A new regiocontrolled and stereospecific total synthesis of (+-) modhephene
by David William Wilkening
A thesis submitted in partial fulfillment of the requirements for the degree Doctor of Philosophy in
Chemistry
Montana State University
© Copyright by David William Wilkening (1984)
Abstract:
A new approach to cyclopentanoid propellanes of theoretical and synthetic interest is presented, A
methodology involving the vicinal dianions of 1,2-diesters is explored as a rapid entry into highly
functionalized bicyclic diesters. An investigation of various electrophiles is conducted to examine the
strengths and limitations of the dianion methodology. It is found that 1,3-primary dihalides,
3-haloesters, and 3-haloketones all react to give cyclopentanoid compounds with the dianions of
cyclopentane and cyclohexane dicarboxylates. Under the conditions employed, the dienolate of
dimethylsuccinate does not react to give the expected product with 3-bromopropionate. To demonstrate
the utility of dienolates of vicinal diesters in organic synthesis, a regiocontrolled and stereoselective
synthesis of racemic modhephene is accomplished. A NEW REGIOOQNTROLLED AND STEREOSPECIFIC
TOTAL SYNTHESIS OF (±) MODHEPHENE
by .
David William Wilkening
A thesis submitted in partial fulfillment
of the requirements for the degree
Doctor of Philosophy
in
Chemistry
MONTANA STATE UNIVERSITY
Bozeman, Montana
May 1984
APPROVAL
of a thesis submitted by
David William Wilkening
This thesis has been read by each member of the thesis committee
and has been found to be satisfactory regarding content, English
usage, format, citations, bibliographic style, and consistency, and is
ready for submission to the College of Graduate Studies.
5/3V/Sry
Date
Approved for the Major Department
Date
Head, Major Department
Approved for the College of Graduate Studies
Date
Graduate Dean
iii
STATEMENT OF PERMISSION TO USE
In p r e s e n t i n g
tnis
thesis
in
partial
fulfillment of the
requirements for a doctoral degree at Montana State University,
I
agree that the Library shall m ake it available to b orrowers under
rules of the Library.
I further agree that copying this thesis is
a l l o w a b l e only for scholarly puposes, consistent w i t h "fair use" as
prescribed in the U.S. Copyright Law.
Requests for extensive copying
or reproduction of this thesis should be referred to University
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right to reproduce and distribute by abstract in any format."
iv
To my father^
for the countless hours he spent teaching
m e to throw a baseball.
"A wise son maketh a glad father.™
Proverbs 10.1
V
VITA
David W i l l i a m Wilkening, the first son of Walter D. and Ruth V.
Wilkening, w a s born in Milwaukee, Wisconsin on the I -It" day of
January, 1958.
He spent m ost of his childhood in Libertyville
Illinois, and in June 1976 graduated from Libertyville High School. He
then attended Rockford College in Rockford Illinois, where he met and
m a r r i e d his w i f e Angela Sue. In June 1980 he graduated w i t h honors
from Rockford College and in September of 1980, he began his graduate
studies at Montana State University. From Montana State University he
then w e n t to the University of South Carolina as a postdoctoral
research associate under Professor Paul Petersen.
vi
ACKNOWLEDGEMENT
In gratitude to those people who helped make this work possible I
would like to name the following . . .
Bradford P. Mundy, for trusting in me and for his belief that
good guys do finish first.
My mother, for teaching m e the virtue of hard work.
My father, for teaching m e perseverance.
My wife, for understanding why, and much more.
vii
TABLE OF CONTENTS
Page
LIST OF FIGURES...............................
viii
LIST OF COMPOUNDS..........
xii
A B S T R A C T ...................
xvi
INTRODUCTION............... i ............ ................... .. .
I
RESULTS AND DISCUSSION .............................
10
EXPERIMENTAL.....................................................
58
LITERATURE AND MDTES . . . . .
A P P E N D I C E S ............
........................
. . . . .
100
109
viii
LIST OF FIGURES
Page
Figure I.
Representative Cyclopentanoid Natural Products........... I
Figure 2.
Oxymercuration of cis-8-oxabicyclo-14.3.0]-oct-3-ene. .
2
Figure 3..
Heteroatom Participation in Aza-Norbornyl Systems . . .
3
Figure 4.
Solvolytic Rearrangement of Oxa-Norbomyl system. . . .
4
Figure 5.
