), 2.27 - 2.46 (m, 2H), 3.20 - 3.29 (m, 1H),
3.59 - 3.69 (m, 1H), 3.93 (dd, J = 2, 8 Hz, 1H), 3.98 - 4.09 (m, 2H), 4.20 - 4.31
(m, 2H), 5.06 - 5.14 (m, 2H), 5.34 (d, J = 21 Hz, 1H), 5.39 (d, J = 28 Hz, 1H),
5.73 - 5.90 (m, 2H); 13C NMR (75 MHz, CDCI3) 8 26.6, 26.7, 31.6, 41.8, 53.9,
62.3, 78.2, 78.8, 109.7, 117.3, 120.2, 134.6, 158.0; MS (CI) m/z 268 (M++1),
226. 210, 168, 140, 127, 97, 86, 69; HRMS (CI) m/z 268.1550 (calcd for
Ci4H2204N: 268.1549).
220
(3aR,11aR,11bR)-2,2-Dimethy1-3a,6,7,11,11a,11b-
hexahydro[1,3]clioxolo[4,5-c][1,3]oxazolo[3,4-a]azocin-9-one
(51). To a stirred solution of 50 (6.0 mg, 0.0224 mmol) in CH2Cl2 (4.5 mL)
under argon atmosphere, a Grubbs' catalyst (4.6 mg, 5.6 gmol) was added,
and the mixture was stirred at room temperature for 5 h. The mixture was
concentrated
under
reduced
pressure,
and the residue was
chromatographed (1 g of silical gel, EtOAc- hexane, 1:2) to afford 5.1 mg (90
%) of 51 as a colorless oil: [a]D23 -7.1 (c 1.47, CHCI3); IR (neat) 2984, 1763,
1421, 1372, 1220, 1079, 874 cm-1; 1H NMR (300 MHz, CDCI3) 5 1.40 (s,
3H), 1.43 (s, 3H), 2.36 - 2.56 (m, 2H), 3.15 - 3.24 (m, 1H), 3.57 (t, J = 9 Hz,
1H), 3.67 - 3.74 (m, 1H), 4.34 - 4.44 (m, 2H), 4.68 - 4.73 (m, 1H), 5.57 - 5.68
(m, 1H), 5.76 (dd, J = 5, 12 Hz, 1H); 13C NMR (75 MHz, d6-acetone) 5 27.0,
27.3, 29.1, 44.3, 58.0, 67.3, 77.7, 83.3, 109.8, 128.2, 130.6, 159.2; MS (CI)
m/z 240.1235 (calcd for C12H1804N: 240.1236).
221
(3aR,3bS,4aS,10aR,10bR)-2,2-
Dimethyloctahydro[1,3]dioxolo[4,5-c][1,3]oxazolo[3,4a]oxireno[2,3-e]azocin-8-one (62). A mixture of the olefin (12.5 mg,
0.0522 mmol), m-CPBA(50 %wt, 54.0 mg, 0.157 mol) and CH2Cl2 (0.7 mL)
was stirred for 18 h at room temperature. The mixture was treated with methyl
sulfide (50p,L) and a saturated solution of Na2CO3 (0.5 mL). Stirring was
continued for 30 min, and the organic phase was separated. The aqueous
solution was extracted with dichloromethane (4x 1 mL) and the combined
organic extracts were dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The obtained residue was chromatographed (1 g of
silica gel, EtOAc- hexane, 1:1) to afford 6.2 mg (64 %) of 62 as a white
crystalline compound: [a]D23 +2.1 (c 0.62, CHCI3); IR (neat) 2984, 2926, 1767,
1377, 1250, 1216, 1079, 863 cm-1; 1H NMR(300 MHz, CDCI3) 8 1.40 (s, 3H),
1.46 (s, 3H), 1.64 - 1.80 (m, 2H), 2.41 2.49 (m, 1H), 3.09 - 3.17 (m, 3H), 3.60
- 3.66 (m, 1H), 1.64 - 1.80 (m, 2H), 2.41 - 2.49 (m, 1H), 3.09 - 3.17 (m, 3H),
3.60 3.66 (m, 1H), 3.73 3.81 (m, 2H), 3.93 - 4.03 (m, 1H), 4.37 (dd, J = 8, 9
Hz, 1H), 4.46 (dd, J = 3, 9 Hz, 1H); 13C NMR (75 MHz, CDCI3) 8 26.9, 27.0,
27.6, 41.4, 52.1, 55.9, 57.2, 67.0, 78.5, 79.9, 110.6, 159.0; MS (CI) m/z 256
(M++1), 240, 198, 182, 123, 85, 83, 68; HRMS (CI) m/z 256.1184 (calcd for
Ci2H1805N: 256.1185).
222
(9R,10R,10aR)-9,10-Dihydroxy-1,5,6,9,10,10a-
hexahydro[1,3]oxazolo[3,4-a]azocin-3-one (63). To a solution of
acetonide 63 (170 mg, 0.797 mmol) in acetonitrile (20 mL), an aqueous
solution of HBr (48%, 1 mL) was added, and the mixture was stirred for 1 h at
room temperature. All volatiles were removed under reduced pressure and
the residue was dissolved in of acetonitrile (20 mL). To the solution was
added solid NaHCO3, and the mixture was stirred for another 30 min at room
temperature. The mixture was filtered over a short pad of silica gel, which
was subsequently rinced with a EtOAc- (5 %)MeOH mixture. The obtained
solution was concentrated under reduced pressure to afford 140 mg of a
crude product which was not further purified. [423 +4.2 (c 0.67, CH3CN); IR
(neat) 3412, 2936, 1736, 1435, 1222, 1080 cm-1 ; 1H NMR (400 MHz, d6acetone) 6 2.29 - 2.38 (m, 2H), 3.13 - 3.22 (m, 2H), 3.48 - 3.58 (m, 3H), 3.81
(d, J = 1Hz, 1H), 4.22 - 4.25 (m, 1H), 4.30 (dd, J = 8, 8 Hz, 1H), 4.41 (dd, J = 2,
8 Hz, 1H), 5.54 - 5.62 (m, 2H); 13C NMR (400 MHz, CDCI3) 6 27.6, 45.1,
59.5, 69.2, 71.6, 126.9, 136.1, 161.2; MS (CI) m/z 200 (M++1), 182, 166, 149,
138, 93, 69; HRMS (CI) nilz 200.0923 (calcd for C9H1404N: 200.0928).
223
N""OH
010
(1 aS,7aR,8R,9S,9aR)-8,9-dihydroxyoctahydro[1,3]oxazolo[3,4a]oxireno[2,3-e]azocin-5-one (64). To a solution of the olefin (4.1 mg,
0.0206 mmol) in THE (1 mL), m-CPBA (50 wt %, 14 mg, 0.0405 mol) was
added, and the mixture was stirred for 7 h at ambient temperature. The
mixture was treated with methyl sulfide (10 gL) and solid Na2CO3 (15 mg).
Stirring was continued for 1 h and the suspension was filtered over a short
column of silica gel, which was subsequently rinced with a EtOAc- (5 %)MeOH
mixture. The obtained solution was concentrated under reduced pressure,
and the residue was chromatographed (1 g of silica gel, EtOAc -MeOH, 10:1)
to afford 2.7 mg (62%) of 64 as a white crystalline compound: 1H NMR (300
MHz, CDCI3) 8 1.32 - 1.52 (m, 1H), 2.18 - 2.26 (m, 1H), 2.78 (dd, J = 4,7Hz,
1H), 2.91 - 2.98 (m, 1H), 3.10 (m, 1H), 3.22 - 3.40 (m, 3H), 3.91 (dt, J = 5, 14
Hz, 1H), 4.19 - 4.26 (m, 1H), 3.45 (d, J = 14 Hz, 1H);
224
)-IN°
HO
[(3aR,4R,9aR)-2,2-Dimethy1-3a,4,5,6,7,9a-
hexahydro[1,3] clioxolo[4,5-c]azocin-4-ylimethanol. To a solution of
carbamate 51 (12 mg, 0.0501 mmol) in EtOAc (10 mL), a 0.5 M solution of
NaOEt in EtOH (1 mL) was added, and the mixture was stirred for 18 h at 70
°C. The mixture was concentrated under reduced pressure and the residue
was treated with a saturated solution of NH4CI (2 mL). The product was
extrated with CHCI3 (4x5 mL), and the combined organic extracts were
washed with a saturated solution of NaCI, and dried over anhydrous
Na2SO4. All volatiles were removed under reduced pressure to afford 11 mg
of the crude product, which was not further purified. [a]D23 -14.4 (c 0.50,
CHCI3); IR (neat) 3370, 2920, 1738, 1465, 1372, 1235, 1142, 1074 cm-1; 1H
NMR (400 MHz, CDCI3) 8 1.41 (s, 3H), 1.42 (s, 3H), 2.06 - 2.30 (m, 1H), 2.35
- 2.42 (m, 1H), 2.68 - 2.73 (m, 1H), 2.89 (ddd, J = 4, 12, 12, 1H), 2.99 (ddd, J =
1, 6, 8 Hz, 1H), 3.20 (dd, J = 9 Hz, 1H), 3.27 (dd, J = 8, 10 Hz, 1H), 3.78 (dd, J
= 5, 10 Hz, 1H), 4.54 (b t, J = 7Hz, 1H), 5.60 - 5.67 (m, 1H), 5.90 - 5.94 (m,
1H); 13C NMR (100MHz, CDCI3) 8 27.1, 27.2, 28.7, 47.0, 58.2, 64.4, 78.5,
82.7, 109.5, 127.4, 130.9; MS (CI) m/z 214 (M++1), 182, 162, 156, 138, 124,
119, 95, 91; HRMS (CI) m/z 214.1443 (calcd for C11 H2003N: 214.1443).
225
(9R,10R,10aR)-9,10-Bis(benzyloxy)-1,5,6,9,10,10a-
hexahydro[1,3]oxazolo[3,4-a]azocin-3-one (65). To a solution of
crude diol 63 (100 mg, 0.502 mmol) in dry THE (10 mL), KH (50 wt %
suspension in mineral oil, 220 mg, 4.5 mmol) and tetra-n-butylammonium
iodide (10 mg) were added, and the mixture was stirred for 30 min at room
temperature. Benzyl bromide (200 1.11, 1.68 mmol) was added, and the
reaction was warmed to 50 °C and stirred for additional 2 h. The mixture was
treated with a saturated solution of NH4CI (3 mL), and the product was
extracted with CHCI3 (4x 4mL). The combined organic extracts were washed
with a saturated solution of NaCI, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The obtained residue was
chromatographed (15 g of silica gel, EtOAc- hexane, 1:2) to afford 160 mg (84
%) of the dibenzyl ether as a colorless oil: [a]D23 +22.8 (c 1.33, CHCI3); IR
(neat) 3023, 2920, 2861, 1753, 1460, 1421, 1215, 1079, 751 cm-1; 1H NMR
(400 MHz, CDCI3) 8 2.26 - 2.37 (m, 1H), 2.39 - 2.44 (m, 1H), 3.10 - 3.16 (m,
1H), 3.43 - 3.52 (m, 1H), 3.76 (dd, J = 5, 13, 13 1H), 4.17 (dd, J = 1, 8 Hz, 1H),
4.18 - 4.33 (m, 3H), 4.51 (d, J = 12 Hz, 1H), 4.58 (d, J = 11 Hz, 1H), 4.73 (d, J
= 11 Hz, 1H), 5.14 (d, J = 11 Hz, 1H), 5.71 - 5.82 (m, 2H), 7.28 - 7.39 (m, 10
H); 13C NMR (100 MHz, CDCI3) 8 27.1, 44.0, 58.8, 68.6, 71.3, 76.0, 78.9,
81.6, 127.8, 128.2, 128.5, 128.6, 128.7, 133.2, 138.0, 138.2, 159.9;MS (CI)
226
m/z 380 (M++1), 279, 272, 182, 149, 107, 91; HRMS (CI) m/z 380.1862
(calcd for C23H2604N: 380.1862).