Charge Stabilization by Oxygen Atom in
cis-Tetrahydrophthalans.......... .. ............. .. .
5
Figure 6.
Steric Bias in cis-Tetrahydrophthalans................... 5
Figure 7.
Conformational Equilibrium in cis-Tetrahydrophthalans .
6
Figure 8.
8-Oxatricyclo-[4.3.3.01-undec-3-ene . . . . . . . . . .
7
Figure 9.
Conformational Equilibrium of Oxa-Propellane............. 8
Figure 10.
Modhephene...................................
Figure 11.
Representative Cyclopentanoid Natural Products. . . . .
10
Figure 12.
Synthetic Routes to cisI f6-Dicarbcanethoxybicyclo-[4.3.0]-non-3-ene . . . . . .
11
8
Figure 13.
Dianion of 3,4-Dicarbornethoxycyclohexene. . ........... 12
Figure 14.
Dianion Mediated Synthesis of
cis-1 ,6-Dicarbcmethoxybicyclo-[4.3.0]-non-3-ene . . . .
13
Figure 15,
Synthesis of 8-Oxatricyclo-[4.3.3.01-undec-3-ene. . . .
14
Figure 16.
Simple cydopentanoid Natural Products. . . . . . . . .
15
Figure 17.
synthesis of I ,2-Dimethylcyclopentane Dicarboxylate . . 15
Figure 18.
Synthesis of 1 ,2-Dimethylcyclopentane Dicarboxylate
fcy Favorski Rearrangement................. ..
Figure 19.
16
Synthesis of 1 ,2-Dicarboxymethylcyclopentene.......... 17
6
ix
Figure 20.
Mechanism of the Dienolate Mediated Oxidation of
1.2- dimethy lcyclopehtane dicar boxy late. . .... ...... 18
Figure 21.
Oxymercuration and Epoxidation Reactions of
8-Oxatricyclo- [4.3.3.01 -undec-3-ene ............... .. . 20
Figure 22.
Proposed Synthesis of Modhephene........ ..
Figure 23.
Synthesis of 7-Oxo-(cis)-I,6-dicarboxymethylbicyclo-[4.3’.Ol -non-3-ene . . .......................... 23
Figure 24.
Attempted Synthesis of
2.3-dicarbomethoxycyclopentanone....................... 24
Figure 25.
Snith1s Wittig Reaction . . . . . . . . . . . . . . . .
25
Figure 26.
Smith's Synthesis of Modhephene ........... . . . . . .
26
Figure 27.
Synthesis of 2-Hydroxy-2-methyl-(cis)1 .5- dicarboxymethylbicyclo-[3.3.01-octane . . . . .
Figure 28.
........... 22
. .27
Dehydration of 2-Hydroxy-2-methyl-(cis)1 .5- dicarboxymethylbicyclo-[3.3.0]-octane . . . . . . .
28
Figure 29.
Proposed Mechanism of Hydrogenation of 2-methylene-(cis)1 .5- dicarboxymethylbicyclo-[3.3.0]-octane . . . . . . . 29
Figure 30.
Stereospecific Hydrogenation to 2-methyl-(cis)-I,5dicarboxymethylbicyclo- [3.3.0] -octane
........ 30
Figure 31.
Proposed Synthesis of Modhephene via Acid Catalyzed
Cyclization of 2-methyl-(cis)-[1-dime thyImethylol-5(l-methylethenyl)lbicyclo-[3.3.03-octane. . . . . . . .
31
Attenpted Synthesis of 2-methy1-1,5-dimethylmethyIolbicyclo-[3.3.01-octene. . . . . . . . . . . . . . . . .
33
Figure 32.
Figure 33.
Mechanism of Sequential A d d i t i m of Methyllithium
to 2-methyl-(cis)-I,5-dicarboxymethylbicyclo[3.3.01-octane.......................................... 34
Figure 34.
Proposed Isonerization of 2-methylene-3-oxa-4,4,8trimethyl tricyclot 3. 3. 3. 01 -decane . . . . . . . . . . .
35
Synthesis of 2-oxo-3-oxa-4,4,8-trimethyltricyclo- [3.3.3.01 -decane
...............
37
Figurg 35.
Figure 36.
6-Methyl-2,4-dioxotricyclo-[3.3.3.0]-undecane . . . . .
37
Figure 37.
Mechanism of Formation of
6-methyl-2,4-dioxotricyclo-[3.3.3.0]-undecane ........
38
Figure 38.
Conformational Equilibrium of
6-methyl-(cis)-l,5-dicarboxymethylbicyclo- [3.3.01 -octane. ................................. 39
Figure 39.
Steric Differentiation of Ester Groups in
6-methyl-(cis)-I,5-dicarboxymethylbicyclo- [3.3.0] -octane................................... 40
Figure 40.
Synthesis of
4,8-dimethylbicyclo-[3.3.01-oct-3-enone.
. 42
Figure 41.
A Formal Total Synthesis of Racemic Modhephene. . . . .
Figure 42.
Proposed Total Synthesis of Modhephene................... 44
Figure 43.
Proposed conversion of
4-acetoxy-8-methyItricyclo-[3.3.3.01-undec-3-ene
to Modhephene . . . . ............... . . . . . . . . .
45
Nonselective Acetylation of
6-methyl-2,4-dioxotricyclo-[3.3.3.01-undecane . . . . .
47
Conversion of 6-methy1-2r4-dioxotricy clo­
ts. 3.3.01-undecane to the vinyl ethers under
equilibrating conditions. . .......................
47
Synthesis of 2-oxo-4-methoxy-8-methyltricyclo-[3.3.3.01-undec-3-ene. . . . . . . . . . . . .
48
Figure 44.
Figure 45.
Figure 46.
43
Figure 47.
Synthesis of 4,6-dimethyl-2-oxatricyclo- [3.3.3.01 -undec-3-ene...........................49
Figure 48.
synthesis of Dimethylzinc ............................... 51
Figure 49.
Synthesis of Dimethyl titanium Dichloride................ 52
Figure 50.
Geminal Dimethylation of Isophorone . .............
Figure 51.
Proposed Mechanism of the Dimethyltitanium Dichloride
Mediated Geminal Dimethylation of Isophorone........... 53
Figure 52.
Total Synthesis of Racemic Modhephene ................
52
54
xi
Figure 53.
Figure 54.
Proposed Alternate Synthesis of
6-methyl-2,.4-t3ioxotricyclO’-[3.3.3.0] -undecane . . .
. 55
Proposed Synthesis of Optically Active Mcxihephene .
. 57
xii
LIST OF COMPOUNDS
Page
Preparation of Ethy1-6-bromo-2-cyclohexanone carboxylate . . . .
58
Preparation of 1 ,2-Cyclopentanedicarboxylic Acid (23).......... 58
Synthesis of dimethyl-1,2-cyclopentane dicarboxylate (22) „ . . .
59
I-Carboxybutyl-2-carboxymethylcyclopentane . . . . . . . . . . .
60
Synthesis of dimethyl-1 r2-cyclopentene dicarboxylate (16). . . . 6 1
I-Buty1-2-methylcyclopentene dicarboxylate..................... 62
Synthesis of dimethyl-1,2-cyclohexene dicarboxylate (49.2) . . .
62
Preparation of 2-oxo-(cis)-I,5-dicarboxymethyl•bicyclo - [3.3.0]-octane (29)............................. ..
63
1 .2- Dicarbomethoxy-l-(3-ethylpropionaty I )cyclopentane (111.2) ......................................
63
Preparation of cis-1,5-dicarbojymethy1bicyclo-[3.3.0]-octane (85.2)...........................
64
A t t m p t e d preparation of 2-methyl- (cis)-1,5-dicarboxymethylbicyclo-[3.3.0]-octane (31). ................... . . . . . . . .
65
1 .2-
Dicarboxymethyl-l-(3-propenyl)-cyclopentane (80.2) ....... 65
Epoxidation of 3,4-dimethy1-8-oxatricyclo-[4.3.3.0]-undec-3-ene
(70.2) at elevated temperature . . ............. . . . . . . . .
66
3.4- Dimethy1-8-oxatricyclo-[4.3.3.01-undec-2,4-diene
(61.2) . . ............................ ........................... 66
3-Methyl-4-methylene-8-oxatricyclo-[4.3.3.01undec-2-ene (60.2a). .......................
67
Epoxidation of 3,4-dimethy 1-8-oxatricyclo-[4.3.3.01-undec-3-ene
(70.2) at room temperature............
67
3.4- Dimethyl-(syn)-3,4-epoxy-8-oxatricyclo-[4.3.3.01Undecane (70.2a) .................................. . . . . . . .