(1aS,7aR,8R,9S,9aS)-8,9-
Bis(Benzyloxy)ocyahydro[1,3]oxazolo[3,4-a]oxireno[2,3-e]azocin5-one (66). A mixture of 65 (160 mg, 0.422 mmol), m-CPBA (50 wt %)
(0.58 g, 1.68 mmol), and CH2Cl2 (5mL) was stirred for 6 h at room
temperature The mixture was treated with Me2S (100 4), and stirring was
continued for additional 15 min. The solution was washed with a saturated
solutions of Na2CO3 and a saturated solution of NaCI, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Chromatography of the
residue (10 g of silica gel, EtOAc- hexane, 1:2) afforded 125 mg (75 %) of the
product as white crystaline compound: [a]D23 + 48.6 (c 0.72, CHCI3); IR (neat)
2911, 2847, 1758, 1465, 1420, 1215, 1137, 1074 cm-1; 1H NMR (400MHz,
CDCI3) 6 1.39 - 1.50 (m, 2H), 2.37 - 2.40 (m, 1H), 3.08 - 3.19 (m, 3H), 3.44 (t,
J = 7 Hz, 1H), 3.52 - 3.59 (m, 2H), 4.04 (dt, J = 5, 14 Hz, 1H), 4.24 (dd, J = 1, 9
Hz, 1H), 4.32 (dd, J = 7, 9 Hz, 1H), 4.59 (d, J = 11 Hz, 1H), 4.72 (d, J = 11 Hz,
1H), 4.97 (d, J = 11 Hz, 1H), 5.16 (d, J = 11 Hz, 1H), 7.19 - 7.43 (m, 10 H);
13C NMR (100 MHz, CDCI3) d 27.2, 42.7, 51.9, 57.2, 58.4, 68.8, 73.1, 76.7,
227
79.3, 81.8, 128.0, 128.2, 128.3, 128.6, 128.8, 137.7, 138.2, 160.4; MS (CI)
m/z 396 (M++1), 380, 306, 184, 165, 113, 107, 91, 79;
(1S,5R,6R,7R,7aR)-6,7-Bis(benzyloxy)-5(hydroxyethyl)hexahydro-1H-pyrrolizin-1-ol (67). To a solution of the
dibenzyl epoxide (50 mg, 0.126 mmol) in a Et0H-H20 (1:1, 20 mL) mixture,
Li0H-H20 (53 mg, 1.26 mmol) was added, and the mixture was stirred for 18
h at 94 °C. The product was extrated with chiorofom, and the combined
organic extracts were washed with a saturated solution of NaCI, dried over
anhydrous Na2SO4 and concentrated under reduced pressure to afford 47
mg (100%) of dibenzyl australine 67 as colorless oil: [a]p23 +13.2 (c 0.94,
CHCI3); IR (neat) 3389, 2876, 1465, 1142, 1074, 1040, 747, 707 cm-1; 1H
NMR (300 MHz, CDCI3) 8 1.93 - 1.99 (m, 2H), 2.74 (q, J = 8 Hz, 1H), 2.98 3.01 (m, 1H), 3.14 - 3.19 (m, 1H), 3.52 (dd, J = 5, 5 Hz, 1H), 4.59 (d, J = 2Hz,
2H), 4.64 (d, J = 4, 7 Hz, 1H), 4.13 - 4.19 (m, 2H), 4.33 (dd, J = 5, 5 Hz, 1H),
4.59 (d, J = 2 Hz, 2H), 4.64 (d, J = 11 Hz, 1H), 4.75 (d, J = 11 Hz, 1H), 7.28
7.40 (m, 10H); 13C NMR (75 MHz, CDCI3) 8 37.0, 51.9, 60.8, 71.3, 71.7,
72.5, 72.9, 73,.1, 81.4, 85.2, 128.0, 128.1, 128.7, 138.0, 138.3; MS(CI) m/z
370(M++1), 338, 262, 229, 207, 135, 107, 91, 79, 69; HRMS (CI) m/z
370.2018 (calcd for C22H2804N: 370.2018).
228
(1R,2R,3R,7S,7aR)-3-(Hydroxymethyl)hexahydro-1H-
pyrrolizidine-1,2,7-triol. Australine (7).
A mixture of dibenzyl
australine (67) (26 mg, 0.06.57 mmol), 10 mg of (20%)Pd(OH)2/C, Me0H (2
mL) was stirred for 24 h under hydrogen atmosphere. The mixture was
filtered over a short column of silica gel and concentrated under reduced
pressure to afford 135 mg (100%) of australine (7) as colorless oil: [a]D23
+16.6 (c 1.37, Me0H); IR (neat) 3331, 2915, 1621, 1426, 1118, 1049 cm-1 ;
1H NMR (400 MHz, CDCI3) 8 1.92 - 2.01 (m, 1H), 2.02 - 2.06 (m, 1H), 2.72 2.78 (m, 2H), 3.15 - 3.22 (m, 2H), 3.63 (dd, J 6, 12 Hz, 1H), 3.81 (dd, J = 3, 12
Hz,1H), 3.91 (t, J = 9 Hz, 1H), 4.25 (t. J = 8 Hz, 1H), 4.39 (br s, 1H); 13C NMR
(100 MHz, D20) 8 35.4, 52.1, 62.9, 69.8, 70.8, 71.0, 73.4, 79.1; MS (CI) m/z
190 (M++1), 184, 172, 158, 152, 140, 112, 99; HRMS (CI) m/z 190.1079
(calcd for C8H16N04: 190.1079).
229
CI
(4R)-3-Benzy1-4-[(4R,5S)-5-(chloromethyl)-2,2-dimethyl-1,3dioxolan-4-y1]-1,3-oxazolidin-2-one (72). To a mixture of alcohol 47a
(261 mg, 0.850 mmol), HMPT (0.310 mL, 1.70 mmol), and THE (30 mL)
maintained at -78 °C, under argon atmosphere, CCI4 (0.82 mL, 8.50 mmol)
was added, and the mixture was stirred for 4 h at -78 °C. The temperature
was gradually raised to 60 °C, and stirring was continued for 12 h. The
mixture was filtered over a short column of silica gel and concentrated under
reduced pressure. Chromatography of the residue (10 g of silica gel, EtOAchexane, 1:4) afforded 230 mg (83 (Y0) of 72 as a colorless oil: [423 -100.0 (c
0.87, CHCI3); IR (neat) 292, 1758, 1437, 1375, 1242, 1071 cm-1; 1H NMR
(300 MHz, CDCI3) 8 1.34 (s, 3H), 1.44 (s, 3H), 3.44 (dd, J = 7, 11 Hz, 1H),
3.60 (dd, J = 4, 11 Hz, 1H), 3.70 - 3.76 (m, 1H), 3.86 - 3.91 (m, 1H), 4.17 (dd,
J = 2, 7 Hz, 11H), 424 - 4.33 (m, 2H), 4.81 (d, J = 15 Hz, 1H), 7.28 - 7.41 (m,
5H); 13C NMR (75 MHz, CDCI3) 5 26.9, 27.2, 44.2, 46.8, 55.2, 62.3, 76.2,
77.0, 110.9, 127.8, 128.3, 128.5, 129.0, 135.8, 158.3; MS (CI) m/z 326
(M++1), 268, 213, 176, 169, 91; HRMS (CI) m/z 326.1160 (calcd for
Ci 6H21 NCI: 326.1159).
230
HN-
'"OH
0 '`o
(4R)-4-[(1S)-1-Hydroxy-2-propeny1]-1,3-oxazolidin-2-one
(73).
Anhydrous ammonia (40 mL) was condesed into a 100 mL, two-necked flask
containing a solution of 72 (44 mg, 0.145 mmol) in THE (2 mL) maintained at
-78 °C. To the mixture, sodium metal was added until the blue colour
persisted. The reaction was stirred for 3 h at -78 °C and quenched with solid
NH4CI. Ammonia was evaporated, and the residue was extracted with a
EtOAc- (5 %)MeOH mixture. The obtained solution was filtered over a short
column of silica gel and concentrated under reduced pressure.
Chromatography of the residue (15 g of silica gel, EtOAc- hexane, 2:1)
afforded 54 mg (61 %) of 73 as colorless oil: [a]D23 -10.1 (c 1.36, CHCI3); IR
(neat) 3345, 1743, 1421, 1250, 1064 cm-1; 1H NMR (300 MHz, CDCI3) 8
3.27 (s br, 1H), 3.89 - 3.95 (m, 1H), 4.23 - 4.27 (m, 1H), 4.32 - 4.41 (m, 2H),
5.30 (d, J = 10 Hz, 1H), 5.41 - 5.47 (m, 1H), 5.72 - 5.83 (m, 1H), 6.60 (s br,
1H); 13C NMR (75 MHz, CDCI3) 8 56.4, 66.0, 72.7, 118.6, 135.1, 161.1; MS
(CI) m/z 144 (M++1), 131, 129, 114, 109, 103, 86, 71; HRMS (CI) m/z
144.0660 (calcd for C6H1003N: 144.0661).
231
(4R)-4-[(4R,5R)-2,2-Dimethy1-5-phenety1-1,3-dioxolan-4-y1]-1,3oxazolidin-2..one (74). [a]o23 +15.5 (c 0.97 CHCI3); IR (neat) 3269, 2981,
1768, 1455, 1375, 1231, 1087, 1022 cm-1 ; 1H NMR (400 MHz, CDCI3) 8
1.37 (s, 3H), 1.41 (s, 3H), 1.77 - 1.87 (m, 2H), 2.63 - 2.71 (m, 1H), 2.80 - 2.87
(m, 1H), 3.56 (t, J = 7Hz, 1H), 3.74 - 3.79 (m, 1H), 3.81 - 3.86 (m, 1H), 4.32
(dd, J = 5, 9 Hz, 1H), 4.46 (t, J = 9 Hz, 1H), 6.42 (br s, 1H), 7.19 - 7.21 (m, 3H),
7.26 - 7.33 (m, 2H); 13C NMR (100 MHz, CDCI3) 8 27.3, 27.5, 54.5, 67.9,
77.5, 81.8, 109.7, 126.3, 128.6, 128.7, 141.6, 160.2; MS(CI) m/z 292 (M++1),
248, 234, 218, 205, 187, 173, 128, 101, 86, 84; HRMS (CI) m/z 292.1547
(calcd for C16H2204N: 292.1549).
HN--
'"OMOM
0 .\ 0
(4R)-4-[(1 S)-1 -(Methoxymethoxy)-2-propeny1)-1,3-oxazolidin-2one (75). To a mixture of 73 (20 mg, 0.140 mmol), CH2(OMe)2 (123 pi,
1.40 mmol), and dry CHCI3 (15 mL), P205 (ca 25 mg) was added, and the
mixture was stirred at ambient temperature until TLC analysis indicated 80%
conversion. The solution was separated from the solid residue and
232
neutralized with solid NaHCO3 (30 mg). The mixture was filtered, and the
resultant solution was concentrated under reduced
pressure.
Chromatography of the residue (3 g of silica gel, EtOAc- hexane, 1:1) afforded
20 mg (75 %) of the product as colorless oil: [a]D23 +80.8 (c 0.73, CHCI3); IR
(neat) 3306, 2915, 1758, 1916, 1240, 1142, 1040 cm-1; 1H NMR (300 MHz,
CDCI3) 5 3.39 (s, 3H), 3.89 - 3.94 (m, 1H), 4.02 (t, J = 6 Hz, 1H), 4.41 (dd, J =
5.9 Hz, 1H), 4.47 (t, J = 7 Hz, 1H), 5.41 - 5.47 (m, 3H), 5.62 - 5.73 (m, 1H);
13C NMR (75 MHz, CDCI3) 5 54.3, 55.4, 67.1, 78.7, 94.1, 122.3, 133.1,
159.5; MS (CI) m/z 188 (M++1), 170, 158, 156, 140, 126, 82; HRMS (CI) m/z
188.0923 (calcd for Gel1404N: 188.0928).
0
O"
CO2H
)----$5
21(4S)-2, 2-Dimethy1-5-oxo-1,3-dioxolan-4-yliacetic Acid (77). To
a solution of L-malic acid (300 mg, 2.24 mmol) in 2,2-dimethoxypropane (20
mL), CSA (10 mg) was added, and the mixture was strred for 18 h at room
temperature. NaOAc was added to the mixture, and stirring was continued for
another 1 h. The solution was filtered and concentrated under reduced
pressure. Recristallyzation of the residue from a CHCI3-hexane mixture
afforded 33.1 mg (85 %) of 77 as white cristaline compound: [a]D23 +4.0 (2.82
CHCI3); 1H NMR (400 MHz, CDCI3) 5 1.57 (s, 3H), 1.63 (s, 3H), 2.86 (dd, J =
7, 18 Hz, 1H), 3.00 (dd, J = 4, 21 Hz, 1H), 4.72 (dd, J = 4, 7 Hz, 1H); 13C NMR
(100 MHz, CDCI3) 5 26.0, 27.0, 36.2, 70.6, 111.6, 172.0, 174.9; MS (CI) m/z
233
175 (M++1), 1'57, 147, 131, 117, 103, 89; HRMS (CI) m/z 175.0606 (calcd for
C7H1105: 175.0606).
(3S)-3-Hydroxydihydro-2(3H)-furanone (79). To a solution of 77
(2.00g, 11.5 mmol) in THF (150 mL) maintained at 0°C, a 1 M solution of BH3
in THF (14.0 mL, 14.0 mmol) was added dropwise over 45 min, and the
mixture was stirred for 2 h at 0°C and for 18 h at room temperature. To the
mixture, Me0H (30 mL) was added, and the mixture was stirred for 1 h at
room temperature. All volatiles were removed under reduced pressure, and
the residue was dissolved in CHCI3 (40 mL) and treated with CSA (1g). The
mixture was stirred for 10 h at room temperature, filtered and concentrated
under reduced pressure. Chromatogaphy of the residue (80g of silica gel,
EtOAc- Hexane, 2:1) afforded 0.840 (72 %) of 79 as colorless oil: [423 -69.7
(c 0.93, CHCI3); IR (neat) 3413, 2916, 1773, 1231, 1181, 1132, 1017 cm-1;
1H
NMR (300 MHz, CDCI3) 8 2.22 - 2.39 (m, 1H), 2.56 - 2.66 (m, 1H), 4.19
4.28 (m, 1H), 4.40 - 4.55 (m, 2H); 13C NMR (75 MHz, CDCI3) 8 31.0, 65.4,
67.6, 178.3; MS (CI) m/z 103 (M++1), 91, 85, 75, 71; HRMS (CI) m/z 103.0396
(C4H703: 103.0395).