67
xiii
3 ,4-Dimethyl-(anti)-3,4-epoxy-8-oxatricyclo-[4.3.3.01undecane (70.2b) . ..................... .........................68
Epoxidation of 8-oxatricyclo-[4.3.3.01-undec-3-ene
(12) ........................................................... „ 6 8
syn-3,4-Epoxy-8-oxatricyclo-[4.3.3.01-undecane (24). . . . . „ . 68
anti-3f4-Epojfy-8-oxatricyclo-[4.3.3.01-undecane (25) . . . . . .
68
Methoxymercuration of 8-oxatricyclo-[4.3.3.01undec-3-ene (12) ................. ............ ..
69
syn-3-Methoxy-8-oxatricydo-[4.3.3.01-undecane (2$). . . . . . . 6 9
anti-3-Methoxy-8-oxatricyclo-[4.3.3.01-undecane (27) . . . . . .
70
Preparation of 3,4-dimethyl-(cis)-I,6-dicarboxymethylbicyclo- [4.3.01 -non-3-ene (50.2) .........................
70
Preparation of 8-oxa-3,4-dimethyltricyclo-[4.3.3.01undec-3-ene (52.2) . ....................................
71
Preparation of cis-1,6-dicarbomethoxybicyclo-[4.3.01non-3-ene ( 1 5 ) ....................................................72
Preparation of 8-oxatricyclo-[4.3.3.01-undec-3-ene (12). . . . . 74
cis-1,6-Dimethylolbicydo- [4.3.01 -non-3-ene ( 5 2 . 2 ).............. 75
Preparation of the ditosylate of 1 ,6-dimethylolbicydo[4.3.01 -non-3-ene (20.3) ........... .........................: . . 75
Preparation of !Hrtethyl-1,2,5,6-tetrahydropthalimide
(91.2).......................................
76
Preparation of N-methyl-7 ,9-dioxo-8-azatricyclo[4.3.3.01 -undec-3-ene (93.2) . ...............
76
Preparation of N-methyl-8-azatricyclo-[4.3.3.01undec-3-ene (94.2) ...........................
77
Preparation of N fN-dimethyl-8-azatricyclo-[4.3.3.01undec-3-ene iodide (95.2)..................
79
Preparation of IHnethy 1-N-deuteromethy 1-8-azatricydo[4.3.3.03 ^undec-3-ene iodide (96.2). . . . . . . . . . . . . . .
79
xiv
Preparation of 4-brcmobutan-2-one (114.2). . . . . . . . . . . .
80
Preparation of 2-methyl-(cis)-I,5-dicarbomethoxybicyclo- [3.3.01 -octan-2-ol. (37) . . . ................... ..
81
I ,2-Dicarboxymethyl-l-(3-oxobutyl)-cyclopentane (118.2). . . ... 83
Preparation of 2-methyl-(cis)-I,5-dicarbcmethoxybicyclo[3.3.0] -oct-l-ene ( 3 8 ) ...................... .............. .. . 83
Preparation of 6-methyl-(cis)-I ,5-dicarbomethoxybicyclo[3.3.0] -octane (31)...................................... ..
84
Attenpted synthesis of I ,6-di-(1-methylethenyl)bicyclo-[4.3.0]-non-3-ene (29.3) ............... . ............. 85
7-Methylene-8-oxa-9,9-dinethyltricyclo-[4.3.3.0]-undec-3-ene
(29.3a).......... .............. ........................... ..
86
I-Acety 1-6-(1-ne thylethenyl)-bicyclo-[4.3.01non-3-ene (29.3b). ................. . . . . . . . . . . . . . .
86
Attanpted Synthesis of I,6-di-(I,1-dimethylmethylol)bicyclo-[4.3.0]-non-3-ene (30.3) ................................
87
7-Methylene-8-oxo-9,9-dimethyltricyclo-[4.3.3.01,undec-3-ene (30.3a)....................
87
7-Oxo-8-oxa-9f9-dimethyl tricyclo-[4.3.3,. 01undec-3-ene (30.3c)........... ...................................88
Preparation of 2-oxo-3-oxa-4,4,8-trinethyltricyclo[3.3.3.01-decane (43). ....................................
88
2 ,4-Dioxo-6-methyltricyclo-[3.3.3.01-undecane (47) ............. 89
Synthesis of 4 ,8-dimethyltricyclo-13.3.3.01undec-3-en-2-one (50)..................
90
Preparation of 2-methylene-3-oxa-4,4,8-trimethyltricyclo- [3.3.3.01 -decane
( 4 5 ) ............................