234
TBSO,
6
0
(3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}dihydro-2(3H)-furanone
(80). To a solution of 79 (100 mg, 0.979 mmol) in dry CH2Cl2 (5 mL)
maintained at 0°C, 2,6-lutidine (0.28 mL, 2.45 mmol) and TBDMSTf (0.34
mL, 1.96 mmol) were added, and the mixture was stirred for 1 h at 0°C. The
solution was concentrated under reduced pressure, and the residue was
chromatographed (10g silica gel, EtOAc- hexane, 1:3) to afford 210 mg (99%)
of 80 as colorless oil: [a]D23 -33.7 (c 1.80, CHCI3) 8 2954, 2852, 1782, 1157,
1020, 996 cm-1; 1H NMR (300 MHz, CDCI3) 8 0.16 (s, 3H), 0.18 (s, 3H), 0.92
(s, 9H), 2.17 - 2.30 (m, 1H), 2.42 - 2.59 (m, 1H), 4.16 - 4.24 (m, 1H), 4.36
4.44 (m, 2H); 13C NMR (75 MHz, CDCI3) 8 -5.0, -4.5, 18.4, 25.8, 32.5, 64.9,
68.4, 176.1; MS (CI) m/z 217 (M4+1), 201, 189, 173, 159, 131, 115; HRMS
(CI) m/z 217.1259 (calcd for C1 oH2103Si: 217.1260).
TBSO,
OH
(3S)- 3- {[tert- Butyl(dimethyl )silyl]oxy }tetrahydro -2- furanol (81). To
a solution of lactone 80 (214 mg, 0.989 mmol) in dry CH2Cl2 (20 mL) cooled
to -78 °C, a 1 M solution of DIBAL in hexanes (1.14 mL, 1.14 mmol) was
added, and the mixture was stirred for 40 min at -78 °C. Solid NH4CI (0.4 g)
was added to the mixture, followed by Me0H (1drop). The mixture was
235
filtered over a short column of silca gel, which was subsequently rinced with
a EtOAc- (5 %)MeOH mixture. The obtained solution was concentrated under
reduced pressure, and the residue was chromatographed (10 g of silica gel,
EtOAc- hexane, 1:1) to afford 137 mg (63 %) of 83 as colorless oil: 1H NMR
(300 MHz, CDCI3) 6 0.096 (s, 3H), 0.099 (s, 3H), 0.14 (s, 6H), 0.90 (s, 9H),
0.93 (s, 9H), 1.77 - 1.92 (m, 2H), 2.03 2.27 (m, 2H), 3.82 (d t, J = 4, 8 Hz,
1H), 4.00 - 4.11 (m, 3H), 4.20 - 4.27 (m, 2H), 5.21 (s, 1H), 5.24 (d, J = 4Hz,
1H); MS (CI) m/z 217, 201, 185, 171, 161, 144, 131, 115, 87, 75; HRMS (CI)
m/z 219.1416 (calcd for Ci oF12303Si: 219.1416).
mom0,
0
0
(3S)-3-(Methoxy)dihydro-2(3H)-furanone (82). To a solution of 79
(120 mg, 1.17 mmol) and CH2(OCH3)2 (1.00 mL, 11.3 mmol) in CHCI3 (5
mL), P205 (ca 50 mg) was added, and the mixture was stirred for 5 h at room
temperature. The organic phase was separated, neutralized with with solid
NaHCO3, filtered, and concentrated under reduced presure. The residue was
chromatographed (15 g of silica gel, EtOAc- Hexane, 1:3) to afford 165 mg
(96 %) of 82 as colorless oil: [a]D23 -122.4 (c 2.59, CHCI3); IR (neat) 2935,
1792, 1460, 1391, 1240, 1157, 1064, 1025 cm-1; 1H NMR (300 MHz, CDCI3)
6 2.23 - 2.36 (m, 1H), 2.53 - 2.63 (m, 1H), 3.43 (s, 3H), 4.20 - 4.28 (m, 1H),
4.40 - 4.47 (m, 2H), 4.72 (d, J = 7Hz, 1H), 4.96 (d, J = 7Hz, 1H); 13C NMR (75
MHz, CDCI3) d 30.1, 56.1, 65.3, 70.4, 96.1, 175.1; MS (CI) m/z 147 (M++1),
236
130, 117, 115, 87, 71; HRMS (CI) m/z 147.0657 (calcd for C6H1104:
147.0657).
OH
(3S)-3-(Methoxymethoxy)tetrahydro-2-furanol (83). To a solution of
the lactone (0.88 mg, 5.47 mmol) in dry CH2Cl2 (30 mL) cooled to - 78 °C, a
1.5 M solution of DIBAL in toluene (4.0 mL, 6 mmol) was added, and the
mixture was stirred for 30 min at -78 °C. Solid NH4CI (0.4 g) and Me0H (1
drop) were added, the mixture was filtered over a short column of silica gel,
which was subsequently rinced with a EtOAc- (5 %)MeOH mixture. The
obtained solution was concentrated under reduced pressure, and the
residue was chromatographed (20 g of silica gel, EtOAc- hexane, 1:1) to
afford 0.62 g (76 %) of 83 as colorless oil: 1 HNMR (300 MHz, CDCI3) S 1.91
- 2.30 (m, 4H), 3.38 (s, 3H), 3.41 (s, 3H), 3.80 - 3.88 (m, 1H), 4.01 - 4.17 (m,
5H), 4.66 (s, 2), 4.68 - 4.74 (m, 2H), 5.31 (d, J = 4 Hz, 1H), 5.40 (s, 1H).
237
MOMa,
OH
(3S)-3-(Methoxymethoxy)-4-pentene-1-ol (84). To a suspension of
methyltriphenylphosphonium bromide (222 mg, 0.62 mmol) in THF (40 mL)
maintained at at 0 °C, under argon atmosphere, a 0.5 M solution of KHMDS
in toluene (1.86 mL, 0.93 mmol) was added, and the mixture was stirred for
30 min at 0 °C. The mixture was cooled to -78 °C, and a solution of the lactol
(85.2 mg, 0.380 mmol) in THF (0.5) was added. The mixture was stirred for
10h at room temperature, and the reaction was quenched with a saturated
solution of NH4CI (5 mL). The product was extracted with diethylether (3x 10
mL), and the combined organic extracts were washed with a saturated
solution of NaCI, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Chromatography of the residue (4 g of silica gel, EtOAc-
Hexane, 1:3) afforded 142.4 mg (65 %) of 84 as colorless oil: [423 -120.5 (c
1.25, CHCI3); IR (neat) 3424, 2955, 2891, 1650, 1474, 1162, 1108, 1040,
927 cm-1; 1H NMR((300 MHz, CDCI3) 8 1.84 (g, J = 6 Hz, 2H), 2.01 (s br,
1H), 3.41 (s, 3H), 3.72 - 3.87 (m, 2H), 4.27 (q, J 6 Hz, 1H), 4.57 (d, J = 7 Hz,
1H), 4.72 (d, J = 7 Hz, 1H), 5.20 - 5.29 (m, 2H), 5.68 - 5.80 (m, 1H); 13C NMR
(75 MHz, CDCI3) 8 37.9, 55.8, 60.2, 76.5, 94.2, 117.6, 137.8;
238
MOMO,,
OTs
(3 S)-3-(Methoxymethoxy)-4-pentenyl
4-methylbenzenesulfonate
(85). A mixture of alcohol 84 (151 mg, 1.03 mmol), p-toluenesuphonyl
chloride (0.197 g, 1.03 mmol), DMAP (10 mg), triethylamine (0.216 mL, 1.54
mmol), and dry CH2Cl2 (20 mL) was stirred for 3 h at ambient temperature.
An aqueous solution of HCI (2%, 15 mL) was added, and the organic phase
was separated, washed with water and a saturated solution of NaCI, dried
over Na2SO4, and concentrated under reduced pressure. Chromatography
of the residue (20 g of silica gel, EtOAc- hexane, 1:3) afforded 284 mg (92 %)
of 84 as colorless oil: [a]D23 -51.6 (c 1.29, CHCI3); IR(neat) 2950, 2876, 1596,
1357, 1192, 1040, 922, 849 cm-1; 1H NMR(300 MHz, CDCI3) 6 1.79 - 2.01
(m, 2H), 2.46 (s, 3H), 3.30 (s, 3H), 4.06 - 4.25 (m, 3H), 4.47 (d, J = 7 Hz, 1H),
4.63 (d, J = 7 Hz, 1H), 5.15 - 5.21 (m, 2H), 5.55 - 5.67 (m, 1H), 7.35 (d, J =
8Hz, 2H), 7.80 (d, J = 8 Hz, 2H); 13C NMR (75 MHz, CDCI3) 6 21.8, 34.9,
55.8, 67.2, 73.6, 94.1, 118.5, 128.1, 130.0, 133.3, 137.2, 145.0; MS (CI) m/z
301 (M÷-1-1), 239, 215, 201, 173, 155, 99, 68; HRMS (CI) m/z 301.1109 (calcd
for C14H2105S: 301.1109).
239
MOMO.,
(4R)-3-[(3S)-3-(Methoxymethoxy)-4-pentenyI]-4-[(1S)-1(methoxymethoxy)-2-propeny1]-1,3-oxazolidin-2-one
(86).
To a
solution of 75 (5.00 mg, 0.0267 mmol) in benzene (0.5 mL), NaH (50 % wt
dispersion in mineral oil, 6.4 mg, 0.133 mmol), tetra-n-butylammonium
bromide (ca 1mg) and a solution of tosylate 84 (12.7 mg, 0.0347 mmol) in
benzene (0.1 mL) were added, and the resulting mixture was refluxed for 10
h. All volatiles were the removed under reduced pressure, and the obtained
residue was chromatographed (4 g of silica gel, EtOAc- hexane, 1:5) to afford
7.1 mg (84 %) of 86 as colorless oil: [a]D23 +39.9 (c 3.03, CHCI3); IR (neat)
2920, 1758, 1426, 1235, 1152, 1108, 1030, 927 cm-1; 1H NMR (300 MHz,
CDCI3) 5 1.84 - 1.93 (q, J = 8 Hz, 2H), 3.17 - 3.32 (m, 1H), 3.36 (s, 3H), 3.39
(s, 3H), 3.67 - 3.79 (m, 1H), 3.86 - 3.97 (m, 1H), 4.21 - 4.32 (m, 3H), 4.57 (d, J
= 7 Hz, 2H), 4.70 (d, J = 7Hz, 2H), 5.21 - 5.33 (m, 2H), 5.37 - 5.48 (m, 2H),
5.60 - 5.79 (m, 2H). 13C NMR (75 MHz, CDCI3) 8 32.9, 38.9, 55.8, 56.1, 58.0,
62.9, 75.1, 75.6, 94.2, 94.4, 118.1, 120.7, 132.9, 137.5, 158.5; MS (CI) m/z
316 (M++1), 284, 254, 240, 210, 184, 170, 156, 130, 100; HRMS (CI) m/z
316.1760 (calcd for C15H2606N: 316.1760).
240
Ho.,)
OH
(4R)-3-[(3S)-3-Hydroxy-4-penteny1] -4-[(18)-1 -hydroxy-2propeny1]-1,3-oxazolidin-2-one (87). To a solution of MOMether 86
(36 mg, 0.114 mmol) in CH3CN (3 mL), an aqueous solution of HBr (48%, 3
drops) was added, and the mixture was stirred for 1 h at ambient
temperature. Solid NaHCO3 (20 mg) was added, and stirring was continued
for another 30 min. The mixture was filtered over a short column of silica gel
and the obtained solution was concentrated under reduced pressure.