91
Preparation of 8-methyl-4-acetoxytricyclo - [3.3.3.03undec-3-en-2-one (51)......... . ................................ 92
Preparation of 6-methy1-4-acetoxytricyclo-[3.3.3.01undec-3-en-2-one (53)......... ...................... ..
92
XV
Preparation of 4-metboxy-8-methyl tr icy d o - [3.3.3.0]undec-3-en-2-one (54)................. . ............... ..
94
Preparation of 4,6-diinet±yltricyclo- [3.3.3.01 -undec-3-enone. . . 95
Synthesis of 1,3,3,5,5-tetramethyIcyclohexene (58).
. . . . . .
96
Synthesis of 2.4.4.8-tetramethyltricyclo-[3.3.3.01undec-2-ene CModhephenel (13). ............... . ............... 97
xvi
ABSTRACT
A new approach to cyclopentanoid propellanes of theoretical and
synthetic interest is presented,
A methodology involving the vicinal
dianions of 1,2-rdiesters is explored as a rapid entry into highly
functionalized bicyclic diesters.
An investigation of various
electrophiles is conducted to examine the strengths and limitations of
the dianion methodology.
It is found that 1,3-primary dihalides, 3haloesters, and 3-haloketones all react to give cyclopentanoid
compounds w i t h the d i a n i o n s of c y c l o p e n t a n e a n d c y c l o h e x a n e
dicarboxylates.
Under the conditions employed, the dienolate of
dimethylsuccinate does not react to give the expected product with 3bromopropionate.
To demonstrate the utility of dienolates of vicinal
diesters in organic synthesis, a regiocontrolled and stereoselective
synthesis of racemic modhephene is accomplished.
-1-
INTRODUCTION
The recent past has witnessed a flourish of interest in cyclo­
pen tanoid chemistry1.
Much of this interest is attributable to the
isolation of biologically important cyclopentanoid and polycondensed
cy cl open tanoid natural products.
Examples of this class of compounds
are illustrated in Figure I.
Figure I.
Representative Cyclopentanoid Natural Products
As is apparent from these examples,
the cy cl opentanoids represent
a complex challenge to the synthetic chemist, as most of these novel
-2-
compounds are highly substituted in addition to possessing the five
membe r e d ring skeleton.
Furthermore, contrary to the situation in
six-membered rings where stereochemistry can be manipulated by
exploiting axial/equatorial biases; in order to perform
stereoselective transformations in cyclopentanoids, the synthetic
chemist must rely upon remote functionality or unique molecular
conformation.
In spite of these obstacles,
and indeed perhaps on
account of them, synthetic approaches to the cyclopentanoids have
become a very competitive and exciting field of research for synthetic
organic chemistry®.
Our interest in cyclopentane annelation methodology resulted as
an offshoot of a structure reactivity project that our group has
maintained an active interest in for the past fifteen years.
The crux
of this problem can be stated as outlined below.
In a study done by Otzenberger in 1971^, oxymercuration of the
tetrahydrophthalan (5) w a s found to give predominantly syn-alcohol (j£)
(Figure 2).
6
5
Figure 2.
7
'a n ti 1
Oxymercuration of cis-8-oxabicyclo-[4.3.0]-oct-3-ene
-3-
It had been previously demonstrated for norbornyl systems® that
heteroatom participation in the transition state leading to the
products was responsible for the observed stereoselectivity of
chemistry occurring at the double bond (Figure 3).
Isolation of the
nitrogen alkylated product (S) was interpreted as firm evidence for
remote heteroatom participation in these systems.
HBre
9 )
H
9
H
8
Figure 3.
Br"
9
Heteroatcm Participation in Aza-Norbornyl Systems
Additional support for heteroatom participation in norbornyl
systems w a s presented by the observed rearrangement of the endo-tetrahydropyran analog (IS) to its exo-isomer
conditions^ (Figure 4).
(11) under solvolytic
Since the comparable carbocyclic norbornyl
compound did not isomerize under identical conditions,
it wa s proposed
that heteroatom participation resulted in charge stabilization, thereby
permitting rearrangement.
-4-
Figure 4.
Solvolytic Rearrangement of Oxa-NOrbornyl System
The question which faced Otzenberger was, therefore, could the
same type of heteroatom effect be operating in the tetrahydrophthalan
case?