Chromatography of the residue (5g of silica gel, EtOAc- hexane, 5:1) afforded
16 mg (93 %) of the product as a white crystaline compound: [4,23 +11.4 (c
1.63, CHCI3); IR (neat) 3420, 2956, 1730, 1432, 1273, 1155, 1026, 934 cm1; 1H NMR(400 MHz, CDCI3) 8 1.17 - 1.81 (m, 1H), 1.85 - 1.93 (m, 1H), 3.03
(br s, 2H), 3.47 (t, J = 7 Hz, 1H), 3.87 - 3.91 (m, 1H), 4.18 - 4.27 (m, 3H), 4.45 -
4.46 (m, 1H), 5.12 (d, J = 10 Hz, 1H), 5.25 - 5.32 (m, 2H), 5.47 (dd, J = 1, 18
Hz, 1H), 5.72 5.80 (m, 1H), 5.87 5.95 (m, 1H); 13C NMR (100 MHz, CDCI3)
8 35.0, 40.0, 60.2, 69.9, 70.7, 115.0, 118.3, 135.0, 140.4, 159.8; MS(CI) m/z
228 (M++1), 210, 170, 156, 144, 116, 112, 88, 71;
241
BOCN__c'OBOC
0 LO
tert-Butyl (4R)-4-{(1S)-1-[(tert-Butoxycarbonyl)oxy]-2-prpenyI}-2oxo-1,3-oxazolidine-3-carboxylate. To a solution of 73 (8.2 mg, 0.0573
mmol) in CH2Cl2 (0.5 mL), triethyl amine (18 mL, 0.129 mmol), di-tertbutylcarbonate (41.2 mL, 0.183 mmol), and DMAP (2 mg) were added, and
the mixture was stirred for 1 h at room temperature. The solution was
concentrated under reduced pressure, and the obtained residue was
chromatographed (1 g of silica gel, EtOAc- hexane, 1:8) to afford 18.4 mg (93
%) of the product as a colorless oil: [aJD23 +47.7 (c 1.36, CHCI3); IR (neat)
2979, 2935, 1826, 1796, 1752, 1371, 1279, 1254, 1162, 1132, 1088 cm-1;
1H NMR (300 MHz, CDCI3) 8 1.47 (s, 9H), 1.57 (s, 9H), 4.24 (d, J = 9 Hz, 1H),
4.33 (d, J = 9 Hz, 1H), 4.34 (d, J = 9 Hz, 1H), 4.37 - 4.42 (m, 1H), 5.37 (d, J =
10 Hz, 1H), 5.41 - 5.49 (m, 1H), 5.72 - 5.78 (m, 1H); 13C NMR (75
MHz,CDCI3) 8 27.8, 28.1, 56.9, 61.7, 74.0, 83.5, 84.5, 119.6, 131.2, 149.2,
151.9, 152.8; MS (CI) m/z 344 (M++1), 321, 232, 216, 188, 170, 144, 126, 86;
HRMS (CI) m/z 344.1707 (calcd for Ci 6H2607N: 344.1709).
242
t
.,..,
H
BOCN
'OH
OH
tert-Butyl
(1R,2S)-2-Hydroxy-1-(hydroxymethyl)-3-
butenylcarbamate (89). To a solution of the carbamate (13.6 mg, 0.0396
mol) in dry EtOH (1 mL) a 2 M solution of EtONa in EtOH (60 11.1_, 0.120 mmol)
was added, and the mixture was stirred for 7 h at room temperature. The
reaction was quenched with solid NH4CI (40 mg), and the resulting mixture
was filtered and concentrated under reduced pressure. Chromatography of
the residue (1.5 mg of silica gel, EtOAc- hexane, 2:1) afforded 6.20 mg (72 %)
of 89 as colorless oil: [aID23 -5.4 (c 1.10, CHCI3); IR (neat) 3389, 2972, 2928,
1703, 1512, 1368, 1262, 1162, 1066 cm-1; 1H NMR (400 MHz, CDCI3)
8
1.44 (s, 9H), 3.08 (s br, 2H), 3.63 (s br, 1H), 3.68 - 3.71 (m, 1H), 3.92 (dd, J =
4, 11 Hz, 1H), 4.36 (s br, 1H), 5.24 - 5.27 (m, 1H), 5.36
5.41 (m, 1H), 5.42 (s
br, 1H), 5.88 - 5.99 (m, 1H); 13C NMR (100 MHz, CDCI3) 8 28.3, 55.0, 62.3,
74.7, 116.5, 137.4, 156.2; MS (CI) m/z 218 (M++1), 202, 188, 172, 162, 144,
118, 114, 104, 100; HRMS (CI) m/z 218.1391 (calcd for Ci 012004N :
218.1392).
243
H
BOCN
tert-Butyl (2R,4S,5R)-2-phenyl -4-vinyl -1,3-dioxan-5-ylcarbamate
(90). A mixture of diol 89 (19.0 mg, 0.0874 mmol) benzaldehyde
dimethylacetal (26.2 ilL, 0.1.75 mmol), CSA ( 2 mg), and CH2Cl2 (1 mL) was
stirred for 6 h at room temperature. Sodium bicarbonate (10 mg) was added,
and stirring was continued for another 1 h. The mixture was filtered and
concentrated under reduced pressure. Chromatography of the residue (2 g of
silica gel, EtOAc- hexane, 1:10) afforded 90 as colorless oil: [a1D23 -29.6 (c
1.55, CHCI3); IR (neat) 3360, 2979, 1694, 1528, 1308, 1235, 1171, 1020 cm-
1; 1H NMR (300 MHz, CDCI3) 6 1.46 (s, 9H), 3.58 3.65 (m, 1H), 3.73 (br s,
1H), 4.31 (d, J 8 Hz, 1H), 4.38 (dd, J = 5, 10 Hz, 1H), 5.31 (dd, J = 1, 10 Hz,
1H), 5.43 (d, J 17 Hz, 1H), 5.23 (s, 1H), 5.92 - 6.09 (m, 1H), 7.32 - 7.41 (m,
3H), 7.50 - 7.53 (m, 2H); 13C NMR (75 MHz, CDCI3) 8 28.5, 47.9, 70.1, 82.3,
101.2, 119.2, 126.4, 128.5, 129.2, 134.7, 137.8; MS (CI) m/z 250, 172, 151,
144, 107, 83, 69.
244
PMBO,
it00
---.../
(3S)- 3 -[(4- Methoxybenzyl )oxy]dihydro- 2(3H)- furanone. To a
mixture of 79 (59.2 mg, 0.405 mmol), p-methoxybenzyl 2,2,2trichloroacetimidate (228 mg, 0.810 mmol), and dry CH2Cl2 (10 mL), a 1 M
solution of trifluoromethanesulfonic acid in CH2Cl2 (12 mt, 0.0120 mmol) was
added, and the mixture was stirred for 4 h at room temperature. The reaction
was neutralized with solid NaHCO3 (10 mg) filtered, and concentrated under
reduced pressure. Chromatography of the residue (12 g of silica gel, EtOAc-
hexane, 1:3) afforded 83 mg (92 %) of the product as colorless oil: [a]p23
-56.3 (c 4.73 CHCI3); IR (neat) 2925, 1772, 1733, 1611, 1513, 1259, 1176,
1137, 1035 cm-1; 1H NMR (300 MHz, CDCI3) 8 2.20
2.32 (m, 1H), 2.38
2.49 (m, 1H), 3.81 (s, 3H), 4.13 - 4.25 (m, 2H), 4.41 (dt, J = 4, 8 Hz, 1H), 4.67
(d, J = 11 Hz, 1H), 4.87 (d, J = 11 Hz, 1H), 6.89 - 6.92 (m, 2H), 7.30 - 7.34 (m,
13C
2H);
NMR (75 MHz, CDCI3) 8 30.1, 55.5, 65.7, 72.0, 72.2, 113.9, 114.1,
129.1, 130.1, 159.7, 175.3; MS (CI) m/z 222 (M++1), 162, 137, 126, 121, 98;
HRMS (CI) m/z 222.0891 (calculated for Ci 2Fli 404: 222.0892).
245
OH
PMBO,,
0
(3S)-3[4-Methoxybenzyl)oxypetrahydo-2-furanol. To a solution of
the lactone (93.6 mg, 0.412 mmol) in CH2Cl2 (15 mL) maintained at - 78 °C,
a 1 M solution of DIBAL in hexanes (0.50 mL, 0.50 mmol) was added, and
the mixture was stirred for 30 min at -78 °C. Solid NH4CI and Me0H (1 drop)
were added, and the mixture was filtered over a short column of silica gel,
wich was subsequently rinced with a EtOAc- (5 %)MeOH mixture. The
obtained solution was concentrated under reduced pressure, and the
residue was chromatographed (10 g of silica gel, EtOAc- Hexane, 1:1) to
afford 57.3 mg (60 %) of the lactol as colorless oil: IR (neat) 3404, 2890,
16116, 1518, 1255, 1127, 1044 cm-1; 1H NMR (300 MHz, CDCI3) 8 1.92 2.25 (m, 4H), 3.79 (s, 3H), 3.80 (s, 3H), 3.97 - 4.09 (m, 4H), 4.48 - 4.56 (m,
4H), 5.30 (d, J = 4 Hz, 1H), 5.41 (s, 1H), 6.85 - 6.91 (m, 2H), 7.25 - 7.28 (m,
2H).
246
PMBO,,
OH
(3S)-3-[(4-Methoxybenzyl)oxy] -4-pentene-1-01
(91). To a
suspension of methyltriphenylphosphonium bromide (271 mg, 0.760 mmol)
in THF (20 mL), cooled to 0 °C, a 0.5 M solution of KHMDS in toluene (2.3
mL, 1.13 mmol) was added, and the mixture was stirred for 30 min at 0 °C.
The solution was cooled to -78 °C, and a solution of the lactol (85.2 mg,
0.380 mmol) in THF (0.5 mL) was added. The mixture was stirred for 18 h at
room temperature and quenched with a saturated solution of NH4CI (5 mL).
The product was extracted with diethylether (3x 8 mL), and the combined
organic extracts were washed with a saturated solution of NaCI, dried over
anhydrous
Na2S 04, and concentrated under reduced pressure.
Chromatography of the residue (4g of silica gel, EtOAc- hexane, 1:3) afforded
180.0 mg (67 %) of the product as a colorless oil: [0E]p23 -56.0 (c 1.42, CHCI3);
IR (neat) 3412, 2929, 1624, 1513, 1248, 1039, 827 cm-1; 1H NMR (300 MHz,
CDCI3) 8 1.74 - 1.92 (m, 2H), 2.15 (s br, 1H), 3.69 - 3.78 (m, 2H), 3.81 (s, 3H),
3.97 - 4.05 (m, 1H), 4.30 (d, J = 11 Hz, 1H), 4.57 (d, J = 11 Hz, 1H), 5.25 (s,
1H), 5.29 - 5.30 (m, 1H), 5.74 - 5.86 (m, 1H), 8.87 - 6.90 (m, 2H), 7.24 - 7.27
(m, 2H); 13C NMR (75 MHz, CDCI3) 6 37.9, 55.5, 60.9, 70.1, 79.8, 114.1,
117.6, 129.6, 130.1, 130.4, 138.4, 159.4; MS (CI) miz 222 (M+-F1), 203, 175,
149, 137, 121, 109, 85; HRMS (CI) m/z 222.1256 (calcd for Ci 3H-1803:
222.1256).
247
PmBa,
tert-Butyl (3S)-3-[(4-Methoxybenzyl)oxy)-4-pentenyl[(4S,5R)-2phenyl-4-vinyl-1,3-dioxolan-5-yljcarbamate (93).
To a mixture of alcohol 91 (10mg, 0.045 mmol), triethylamine (31 mL, 0.225
mmol), and CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (9.8 mL,
0.058 mmol) was added and the mixture was stirred for 1 h at 0°C. An
aqueous solution of HCI (5%, 1 mL) was added, and the organic phase was
separated and washed with a saturated solution of NaCI, dried over
anhydrous Na2SO4, concentrated under reduced pressure to afford 15.3 mg
of trifluoromethanesulfonate 92 which was not further purified.
To a solution of carbamate 75 (3.8 mg, 0.0129 mmol) in THF (0.5 mL), NaH
(50 wt % dispersion in mineral oil, 6.2 mg, 0.139 mmol) was added, and the
mixture was stirred at room temperature for 1 h. The solution was cooled to
-78 °C, and a solution of trifluoromethanesulfonate 92 (5.1 mg, 0.0193 mmol)
THF (0.2 mL) was added. The mixture was warmed to room temperature
stirred for another 10 h. The reaction was quenched with a saturated solution
of NH4CI (0.5 mL), and the product was extracted with CH2Cl2 (3x 1mL). The
obtained organic extracts were washed with a saturated solution of NaCI,
dried over anhydrous Na2SO4, and concentrated under reduced pressure.
Chromatography of the rsidue (1g of silica gel, hexane- EtOAc, 10:1) afforded
93 as colorless oil: IR (neat) 2962, 2926, 1694, 1509, 1365, 1247, 1139,
248
1108 cm-1;
1H
NMR (300 MHz, CDCI3) 8 1.48 - 1.57 (m, 9H), 1.64 - 1.82 (m,
2H), 2.01 -2.13 (m, 2), 2.99 -3.32 (m, 2H), 3.62 - 3.73 (s br, 1H), 3.79 (s, 3H),
4.13 (s br, 1H), 4.24 (d, J = 11Hz, 1H), 4.52 (d, J = 11 Hz, 1H), 5.25 (d, J = 10
Hz, 1H), 5.33 (d, J = 15 Hz, 1H), 5.36 (d, J = 15 Hz, 1H), 5.50 - 5.69 (m, 2H),
5.84 5.95 (m, 1H), 6.88 (d, J = 8 Hz, 2H), 7.26 (d, J = 8 Hz, 2H), 7.35 - 7.37
(m, 3H), 7.49 - 7.51 (m, 2H).
OTs
4-Pentenyl 4-Methylbenzenesulfonate (94a). A mixture of 4-pentene1-01 (45 gl.., 0.24 mmol), tosyl chloride (81.2 mg, 0.426 mmol), triethylamine
(77 mL, 0.554 mmol), DMAP (4 mg), and CHCI3 (2 mL) was stirred for 3 h at
ambient temperature. An aqueous solution of HCI (5%, 2 mL) was added,
and the organic phase was separated, washed with a saturated solution of
NaCI, dried over anhydrous Na2SO4, and concentrated under reduced
pressure to afford tosylate 95, which was not further purified: IR (neat) 3070,
2911, 1648, 1604, 1360, 1177, 1097, 988, 928, 824 cm-1; 1H NMR (400
MHz, CDCI3) 8 1.68 - 1.76 (m, 2H), 201 - 2.10 (m, 2H), 2.44 (s, 3H), 4.02 (t, J
= 6 Hz, 1H), 4.93 (s, 1H), 4.95 - 4.97 (m, 1H), 5.63 5.73 (m, 1H), 7.34 (d, J =
8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H); 13C NMR (100 MHz, CDCI3) 8 21.8, 28.2,
29.5, 70.0, 116.0, 128.1, 130.0, 133.4, 136.1, 144.9; MS (CI) m/z 3070, 2911,
1648, 1604, 1360, 1177, 1097, 988, 928, 824; HRMS (CI) m/z 241.0899
(calcd for Ci 2H-1703S: 241.0894).
249
(4R)-4-[(1S)-1-(Methoxymethoxy)-2-propeny1]-3-(4-penteny1)-1,3oxazolidin-2-one (95). To a solution of 75 (7.3 mg, 0.0390 mmol) in dry
THE (2 mL), NaH (50 wt % dispersion in mineral oil, 8 mg, 0.390 mmol),
tetrabutylammonium iodide (1 mg), and 4-pentene-1-ol-tosylate (12.2 mg,
0.055 mmol) were added, and the mixture was stirred for 16 h at 70 °C. The
reaction was quenched with a saturated solution of NH4CI, and the organic
phase was saparated, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. Chromatography of the residue (2 g of silica gel,
EtOAc- hexane, 3:1) afforded 7.0 mg (70 %) of 95 as colorless oil: [a]D23 +91.3
(c 0.53, CHCI3); IR (neat) 2920, 1753, 1435, 1235, 1167, 1044, 922 cm-1; 1H
NMR (400 MHz, CDCI3) 8 1.61 - 1.79 (m, 2H), 2.08 - 2.13 (q, J = 7 Hz, 1H),
2.99 - 3.19 (m, 1H), 3.32 (s, 3H), 3.58 3.66 (m, 1H), 3.85 - 3.89 (m, 1H), 4.21
- 4.29 (m, 3H), 4.55 (d, J = 7 Hz, 1H), 4.69 (d, J = 7 Hz, 1H), 4.99 - 5.08 (m,
2H), 5.39 - 5.45 (m, 2H), 5.62 - 5.71 (m, 1H), 5.79 - 5.86 (m, 1H); 130 NMR
(100 MHz, CDCI3) 8 26.4, 31.0, 41.7, 56.2, 57.8, 62.8, 75.0, 94.4, 115.6,
120.7, 133.0, 137.6, 158.6; MS (CI) m/z 256 (M++1), 226, 224, 196, 194,
180, 170, 156, 154, 126, 110, 100, 95, 86; HRMS (CI) m/z 256.1550 (calcd
for: C13H2204N: 256.1549).
250
(10S,10aR)-10-(Methoxymethoxy)-1,5,6,7,10,10a-
hexahydro[1,3]oxazolo[3,4-a]azocin-3-one (96). To a solution of
diene 95 (6.3 mg, 0.0246 mmol) under an argone atmosphere, a Grubbs'
catalyst (4.5 mg, 5.50 grnol) was added, and the mixture was stirred for 18 h
at 60 °C. The mixture was the concentrated under reduced pressure, and the
residue was chromatographed (3 g of silica gel, EtOAc- hexane, 1:1) to afford
4.12 mg (75%) as colorless oil: [a]023 +89.7 (c 0.38, CHCI3); IR (neat) 2931,
2847, 1758, 1455, 1420, 1375, 1241, 1162, 1112, 1042, 993 cm-1; 1H NMR
(400 MHz, CDCI3) 8 1.40 - 1.48 (m, 1H), 2.10 - 2.31 (m, 3H), 2.85 - 2.93 (m,
1H), 3.42 (s, 3H), 3.46 - 3.52 (m, 1H), 3.73 (dd, J = 5, 14 Hz, 1H), 4.29 (dd, J =
5, 9 Hz, 1H), 4.38 4.46 (m, 2H), 4.78 (d, J = 7Hz, 1H), 4.57 (d, J = 6 Hz, 1H),
5.58 (dd, J = 6 Hz, 1H), 5.77 - 5.84 (m, 1H); 13C NMR (100 MHz, CDCI3) 8
24.0, 26.5, 42.9, 56.5, 61.3, 66.8, 76.1, 94.9, 131.8, 132.2, 159.1; MS (CI) m/z
228 (M++1), 214, 198, 194, 182, 166, 154, 138, 122, 97, 83; HRMS (CI) m/z
228.1236 (calcd for C11 H1804N: 228.1236).
251
(10S,10aR)-10-Hydroxy-1,5,6,10,10a-hexahydro[1,3]oxazolo[3,4a]azocin-3-one (98). To a solution of MOMether 96 (6 mg, 0.0264 mmol)
in CH3CN (1 mL), an aqueous solution of HBr (48 %, 1 drop) was added,
and the mixture was stirred for 2 h at ambient temperature. The mixture was
neutralized with solid NaHCO3, and filtered over a short column of silica gel.
The resulting solution was concentrated under reduced pressure, and the
residue was chromatographed (2 g of silica gel, EtOAc- hexane, 2:1) to afford
4.5 mg (94%) of the product as a white solid: [a]D23 +28.6 (c 1.26, CHCI3); IR
(neat) 3321, 2935, 1738, 1465, 1377, 1245, 1074 cm-1; 1H NMR (300 MHz,
CDCI3) 8 1.37 - 1.47 (m, 1H), 2.08 - 2.24 (m, 3H), 2.17 (s, 3H), 2.58 (br s, 1H),
2.85 - 2.95 (m, 1H), 3.39 - 3.47 (m, 1H), 3.69 (dd, J = 5, 14 Hz, 1H), 33.39
4.46 (m, 2H), 5.64 - 5.72 (m, 2H); 13C NMR (75 MHZ, CDCI3) 8 23.9, 26.3,
42.7, 62.4, 67.0, 71.7, 129.9, 134.2, 159.4; MS (CI) m/z 184 (KA-1F1), 170,
140, 122, 96, 88, 70; HRMS (CI) m/z 184.0971 (calcd for C9H1403N:
184.0974).
252
H
(1 aR,8aR,9R,9aS)-9-Hydroxyoctahydro[1,3]oxazolo[3,4a]oxireno[2,3-d]azocin-6-one (99). To a solution of the olefin (12 mg,
0.0655 mmol) in CH2Cl2 (2 mL), m-CPBA (50 wt %, 56.5 mg, 0.162 mol) was
added, and the mixture was stirred for 7 h at ambient temperature. Methyl
sulfide (50 gL) and solid NaHCO3 (40 mg) were added, and the reaction was
stirred for another 1 h at room temperature. The mixture was filtered over
short column of silica gel and concentrated under reduced pressure.
Chromatography of the residue (2 g of silica gel, EtOAc- hexane, 3:1) afforded
9.6 mg (74%) of 99 as a white crystalline compound: [a]D23 +34.2 (c 0.88,
CH3CN); IR (neat) 3292, 2915, 1714, 1450, 1264, 1250, 1079 cm-1; 1H NMR
(400 MHz, CDCI3) 1.19 - 1.38 (m, 1H), 1.61 - 1.68 (m, 1H), 2.14 - 2.23 (m,
1H), 2.96 - 3.04 (m, 2H), 3.06 - 3.11 (m, 1H), 3.59 (dd, J = 7, 10 Hz, 1H), 3.66
- 3.72 (m, 1H), 3.88 (dd, J = 5, 14 Hz, 1H), 4.35 (dd, J 6, 9 Hz, 1H), 4.46 (t, J =
9Hz, 1H); 13C NMR (100 MHz, CDCI3) 8 23.0, 23.7, 43.9, 55.2, 58.4, 59.2,
65.8, 74.8, 158.9;
253
(1aR,8aR,9R,9aR)-9-(Benzyloxy)octahydro(1 ,3]oxazolo[3,4-
a]oxireno[2,3-d]azocon-6-one (100). A mixture of the secondary
alcohol (3.0 mg, 0.0150 mmol), benzyl bromide (20 gL, 0.168 mmol), tetra-n-
butyl ammonium iodide (1 mg), and of THE (2 mL) was stirred for 4 h at
ambient temperature. A saturated solution of NH4CI was added, and the
product was extracted with EtOAc (3x 2 mL). The combined organic extracts
were washed with a saturated solution of NaCI, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Chromatography of the
residue (3 g of silica gel, EtOAc- hexane, 1:1) afforded 4.3 mg (98 %) of 100
as white crystaline compound: [a]D23 +64.2 (c 0.24, CHCI3); IR(neat) 2911,
2842, 1763, 1454, 1426, 1377, 1259, 1147, 1003 cm-1; 1H NMR (400 MHz,
CDCI3) 8 1.20 - 1.31 (m, 1H), 1.61 - 1.70 (m, 2H), 2.05 2.23 (m, 2H), 2.96
3.05 (m, 2H), 3.36 (dd, J = 7, 10 Hz, 1H), 3.69 - 3.75 (m, 1H), 3.88 (dd, J = 5,
14 Hz, 1H), 4.15 (dd, J = 6, 9 Hz, 1H), 4.43 (t, J = 9 Hz, 1H), 4.61 (d, J = 11
Hz, 1H), 4.90 (d, J = 11 Hz, 1H), 7.31 - 7.53 (m, 5H); 13C NMR (100 MHz,
CDCI3) 8 23.1, 23.7, 44.1, 53.0, 57.1, 58.7, 66.2, 71.9, 80.6, 127.9, 128.4,
128.5, 128.8, 137.2, 158.8;
254
(1 R,2R,3R,7aS)- Benzyloxy -3- (hydroxymethyl)hexahydro -1 Hpyrrolizine -1,2 -diol (101). To a solution of epoxide 100 (2.5 mg, 8.6
grid) in a Et0H-H20 mixture (0.5 mL), Li0H-H20 (3.6 mg, 0.086 mmol) was
added, and the mixture was stirred for 24 h at 96 °C. The mixture was
concentrated under reduced pressure, and the product was extracted with
CHC13 (5x0.5 mL). The combined organic extracts were dried with
anhydrous Na2SO4 amd concentrated under reduced pressure. to afford 2.2
mg (100 %) of 101 as colorless oil: 1H NMR (300 MHz, CDCI3) 6 1.80
1.89
(m, 1H), 1.91 - 2.07 (m, 3H), 2.84 - 2.94 (m, 1H), 3.01 (q, J = 8 Hz, 1H), 3.24
(br s, 1H), 3.55 - 3.67 (m, 1H), 3.73 (dd, J = 6, 12 Hz, 1H), 3.89 (dd, J = 3, 12
Hz, 1H), 3.95 - 3.96 (m, 1H), 4.08 - 4.09 (m, 1H), 4.61 (d, J = 12 Hz, 1H), 4.66
(d, J = 12 Hz, 1H), 7.28 7.37 (m, 5H).
255
Chapter VIII. Conclusion
The research presented above resulted in the total synthesis of two
alkaloidal compounds, (+)-morphine and australine, and a derivative of a
third, namely 2-0-benzyI-7-deoxyalexine.
The synthesis of (+)-morphine was accomplished by a novel
sequence that required 28 steps and resulted in a 2.5% overall yield. The
morphine pentacyclic framework 119 was constructed by a regioselective C-
H carbenoid insertion which established configuration at the C13 quaternary
center in a stereospecific manner. The nitrogen atom of morphine was
incorporated via Beckmann rearrangement of oxime 136. This sequence of
transformations affords a series of novel morphine analogs which may find
application in medical practice or in investigations of the mode of action of
this important analgesic.
Synthesis of australine and its close relative 2-O- benzyl -7- deoxyalexine is based on transannular opening of an azacyclooctene epoxide by
an amine generated in situ through cleavage of an oxazolidinone. The
configuration of epoxides 66 and 99 was dictated by substrate directed
epoxidation of the corresponding azacyclooctene precursor, which was
prepared from an acyclic diene via ring-closing metathesis.
Thus, ring-
closing metathesis in tandem with transannular cyclization was shown to be
a concise and efficient strategy for assembly of the polyhydroxylated
pyrrolizidine alkaloids australine and 7-deoxyalexine. Modification of this
route by altering the configuration of the initial epoxide 41 should afford
access to other members of the alexine family of alkaloids.
256
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263
Appendices
264
APPENDIX A
SUPPLEMENTARY CRYSTALLOGRAPHIC INFORMATION ON
EPDXIDE 62
265
Table 1.
Crystal Data and Structure Refinement for Epoxide 62.
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
C12H17N05
255.27
296(2) K
1.54178 A
Monoclinic
12
a = 18.5115(7)A
a = 90°.
b = 6.3719(3)A
b = 102.615(4)°.
g = 90°.
c = 11.2035(4)A
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [1>2sigma(1)]
R indices (all data)
Absolute structure parameter
Extinction coefficient
Largest diff. peak and hole
1289.59(9)A3
4
1.315 Mg/m3
0.863 mm-1
544
0.75 x 0.25 x 0.15 mm3
4.24 to 57.30°.