In light of the experimental results, and by analogy to the
norbornyl system, Otzenberger suggested that the heteroatom effect was
probably the m a i n causative factor in determining the outcome of the
oxymercuration of (5).
Figure 5 shows the transformation of the
tetrahydrophthalan (5) to the syn-alcohol
(£) via intermediate
(5a),
for which Otzenberger proposed that the developing charge of the
mercurinium ion was stabilized by the neighboring oxygen atom.
Subsequent trans hydroxylation would yield
(£).
-5-
Figure 5.
Charge Stabilizaticxi by Oxygen Atan in
cis-Tetrahydrophthalans
One unexplored possibility pertaining to this question was the
potential for simple steric effects to dominate the course of the
reaction.
As illustrated below, the pi-system of the cyclohexene ring
is facially dissimilar
(Figure 6); one face of the double bond is syn
to the oxapropano group while the opposite face of the double bond
experiences only t w o hydrogen atoms.
Figure 6.
Steric Bias in cis-Tetrahydrophthalans
-6-
Thus, the question to be asked was:
could observed product
ratios be attributed to merely steric factors?
Nuclear magnetic
resonance experiments had suggested1® that the conformation of the
tetrahydrophthalan molecule was predominantly the more stable
'unfolded'
isomer depicted in figure 7.
"unfolded"
Figure 7.
"folded"
Conformational Equilibrium in cis-Tetrahydrophthalans
This w a s used to support the assertion by Otzenberger that the
heteroatom effect was in fact being expressed, since in the unfolded
isomer the degree of steric bias is at a m i n i m u m for that system.
In
spite of these facts, the question of steric control remained
insoluble for the system at hand.
Clearly, in order to unambiguously address this question, a more
propitious candidate for oxymercuration w as needed.
Ideally, the
proposed molecule should eliminate the steric discrepancies inherent
in the tetrahydrophthalan system, while concomitantly retaining the
relationship of the oxygen atom to the alkene function.
The best such
-7-
molecule presented itself as the propellane (12) illustrated below
(Figure 8).
12
F i g u r e 8.
8 -Oxatricyclo- [4.3.3.01 -undec-3-ene
As can be seen from the drawing,
the propellane presents nearly
identical steric bulk to each face of the double bond; thereby permit­
ting facial distinction only on the basis of heteroatom character.
A
possible objection to this statement could be proposed on the basis of
a conformational preference for the double bond to fold toward or away
from the heteroatom (Figure 9); however since the energy required to
permit conformational isomerization is on the order of 6.9
k c a l s / m o l e ^ , no conformational bias seemed likely.
Thus, a synthesis of the propellane (12) was compulsory, and
since the major obstacle to achieving this goal was formation of the
propane bridge from C-I to C-6 of the tetrahydrophthalan molecule, w e
w e r e provided with an impetus to explore methodology for construction
of cyclopentanoid rings.
-8-
Figure 9.
Conformational Equilibrium of Oxa-Propellane
A greater and more important goal which motivated the synthesis
of the propellane (12) and the development of cyclopentannelation
methods w a s our intrigue w i t h the unique naturally occurring
[3.3.3.01 - p r o p e l l a n e m o d h e p h e n e ^
(13) (Figure 10).
13
Figure 10.
Modhephene
-9-
The simplicity of the heteroatom containing propellane (12)
suggested to us that it would provide an ideal model system for a new
synthesis of modhephene, which, since its isolation from rayless
goldenrod in 1978 fcy Zalkow13, has attracted considerable attention in
the synthetic community1^.
The following text therefore discusses the development of a new
cyclopentanoid annelation methodology within the constraints
prescribed for the synthesis of the heteroatom propellane (12). and
proceeds in a discourse of the further developments and refinements to
the methods which were necessitated in order to accomplish the formal
and total synthesis of modhephene.
—ID-
RESULTS AND DISCUSSION
To begin the synthesis ot 8-oxatricyclo- [4.3.3.0] -undec-3-ene
(12). a suitable retrosynthetic pathway was needed.
Previous work
suggested that the tetrahydrofuran ring of the propellane was most
judiciously constructed by dehydration of a 1,4-diol,
as had been
demonstrated for the tetrahydrophthalans fcy Otzenberger15, as well as
others16
(Figure 11).
CGh
14
5
Figure 11.
Synthesis of Tetrahydrofurans
Since 1,4-dihydroxy functionality is easily obtained from
succinate derivatives, the key intermediate for an expeditious
synthesis of the desired propellane w a s ostensibly the diester
(15);
which presented t w o practical options for synthesis (Figure 12).
The
first of these required an addition of butadiene to a I,2-dicarboxycyclopentene such as the dimethyl ester
(16.).
Literature preparations
of (16) gave either unsatisfactory yields17, or were not reproducible
in our hands18.
There was ample reason for concern regarding the
-11Diels-Alder reaction of (15) with butadiene as well; as tetrasubstituted alkenes are often sterically and/or electronically
inhibited as dienophiles19.
COCH3
OC
GOCH3
COOCH3
0
cp
COOCH3
X
15
C00CH:
CX
COOCH-j
17
Figure 12.
Synthetic Routes to cis1,6-Dicarbomethoxybicyclo-[4.3.0]-non-3-ene
The alternative approach proceeded from the readily available
3,4-d i car borne thoxy cy cl ohexene (12); but demanded attachment of the
propano group by uncertain methods in order to form the cyclopentane
ring20.
Since one goal of this project w as to develop this type of
transformation as a new synthetic method for constructing five
membered rings, w e chose to pursue this approach toward the propellane
precursor
(15).
-12-
There have been numerous reviews published dealing with new
synthetic entries into the cyclopentanoids21; however, no avenue into
the class of annelated vicinal dicarboxylates had been reported which
wou l d permit facile construction of the type of bicyclodicarboxylate
represented by (15).
Consideration of the requisite cyclopentane
annelation reaction prompted us to explore the possibility of
exploiting the ester functionalities as a means of affecting the
cyclization.
Thus,
it was postulated that a vicinal ester dianion
generated from (H) might be a legitimate intermediate if a
disubstituted propane could be found to act as an electrophile in this
reaction (Figure 13).
O- Li+
Figure 13.
Dianion of 3,4-Dicarbomethoxycyclohexene
Additional credence to this approach w as gleaned from the antici­
pated stability of the dianion generated from the vicinal diester, as
conjugation of the enolates would serve to stabilize the developing
charge.
One final boon this reaction offered was the expected
-13-
formation of only cis—vicinal diester.
planar to permit conjugation,
The dienolate being presumably
implied that once the first alkylation
had occurred the second displacement would proceed from the same face,
since formation of the trans ring juncture would require the propane
group to twist between the t w o ester residues.
This hypothesis was
examined by performing the experiment outlined in Figure 14.
Quite happily, when 1.5 equivalents of 1,3-dibromopropane were
added to the cooled, bright red THF solution of the dienolate of
3,4-dicarbomethoxycyclohexene, the bicyclic diester was obtained in
high yield.
a.
b.
(a) 2.5 LDA, T H F , -78°C.
(b) I,3-dibranopropane
Figure 14.
Dianion Mediated Synthesis of
cis - 1 ,6-Dicarbomethoxybicyclo-[4.3.0]-non-3-ene
As expected, subsequent cyclization to the tetrahydrofuranyl
ether,
revealed that only cis-diester had been formed.
Having thus
established the practicality of the dianion mediated cyclization
reaction,
the remainder of the synthesis of the propellane was
accomplished in a straight-forward manner as described in Figure 15.
-14-
COOCH3
a.
b.
COOCH3
^ ^ ^ C 0 0 C H 3
_
15
n COOCH3
J
c.d
(a)
(b)
(c)
(d)
2.5 LEftf THFf -78°C
I ,3-dibrcmopropane
IAHf ether
p-toluenesulfonyl chloride
12
Figure 15.
Synthesis of 8-Oxatricyclo-[4.3.3.0]-undec-3-ene
Another versatile aspect of the vicinal ester dianion was
revealed during the course of experimentation aimed at the synthesis
of 1,2-dicarbomethoxycyclcpentene.
As stated abovef previously
reported methods for the preparation of (15) were uniformly unsatis­
factory.
Due to recent interest in simple cyclopentanoids such as the
antibiotic
Sarkomycin2^f and
the related compounds shown belowf
(Figure 16) we felt that the dianion methodology could be fruitfully
employed in this area.
-15O
0
r r V CH20H
COOH
18
OH
Sarkoirycin22
19
Pentencnycin23
O
HO
HO
COOH
tO O H
20
Xanthocidin2^
Figure 16.