-20<=h<=20, -6<=k<=6, -12<=k=12
1908
1666 [R(int) = 0.0319]
Empirical (psi-scans)
0.8814 and 0.5637
Full-matrix least-squares on F2
1666 / 1 / 173
1.046
R1 = 0.0410, wR2 = 0.1080
R1 = 0.0414, wR2 = 0.1083
0.3(3)
0.0104(8)
0.155 and -0.154 e.A-3
266
Table 2. Atomic Coordinates ( x 104) and Equivalent Isotropic
Displacement Parameters (A2x 103) for Epoxide 62.
U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
Atom
N
0(1)
0(2)
0(3)
0(4)
0(5)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
x
7672(1)
7024(1)
8840(1)
9399(1)
7265(1)
8467(1)
8389(1)
8650(1)
8276(1)
7598(2)
6896(2)
6818(2)
6947(1)
7747(1)
8864(1)
9531(1)
10053(2)
9828(2)
y
7053(3)
3137(5)
3016(4)
5408(4)
6810(3)
7217(3)
7249(4)
5166(4)
4346(5)
3097(5)
4142(6)
6476(6)
7467(4)
7019(4)
7935(5)
3954(6)
2250(7)
5177(9)
z
4018(2)
6612(2)
7119(2)
6104(2)
1924(2)
2798(2)
4861(2)
5449(2)
6432(2)
5939(2)
5431(3)
5427(3)
4275(2)
2839(2)
3980(2)
7097(2)
6871(3)
8238(3)
U(eq)
43(1)
93(1)
68(1)
60(1)
67(1)
62(1)
43(1)
42(1)
47(1)
59(1)
66(1)
63(1)
55(1)
50(1)
60(1)
63(1)
93(1)
113(2)
267
Table 3.
Bond Lengths [A] and Angles [°] for Epoxide 62.
N-C(8)
N-C(7)
1.358(3)
1.457(3)
N-C(1)
1.457(3)
O(1) -C(4)
1.431(4)
O(1) -C(5)
1.442(3)
0(2)-C(10)
O(3) -C(2)
1.416(4)
1.432(3)
1.427(3)
1.429(3)
0 (4)-C (8)
1.210(3)
O(5) -C(8)
O(5) -C(9)
1.349(3)
1.441(3)
C(1)-C(2)
C(1)-C(9)
1.514(4)
1.523(3)
C (2)-C (3)
1.516(4)
C(3)-C(4)
C(4)-C(5)
C(5) -C(6)
1.486(4)
1.461(4)
1.494(5)
C(6)-C(7)
1.501(4)
C(10)-C(12)
C(10)-C(11)
1.496(5)
1.511(5)
O(2) -C(3)
0(3)-C(10)
C(8)-N-C(7)
C(8)-N-C(1)
C(7)-N-C(1)
C(4)-0(1)-C(5)
C(10)-0(2)-C(3)
119.35(19)
111.1(2)
C(10)- O(3) -C(2)
108.15(19)
107.98(19)
111.5(2)
C(8)- O(5) -C(9)
N-C(1)-C(2)
N-C(1)-C(9)
C(2)-C(1)-C(9)
O(3)- C(2) -C(1)
127.17(19)
61.12(17)
107.3(2)
100.24(18)
111.0(2)
108.1(2)
268
O(3)- C(2) -C(3)
102.17(17)
C(1)-C(2)-C(3)
117.7(2)
O(2)- C(3) -C(4)
109.9(2)
0(2)-C(3)-C(2)
C(4)-C(3)-C(2)
0(1)-C(4)-C(5)
0(1)-C(4)-C(3)
C(5)-C(4)-C(3)
0(1)-C(5)-C(4)
0(1)-C(5)-C(6)
C(4)-C(5)-C(6)
C(5)-C(6)-C(7)
N-C(7)-C(6)
0(4)-C(8)-0(5)
101.44(18)
113.4(2)
59.80(18)
117.3(3)
120.5(3)
59.08(18)
116.2(3)
122.1(3)
112.8(3)
114.8(2)
122.1(2)
O(4)- C(8) -N
127.8(2)
0(5)-C(8)-N
110.1(2)
O(5)- C(9) -C(1)
104.6(2)
O(2)- C(10) -O(3)
106.64(17)
0(2)-C(10)-C(12)
0(3)-C(10)-C(12)
0(2)-C(10)-C(11)
0(3)-C(10)-C(11)
C(12)-C(10)-C(11)
111.6(2)
107.3(3)
108.2(3)
110.0(2)
112.9(3)
Symmetry transformations used to generate equivalent atoms:
269
Table 4.
Anisotropic Displacement Parameters (A2x 103) for
Epoxide 62.
The anisotropic displacement factor exponent takes the form:
-2 p2[ h2a*2U11 + ... + 2 h k a* b* U12 ]
Ull
U22
U33
U23
U13
U12
N
39(1)
40(1)
7(1)
3(1)
0(1)
0(1)
0(2)
0(3)
0(4)
0(5)
56(1)
47(1)
135(2)
96(2)
89(1)
66(1)
76(1)
45(1)
54(1)
63(2)
60(2)
92(2)
90(3)
62(2)
44(1)
66(2)
103(2)
115(3)
186(5)
91(2)
62(2)
26(1)
-1(1)
56(1)
52(1)
42(1)
51(1)
43(1)
36(1)
13(1)
19(1)
20(1)
4(1)
5(1)
-5(1)
5(1)
-3(1)
14(1)
20(1)
2(1)
1(1)
4(1)
-1(1)
36(1)
4(1)
7(1)
5(1)
39(1)
9(1)
9(1)
9(1)
64(2)
59(2)
57(2)
15(1)
16(1)
20(2)
5(2)
8(1)
14(1)
-3(1)
-8(2)
15(1)
17(1)
6(1)
9(1)
9(1)
8(1)
0(1)
19(2)
10(1)
-6(1)
41(1)
16(1)
7(1)
15(1)
96(2)
54(2)
26(2)
-19(3)
22(2)
38(2)
10(2)
-11(3)
Atom
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
54(1)
37(1)
84(1)
63(1)
39(1)
35(1)
41(1)
55(2)
48(2)
45(1)
42(1)
60(2)
48(1)
44(1)
71(2)
95(3)
60(1)
45(1)
64(2)
270
Table 5.
Hydrogen Coordinates ( x 104) and Isotropic
Displacement Parameters (A2x 103) for Epoxide 62.
Atom
H(1A)
x
H (3A)
8378(1)
8625(2)
8156(5)
H(4A)
7671(4)
H (5A)
6574(13)
7177(9)
6314(13)
6576(10)
6886(2)
8922(2)
9363(13)
9838(3)
10137(3)
10515(2)
9476(2)
10287(2)
9910(2)
H(2A)
H(6A)
H(6B)
H(7A)
H(7B)
H(9A)
H(9B)
H(11A)
H(11B)
H(11C)
H(12A)
H(12B)
H(12C)
y
8290(5)
4040(4)
5600(5)
1840(6)
3420(3)
7062(16)
6841(11)
6973(13)
8950(4)
9490(4)
7280(17)
1523(13)
1277(8)
2867(6)
6237(11)
5830(10)
4248(8)
z
5460(3)
4780(3)
6980(2)
5592(16)
4790(3)
6136(18)
5524(4)
3602(18)
4330(2)
3987(2)
4200(6)
6127(5)
7542(5)
6800(6)
8337(3)
8181(4)
8930(4)
U(eq)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
82(3)
271
APPENDIX B
SUPPLEMENTARY CRYSTALLOGRAPHIC INFORMATION ON
EPDXIDE 66
C(123)
C(124)
C(125)
272
Table 1.
Crystal Data and Structure Refinement for Epoxide 66.
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
C23H25N05
395.44
296(2) K
1.54178 A
Monoclinic
P21
a = 12.786 (1) A
b = 8.207 (1) A
c = 19.320(1) A
2026.5(1) A 3
4
1.296 Mg/m3
0.746 mm-1
a= 90°
b= 91.68(1) °
g = 90°
840
0.50 x 0.40 x 0.10 mm3
2.29 to 57.26 °.
-13<=h<=13, -8<=k<=8, -21<=k=21
6002
5305 [R(int) = 0.0220]
Psi-scans
0.9292 and 0.7069
Full-matrix least-squares on F2
5305 / 228 / 590
Absolute structure parameter
1.051
R1 = 0.0418, wR2 = 0.1061
R1 = 0.0475, wR2 = 0.1116
0.0(2)
Extinction coefficient
Largest diff. peak and hole
0.00236(19)
0.156 and -0.153 e. A -3
Final R indices [1>2sigma(I)]
R indices (all data)
273
Table 2. Atomic Coordinates ( x 104) and Equivalent Isotropic
Displacement Parameters (A 2x 103) for Epoxide 66.
U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
Atom
x
N(1)
3742(2)
2320(2)
3849(2)
5785(2)
4648(2)
5256(2)
5534(2)
4846(2)
3828(2)
2910(2)
2903(2)
1948(2)
3362(3)
1947(1)
1378(2)
289(2)
-467(2)
-1479(2)
-1748(3)
-1013(3)
0(111)
0(112)
0(113)
C(111)
C(112)
C(113)
C(114)
C(115)
C(116)
C(117)
C(118)
C(119)
0(121)
C(121)
C(122)
C(123)
C(124)
C(125)
C(126)
C(127)
0(131)
C(131)
C(132)
C(133)
C(134)
C(135)
C(136)
3(2)
3563(2)
4148(2)
3813(2)
2768(3)
2451(3)
3188(4)
4225(4)
y
912(3)
-281(3)
-704(3)
979(3)
1945(5)
2338(4)
842(5)
127(4)
832(4)
434(3)
1373(3)
925(5)
-68(4)
899(2)
-425(4)
135(4)
211(4)
666(4)
1061(5)
1022(5)
554(4)
71(3)
671(4)
2336(4)
2707(5)
4201(5)
5361(5)
5005(5)
z
8981(1)
9388(1)
9957(1)
7401(1)
9137(2)
8504(2)
8122(2)
7589(1)
7332(1)
7796(1)
8485(1)
8894(2)
9487(2)
7454(1)
7139(2)
6957(2)
7450(2)
7278(2)
6614(2)
6119(2)
6286(2)
6676(1)
6105(1)
5870(1)
5784(2)
5537(2)
5387(2)
5469(2)
U(eq)
52(1)
68(1)
88(1)
76(1)
68(1)
70(1)
65(1)
55(1)
48(1)
44(1)
50(1)
68(1)
61(1)
47(1)
62(1)
52(1)
61(1)
72(1)
80(1)
75(1)
62(1)
60(1)
64(1)
56(1)
67(1)
78(1)
89(1)
90(1)
274
C(137)
N (2)
0(211)
0(212)
0(213)
C(211)
C(212)
C(213)
C(214)
C(215)
C(216)
C(217)
C(218)
C(219)
0(221)
C(221)
C(222)
C(223)
C(224)
C(225)
C(226)
C(227)
0(231)
C(231)
C(232)
C(233)
C(234)
C(235)
C(236)
C(237)
C(241)
C(242)
C(243)
C(244)
C(245)
4541(3)
11961(2)
10602(2)
12212(2)
13619(2)
12935(2)
13418(2)
13531(2)
3508(5)
864(3)
-165(3)
-786(3)
682(3)
1765(5)
2069(4)
537(4)
12702(2)
11678(2)
-86(4)
734(4)
10871(2)
11047(2)
422(3)
1404(4)
1058(5)
-86(4)
912(2)
-425(4)
215(4)
318(4)
788(5)
1189(4)
1140(4)
653(4)
47(3)
10176(3)
11652(3)
9861(1)
9217(3)
8159(2)
7359(3)
6379(3)
6176(3)
6947(3)
7939(3)
11225(2)
11629(18)
11697(14)
10816(15)
10825(16)
11763(17)
12660(14)
12636(13)
11935(17)
11709(14)
10696(13)
10508(14)
11330(16)
350(2)
2120(2)
3090(2)
4690(2)
5366(19)
4430(2)
2820(2)
458(19)
2160(2)
2710(2)
4300(2)
5360(2)
5711(2)
3926(1)
4475(1)
4881(1)
2157(1)
3983(2)
3291(2)
2893(2)
2436(2)
2279(1)
2838(1)
3510(1)
4013(2)
4466(2)
2581(1)
2356(2)
2136(2)
2594(2)
2379(2)
1707(2)
1254(2)
1458(2)
1658(1)
1024(13)
850(2)
804(12)
579(12)
406(9)
445(9)
658(9)
1058(10)
820(2)
677(11)
483(10)
441(13)
73(1)
56(1)
76(1)
96(1)
82(1)
72(1)
71(1)
67(1)
65(1)
55(1)
50(1)
52(1)
80(1)
67(1)
57(1)
89(1)
57(1)
69(1)
81(1)
80(1)
76(1)
68(1)
79(1)
83(5)
75(5)
86(5)
92(5)
84(4)
86(4)
74(4)
69(4)
72(4)
77(4)
89(4)
96(5)
275
C(246)
C(247)
12351(15)
12521(13)
4890(2)
3280(2)
574(11)
775(11)
97(5)
84(5)
276
Table 3.
Bond Lengths [A] and Angles [°] for Epoxide 66.
N(1)-C(119)
N(1)-C(111)
N(1)-C(117)
0(111)-C(119)
0(111)-C(118)
0(112)-C(119)
0(113)-C(113)
0(113)-C(114)
C(111)-C(112)
C(112)-C(113)
C(113)-C(114)
C(114)-C(115)
C(115)-0(131)
C(115)-C(116)
C(116)-0(121)
C(116)-C(117)
C(117)-C(118)
0(121)-C(121)
C(121)-C(122)
C(122)-C(123)
C(122)-C(127)
C(123)-C(124)
C(124)-C(125)
C(125)-C(126)
C(126)-C(127)
0(131)-C(131)
C(131)-C(132)
C(132)-C(133)
C(132)-C(137)
C(133)-C(134)
C(134)-C(135)
C(135)-C(136)
1.367(4)
1.459(4)
1.467(3)
1.352(4)
1.446(4)
1.205(4)
1.443(4)
1.445(3)
1.503(4)
1.482(5)
1.458(4)
1.496(4)
1.443(3)
1.533(3)
1.432(3)
1.537(4)
1.519(4)
1.433(3)
1.499(4)
1.379(4)
1.381(4)
1.377(4)
1.359(5)
1.360(5)
1.383(5)
1.438(3)
1.499(5)
1.376(4)
1.379(5)
1.373(5)
1.377(6)
1.363(5)
277
C(136)-C(137)
N(2)-C(219)
N(2)- C(211)
N(2)- C(217)
0(211)-C(219)
0(211)-C(218)
0(212)-C(219)
0(213)-C(213)
0(213)-C(214)
C(211)-C(212)
C(212)-C(213)
C(213)-C(214)
C(214)-C(215)
C(215)-0(231)
C(215)-C(216)
C(216)-0(221)
C(216)-C(217)
C(217)-C(218)
0(221)-C(221)
C(221)-C(222)
C(222)- C(223)
C(222)-C(227)
C(223)- C(224)
C(224)-C(225)
C(225)- C(226)
C(226)-C(227)
0(231)-C(231)
0(231)-C(241)
C(231)-C(232)
C(232)-C (233)
C(232)-C(237)
C(233)-C(234)
C(234)-C (235)
C(235)-C(236)
C(236)-C(237)
1.371(6)
1.369(4)
1.449(4)
1.468(3)
1.345(4)
1.440(4)
1.204(4)
1.434(4)
1.449(4)
1.509(4)
1.483(5)
1.453(5)
1.495(4)
1.433(3)
1.537(4)
1.428(3)
1.539(4)
1.525(4)
1.432(4)
1.502(4)
1.374(4)
1.378(4)
1.364(5)
1.358(5)
1.337(5)
1.377(5)
1.37(2)
1.531(19)
1.493(12)
1.380(11)
1.390(12)
1.379(12)
1.374(12)
1.378(12)
1.387(13)
278
C(241)-C(242)
C(242)-C(243)
C(242)-C(247)
C(243)-C(244)
C(244)-C(245)
C(245)-C(246)
C(246)-C(247)
C(119)-N(1)-C(111)
C(119)-N(1)-C(117)
C(111)-N(1)-C(117)
C(119)-0(111)-C(118)
C(113)-0(113)-C(114)
N(1)-C(111)-C(112)
C(113)-C(112)-C(111)
0(113)-C(113)-C(114)
0(113)-C(113)-C(112)
C(114)-C(113)-C(112)
0(113)-C(114)-C(113)
0(113)-C(114)-C(115)
C(113)-C(114)-C(115)
0(131)-C(115)-C(114)
0(131)-C(115)-C(116)
C(114)-C(115)-C(116)
0(121)-C(116)-C(115)
0(121)-C(116)-C(117)
C(115)-C(116)-C(117)
N(1)-C(117)-C(118)
N(1)-C(117)-C(116)
C(118)-C(117)-C(116)
0(111)-C(118)-C(117)
0(112)-C(119)-0(111)
0(112)-C(119)-N(1)
0(111)-C(119)-N(1)
C(116)-0(121)-C(121)
0(121)-C(121)-C(122)
1.502(11)
1.389(12)
1.389(12)
1.380(12)
1.369(12)
1.379(13)
1.393(13)
119.4(2)
110.5(2)
123.1(2)
108.0(2)
60.64(18)
112.5(3)
111.4(3)
59.73(18)
118.7(3)
122.4(3)
59.63(18)
116.8(2)
125.5(3)
107.7(2)
104.9(2)
113.3(2)
109.57(19)
103.79(19)
115.1(2)
100.4(2)
114.3(2)
110.8(2)
104.8(2)
122.4(3)
127.4(3)
110.2(3)
114.4(2)
108.9(2)
279
C(123)-C(122)-C(127)
C(123)-C(122)-C(121)
C(127)-C(122)-C(121)
C(124)-C(123)-C(122)
C(125)-C(124)-C(123)
C(124)-C(125)-C(126)
117.8(3)
121.2(3)
121.0(3)
121.2(3)
120.2(3)
119.8(3)
C(125)-C(126)-C(127)
C(122)-C(127)-C(126)
120.5(3)
C(131)- O(131)- C(115)
114.3(2)
0(131)-C(131)-C(132)
C(133)-C(132)-C(137)
C(133)-C(132)-C(131)
C(137)-C(132)-C(131)
C(134)-C(133)-C(132)
C(133)-C(134)-C(135)
C(136)-C(135)-C(134)
C(135)-C(136)-C(137)
C(136)-C(137)-C(132)
C(219)-N(2)-C(211)
C(219)-N(2)-C(217)
C(211)-N(2)-C(217)
C(219)-0(211)-C(218)
C(213)-0(213)-C(214)
N(2)-C(211)-C(212)
C(213)-C(212)-C(211)
0(213)-C(213)-C(214)
0(213)-C(213)-C(212)
C(214)-C(213)-C(212)
0(213)-C(214)-C(213)
0(213)-C(214)-C(215)
C(213)-C(214)-C(215)
0(231)-C(215)-C(214)
0(231)-C(215)-C(216)
C(214)-C(215)-C(216)
0(221)-C(216)-C(215)
113.2(2)
120.5(3)
118.6(3)
120.4(3)
121.0(3)
121.0(3)
119.6(4)
119.8(4)
120.5(4)
120.5(4)
120.0(3)
110.2(2)
123.7(3)
108.5(2)
60.50(19)
113.0(3)
111.6(3)
60.3(2)
117.1(3)
122.2(3)
59.2(2)
116.3(3)
125.7(3)
108.8(3)
105.1(2)
112.6(2)
109.1(2)
280
0(221)-C(216)-C(217)
C(215)-C(216)-C(217)
N(2)-C(217)-C(218)
N(2)-C(217)-C(216)
C(218)-C(217)-C(216)
0(211)-C(218)-C(217)
0(212)-0(219)-0(211)
0(212)-C(219)-N(2)
0(211)- C(219) -N(2)
C(216)-0(221)-C(221)
0(221)-C(221)-C(222)
C(223)-C(222)-C(227)
C (223)-C(222)-C (221)
C(227)-C (222)-C (221)
C (224)-C (223)-C(222)
C(225)- C(224)- C(223)
C (226)-C (225)-C(224)
C(225)-C (226)-C (227)
C (226)-C (227)-C(222)
C(231)-0(231)-C(215)
C(231)-0(231)-C(241)
C(215)-0(231)-C(241)
0(231)-C(231)-C(232)
C(233)-C(232)-C(237)
C (233)-C (232)-C(231)
C(237)-C(232)-C(231)
C(234)-C (233)-C (232)
C (235) -C (234) -C (233)
C(234)-C(235)-C(236)
C(235)-C(236)-C(237)
C(236)-C(237)-C(232)
C(242)-C(241)-0(231)
C(243)-C (242) -C (247)
C(243)-C(242)-C(241)
C(247)-C(242)-C(241)
104.7(2)
114.9(2)
100.4(2)
113.4(2)
110.3(3)
104.8(2)
122.8(3)
126.8(4)
110.4(3)
113.3(2)
108.9(3)
117.4(3)
121.4(3)
121.1(3)
121.1(3)
120.5(3)
119.6(3)
120.8(3)
120.5(3)
121.6(10)
14.6(15)
108.3(8)
114(2)
117.1(12)
121.4(13)
121.2(13)
123.5(13)
118.6(12)
119.5(11)
121.3(12)
120.0(12)
109.2(16)
118.1(11)
122.0(13)
119.8(14)
281
C(244)-C(243)-C(242)
120.7(12)
C(245)-C(244)-C(243)
C(244)-C(245)-C(246)
C(245)-C(246)-C(247)
C(242)-C(247)-C(246)
119.5(13)
122.3(14)
117.2(13)
122.2(12)
282
Table 4.
Anisotropic Displacement Parameters (A2x 103) for
Epoxide 66.
The anisotropic displacement factor exponent takes the form:
-2 p2[ h2a*2U11 + ... + 2 h k a* b* U12 ]
Atom
U11
U22
U33
U23
U13
U12
N(1)
48(1)
51(1)
5(1)
-5(1)
0(111)
0(112)
0(113)
C(111)
C(112)
70(1)
58(1)
73(2)
90(2)
99(2)
78(2)
73(2)
80(2)
55(2)
44(2)
43(2)
52(2)
93(2)
56(2)
42(1)
50(2)
46(2)
59(2)
61(2)
54(2)
57(2)
59(2)
61(1)
75(2)
65(2)
78(2)
92(3)
72(3)
75(3)
60(1)
5(1)
4(1)
-7(1)
64(1)
20(1)
77(1)
3(1)
68(2)
-7(2)
-8(2)
-7(2)
79(2)
1(2)
-5(2)
70(2)
11(2)
2(1)
-13(2)
5(2)
63(2)
1(1)
14(1)
1(1)
47(1)
-1(1)
5(1)
0(1)
47(1)
5(1)
0(1)
3(1)
50(2)
-2(1)
-2(1)
5(1)
55(2)
4(2)
7(1)
9(2)
54(2)
0(2)
5(2)
7(2)
58(1)
0(1)
-7(1)
2(1)
83(2)
-14(2)
63(2)
-11(2)
-4(1)
-3(1)
-7(1)
59(2)
-5(1)
3(1)
101(3)
13(2)
-20(2)
2(2)
82(2)
-15(2)
-7(2)
9(2)
-6(2)
-2(2)
-26(2)
-6(2)
64(2)
1(2)
0(1)
46(1)
-4(1)
9(1)
49(2)
5(2)
14(1)
-13(2)
-8(1)
9(2)
44(2)
-4(1)
59(2)
1(2)
61(2)
C(113)
C(114)
C(115)
C(116)
C(117)
C(118)
C(119)
0(121)
C(121)
C(122)
C(123)
C(124)
C(125)
110(2)
51(1)
58(2)
57(2)
45(2)
46(2)
51(1)
42(1)
46(1)
56(2)
72(2)
41(1)
51(2)
48(2)
66(2)
54(2)
57(2)
C(126)
C(127)
84(2)
0(131)
72(1)
C(131)
C(132)
C(133)
C(134)
C(135)
C(136)
68(2)
64(2)
60(2)
64(2)
82(2)
130(4)
111(3)
127(3)
14(1)
-9(1)
17(1)
-4(1)
25(2)
-8(1)
5(1)
2(2)
13(2)
7(2)
-4(2)
9(2)
25(2)
66(2)
8(2)
1(2)
24(3)
83(2)
10(2)
-4(2)
-17(2)
283
C(137)
70(2)
82(3)
66(2)
2(2)
-2(2)
N (2)
57(1)
57(1)
53(1)
6(1)
1(1)
0(211)
0(212)
0(213)
C(211)
94(2)
72(2)
62(1)
10(1)
19(1)
139(2)
72(2)
74(2)
16(1)
-33(2)
69(1)
84(2)
1(1)
69(2)
C(212)
C(213)
C(214)
C(215)
C(216)
C(217)
C(218)
C(219)
54(2)
96(2)
82(2)
77(3)
-3(2)
7(2)
36(1)
-4(2)
4(2)
53(2)
73(2)
77(2)
10(2)
16(2)
65(2)
56(2)
75(2)
1(2)
24(2)
61(2)
50(2)
45(1)
55(2)
48(2)
49(2)
53(2)
53(2)
75(2)
96(3)
49(2)
41(1)
70(2)
-3(2)
9(1)
3(1)
14(2)
55(2)
0(2)
83(1)
4(1)
48(2)
42(2)
58(2)
155(4)
3(2)
64(2)
97(3)
0(221)
47(1)
C(221)
C(222)
C(223)
C(224)
C(225)
C(226)
C(227)
64(2)
51(2)
88(2)
60(2)
65(2)
104(3)
76(2)
0(231)
105(2)
C(231)
C(232)
C(233)
C(234)
C(235)
C(236)
C(237)
C(241)
C(242)
C(243)
C(244)
C(245)
88(11)
87(8)
105(8)
107(11)
118(14)
112(8)
92(7)
89(9)
89(8)
76(6)
92(8)
98(12)
60(2)
-3(1)
3(2)
-29(2)
-6(1)
2(2)
68(2)
58(2)
116(3)
-13(2)
30(2)
-6(2)
4(1)
-14(1)
-2(2)
5(1)
-9(2)
-11(2)
8(2)
2(2)
-5(2)
-1(1)
6(1)
11(2)
-3(2)
0(1)
-6(2)
-7(1)
-10(2)
-10(2)
115(3)
-8(2)
-18(2)
1(2)
55(2)
59(2)
82(2)
93(8)
90(8)
69(2)
3(2)
69(2)
1(2)
51(1)
63(9)
-5(1)
-11(5)
-10(7)
-7(7)
-20(2)
16(2)
4(1)
5(6)
2(8)
89(9)
5(7)
30(8)
57(6)
10(5)
15(9)
60(5)
61(6)
-2(6)
-8(6)
-9(5)
0(7)
-17(6)
-15(7)
87(8)
5(7)
-7(2)
-12(2)
-25(1)
-19(6)
-7(8)
-9(7)
-3(8)
-9(8)
-27(7)
-16(5)
-2(6)
-12(8)
-17(5)
2(7)
-8(8)
90(9)
81(9)
78(7)
88(9)
82(8)
88(8)
90(8)
96(9)
113(11)
101(9)
81(2)
57(2)
78(2)
68(7)
48(9)
49(5)
31(4)
37(7)
61(7)
5(1)
2(1)
9(1)
25(2)
-2(2)
-9(1)
27(6)
5(6)
4(4)
12(5)
13(7)
16(5)
5(6)
-5(9)
284
C(246)
102(11)
99(10)
89(10)
7(8)
-31(7)
-16(9)
C(247)
82(7)
98(9)
71(8)
0(7)
-28(6)
-7(6)
285
Table 5. Hydrogen Coordinates ( x 104) and Isotropic
Displacement Parameters (A2x 103) for Epoxide 66.
Atom
x
y
z
U(eq)
H(11A)
5104
4413
4841
5890
1397
9472
9345
8202
86(2)
86(2)
H(11B)
H(11C)
H(11D)
H(11E)
H(11F)
H(11G)
H(11H)
H(11I)
H(11J)
H(11K)
H(12A)
H(12B)
H(12C)
H(12D)
H(12E)
H(12F)
H(12G)
H(13A)
H(13B)
H(13C)
H(13D)
H(13E)
H(13F)
H(13G)
H(21A)
H(21B)
H(21C)
H(21D)
5961
4891
3892
2901
2918
1675
1401
1356
1723
-291
-1979
-2433
-1194
498
4065
4884
2269
1742
2979
4723
5251
13427
12806
12984
14101
2952
3045
2918
57
-1062
2014
-739
2550
1872
476
-1337
-780
-50
702
1358
1311
522
-81
700
1933
4428
6384
5784
3280
1163
2804
2825
2564
8641
8389
7554
7273
7890
8399
9129
8592
7458
6725
7908
7618
6497
5666
5943
5719
6240
5895
5472
5229
5361
5768
4276
4204
3026
3365
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
286
H(21E)
H(21F)
H(21G)
13979
12686
11783
H (21H)
10859
H(211)
11091
H(21J)
H(22E)
9996
9555
9149
9535
7488
5846
5504
H (22F)
6811
H (22G)
8465
11197
12324
10182
10210
11793
13294
13248
12662
11809
10138
9829
11194
12904
13199
H (21K)
H (22A)
H (22B)
H (22C)
H (22D)
H (23A)
H (23B)
H(233)
H(234)
H(235)
H(236)
H(237)
H (24A)
H(24B)
H(243)
H(244)
H(245)
H(246)
H(247)
-293
-1275
1908
-743
2573
2035
657
-1202
-976
64
834
1495
1439
618
-185
-115
2646
5288
6447
4897
2208
368
-302
1991
4652
6440
5619
2945
3114
2392
2220
2949
3410
4265
3767
2730
1971
3057
2696
1562
796
1136
672
1011
932
546
263
326
673
1209
680
716
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
86(2)
100
100
103
110
101
104
89
83
83
93
381
106
318
115
531
117
886
101
287
Table 6. Torsion Angles [O] for Epoxide 66.
C(119)-N(1)-C(111)-C(112)
C(117)-N(1)-C(111)-C(112)
N(1)-C(111)-C(112)-C(113)
C(114)-0(113)-C(113)-C(112)
C(111)-C(112)-C(113)-0(113)
C(111)-C(112)-C(113)-C(114)
C(113)-0(113)-C(114)-C(115)
C(112)-C(113)-C(114)-0(113)
0(113)-C(113)-C(114)-C(115)
C(112)-C(113)-C(114)-C(115)
0(113)-C(114)-C(115)-0(131)
C(113)-C(114)-C(115)-0(131)
0(113)-C(114)-C(115)-C(116)
C(113)-C(114)-C(115)-C(116)
0(131)-C(115)-C(116)-0(121)
C(114)-C(115)-C(116)-0(121)
0(131)-C(115)-C(116)-C(117)
C(114)-C(115)-C(116)-C(117)
C(119)-N(1)-C(117)-C(118)
C(111)-N(1)-C(117)-C(118)
C(119)-N(1)-C(117)-C(116)
C(111)-N(1)-C(117)-C(116)
0(121)-C(116)-C(117)-N(1)
C(115)-C(116)-C(117)-N(1)
0(121)-C(116)-C(117)-C(118)
C(115)-C(116)-C(117)-C(118)
C(119)-0(111)-C(118)-C(117)
N(1)-C(117)-C(118)-0(111)
C(116)-C(117)-C(118)-0(111)
C(118)-0(111)-C(119)-0(112)
C(118)-0(111)-C(119)-N(1)
C(111)-N(1)-C(119)-0(112)
154.1(3)
-58.1(4)
-52.5(4)
-112.9(3)
158.8(2)
88.3(4)
117.2(3)
106.7(3)
-103.0(3)
3.7(4)
91.8(3)
162.2(3)
-152.6(2)
-82.2(3)
-52.7(3)
-169.9(2)
-169.1(2)
73.7(3)
15.7(3)
-134.6(3)
-102.9(3)
106.7(3)
171.2(2)
-69.0(3)
58.6(3)
178.4(2)
23.9(3)
-23.1(3)
98.1(3)
166.8(3)
-14.4(3)
-31.3(5)
288
C(117)-N(1)-C(119)-0(112)
C(111)-N(1)-C(119)-0(111)
C(117)-N(1)-C(119)-0(111)
C(115)-C(116)-0(121)-C(121)
C(117)-C(116)-0(121)-C(121)
C(116)-0(121)-C(121)-C(122)
0(121)-C(121)-C(122)-C(123)
0(121)-C(121)-C(122)-C(127)
C(127)-C(122)-C(123)-C(124)
C(121)-C(122)-C(123)-C(124)
C(122)-C(123)-C(124)-C(125)
C(123)-C(124)-C(125)-C(126)
C(124)-C(125)-C(126)-C(127)
C(123)-C(122)-C(127)-C(126)
C(121)-C(122)-C(127)-C(126)
C(125)-C(126)-C(127)-C(122)
C(114)-C(115)-0(131)-C(131)
C(116)-C(115)-0(131)-C(131)
C(115)-0(131)-C(131)-C(132)
0(131)-C(131)-C(132)-C(133)
0(131)-C(131)-C(132)-C(137)
C(137)-C(132)-C(133)-C(134)
C(131)-0(132)-C(133)-C(134)
C(132)-C(133)-C(134)-C(135)
C(133)-C(134)-C(135)-C(136)
C(134)-C(135)-C(136)-C(137)
C(135)-C(136)-C(137)-C(132)
C(133)-C(132)-C(137)-C(136)
C(131)-C(132)-C(137)-C(136)
C(219)-N(2)-C(211)-C(212)
C(217)-N(2)-C(211)-C(212)
N(2)-C(211)-C(212)-C(213)
C(214)-0(213)-C(213)-C(212)
0(211)-C(212)-C(213)-0(213)
C(211)-C(212)-C(213)-C(214)
177.1(3)
149.9(3)
-1.7(3)
100.9(3)
-135.7(2)
166.2(2)
-80.2(3)
101.4(3)
0.9(5)
-177.5(3)
-0.4(5)
-0.6(5)
1.1(6)
-0.4(5)
178.0(3)
-0.6(5)
-76.4(3)
162.6(2)
-73.7(3)
-45.5(4)
137.0(3)
0.8(5)
-176.8(3)
-1.4(5)
1.4(5)
-0.9(6)
0.3(6)
-0.3(5)
177.3(3)
152.5(3)
-57.5(4)
-52.6(4)
-113.4(3)
158.4(3)
88.0(4)
289
C(213)-0(213)-C(214)-C(215)
0(212)-C(213)-C(214)-0(213)
0(213)-C(213)-C(214)-C(215)
C(212)-C(213)-C(214)-C(215)
0(213)-C(214)-C(215)-0(231)
0(213)-C(214)-C(215)-0(231)
0(213)-C(214)-C(215)-C(216)
C(213)-C(214)-C(215)-C(216)
0(231)-C(215)-C(216)-0(221)
C(214)-C(215)-C(216)-0(221)
0(231)-C(215)-C(216)-C(217)
C(214)-C(215)-C(216)-C(217)
C(219)-N(2)-C(217)-C(218)
C(211)-N(2)-C(217)-C(218)
C(219)-N(2)-C(217)-C(216)
C(211)-N(2)-C(217)-C(216)
-82.3(4)
-48.5(3)
0(221)- C(216)- C(217) -N(2)
169.5(2)
C(215)-C(216)-C(217)-N(2)
0(221)-C(216)-C(217)-C(218)
C(215)-C(216)-C(217)-C(218)
C(219)-0(211)-C(218)-C(217)
N(2)-C(217)-C(218)-0(211)
C(216)-C(217)-C(218)-0(211)
0(218)-0(211)-C(219)-0(212)
-70.9(3)
57.7(3)
22.7(4)
C(218)- 0(211)- C(219) -N(2)
-12.6(3)
C(211)-N(2)-C(219)-0(212)
C(217)-N (2)-C(219)-0(212)
C(211)-N(2)-C(219)-0(211)
C(217)-N(2)-C(219)-0(211)
C(215)-C(216)-0(221)-C(221)
C(217)-C(216)-0(221)-C(221)
0(216)-0(221)-C(221)-C(222)
0(221)-C(221)-C(222)-C(223)
0(221)-C (221)-C (222)-C(227)
C(227)-C (222)-C(223)-C (224)
-30.4(5)
117.6(3)
105.1(3)
-101.9(3)
3.2(5)
91.9(3)
161.6(3)
-152.0(3)
-166.8(2)
-165.7(2)
76.0(3)
16.4(3)
-136.0(3)
-101.3(3)
106.3(3)
177.4(3)
-22.8(3)
97.1(3)
168.0(3)
176.0(3)
150.3(3)
-3.4(3)
101.7(3)
-134.8(3)
176.7(3)
-91.4(4)
91.5(4)
2.0(5)
290
C(221)-C(222)-C(223)-C(224)
C(222)-C(223)-C (224)-C (225)
C (223)-C(224)-C(225)-C (226)
C(224)-C(225)-C (226)-C (227)
-175.2(3)
C(225)-C(226)-C(227)-C(222)
C(223)-C (222)-C(227)-C (226)
-0.4(5)
C(221)-C(222)-C(227)-C(226)
C(214)-C(215)-0(231)-C(231)
C(216)-C(215)-0(231)-C(231)
C(214)-C(215)-0(231)-C(241)
C(216)-C(215)-0(231)-C(241)
C(215)-0(231)-C(231)-C(232)
C(241)-0(231)-C (231)-C (232)
175.9(3)
-1.0(5)
-0.8(6)
1.5(6)
-1.3(5)
-71.5(10)
167.7(10)
-64.7(7)
174.4(7)
-56(2)
-82(5)
0(231)-C(231)-C(232)-C(233)
0(231)-C(231)-C(232)-C(237)
-61(4)
C(237)-C (232)-C(233)-C (234)
0(5)
C(231)- C(232)- C(233)- C(234)
C(232)-C(233)-C(234)-C(235)
-174(3)
-2(3)
C(233)-C (234)-C (235)-C (236)
1(3)
C(234)-C(235)-C(236)-C(237)
C(235)-C (236)-C(237)-C (232)
C(233)-C(232)-C(237)-C(236)
C (231)-C (232)-C(237)-C(236)
0(3)
126(3)
-1(3)
1(4)
175(3)
C(231)-0(231)-C(241)-C(242)
C(215)-0(231)-C(241)-C(242)
0(231)-C(241)-C(242)-C (243)
0(231)-C(241)-C(242)-C(247)
C(247)-C(242)-C(243)-C(244)
C(241)-C(242)-C(243)-C(244)
76(5)
C(242)-C (243)-C(244)-C (245)
-1(3)
C(243)-C (244)-C(245)-C (246)
C(244)-C(245)-C(246)-C(247)
1(3)
C(243)-C (242)-C(247)-C (246)
-3(5)
C (241)-C(242)-0(247)-C (246)
C(245)-C(246)-C(247)-C(242)
-178(2)
3(3)
-81.0(18)
-49(4)
126(3)
2(4)
177(2)
-2(3)