Accordingly,
21
Methylenoiycin
Simple Cyclopentanoid Natural Products
when the dianion of dimethylsuccinate was treated
with 1 ,3-dibr omopr opane, 1 ,2-dicar borne thoxy (22) was obtained in 51%
yield following distillation
(Figure 17).
Il
O
. f
I
Il
C H 3C K cS
C H 3CK
K
O
«
/^ ,C O O C H
3
xv^ C O O C H
3
22
(a) 2.5 LDA, T H F , -78°C
Figure 17.
Synthesis of 1 ,2-Dimethylcyclopentane Dicarboxylate
25
-16-
In the course of our study, another new synthesis of the cyclopentane diesters was developed involving the Favorski rearrangement
of 2-bromo-2-carboxymethylcyclohexanone.
Figure 18 outlines this
preparation of (22).
O
COOEt
Cr'
COOCH 3
q.b .c.d
70%
COOCH 3
22
^ (a) Bromine, CH2Cl2 .
(c) reflux, 18 hr.
Figure 18.
(b) 15% ethanolic KOH, 0°C, I hr.
(d) absolute methanol, H+ , reflux.
Synthesis of I ,2-Dimethylcyclopentane Dicarboxylate
by Favorski Rearrangement
In an initial attempt to prepare (22) directly, sodium methoxide
was used as the base in the Favorski rearrangement.
This resulted
in an intractable tar; however, when sodium hydroxide was used in
place of the alkoxide, the diacid of 1 ,2-dimethylcyclopentane
dicarboxylate
(23.) was isolated in good yield.
The material prepared
by the dianion method was identical in all respects to the Favorski
d e r i v e d product.
In order to introduce the 1,2-double bond in (22). a number of
suitable oxidizing agents were tried - all to no avail.
However, when
-17the dienolate of (22) was prepared and reacted with 1.1 equivalents of
iodine,
the desired cyclopentene (16) w a s formed in 85% yield
(Figure 19).
0
0
COCH3
COCH3
Ii
o
22
Figure 19.
COCH3
1)
2.5 LDA
2) I 2
COCH3
J
Il
0
J
16
Synthesis of I ,2-Dicarboxymethylcyclopentene
The proposed mechanism of this transformation is shown in figure
20.
In subsequent experiments it was discovered that cuprous iodide
also affected this transformation in high yield, presumably by the
same pathway.
Attempted Diels-Alder reaction of the cyclopentene diester (Ifi)
with butadiene or 2,3-dimethylbutadiene in the presence of various
catalysts2 7 , and in a number of solvents proved, as anticipated,
fruitless.
The experiments just described served to establish that the
dienolates of acyclic as well as cyclic systems could be successfully
utilized in this reaction, and also defined a new use of the dienolate
-18-
as an intermediate in the simple,
one pot oxidation of vicinal diester
alkanes to alkenes.
Figure 20.
Mechanism of the Dienolate Mediated Oxidation of
I ,2-dimethylcyclopentane dicarboxylate
With the synthesis of the propellane (12.) accomplished, it now
became feasible to repeat the oxymercuration experiments of
Otzenberger to examine the steric control hypothesis proposed earlier.
Accordingly, the propellane was added to a rIHFZwater slurry of
mercuric acetate under conditions identical to those reported by
Otzenberger - and m u c h to our chagrin, whereas the tetrahydrophthalans
-19-
had reacted quantitatively within 15 minutes at room temperature,
propellane proved to be quite unreactive!
the
Obviously, the steric
environment of the double bond had been altered drastically, for even
on prolonged exposure to the reaction conditions, no product was
observed,
It had been reported^® that oxymercuration reactions could
be catalyzed by trace amounts of nitric acid in methanol.
When the
propellane w a s subjected to these conditions t w o methoxy ether propellanes resulted,
which by GLC (13% DECS,
lO'xl/4"), were present in a
1:1 r a t i o (Figure 21).
Epoxidation studies also demonstrated the reduced reactivity of
the double bond, however upon extended exposure to metachl oroperbenzoic acid at 20°C, t w o epoxides w e r e obtained, once again in a 1:1
ratio (Figure 21).
Spectra wh i c h were crucial to the interpretation
of these results are contained in Appendix A.
In light of these findings, it w a s concluded that for the
tetrahydrophthalans such as (5), simple steric factors w e r e
responsible for the observed product composition, not heteroatom
participation as had been initially proposed.
The results of this study also imply that great care must be
exercised in drawing analogies between the chemistry characteristic
for norbornyl systems and that associated wi t h more c o m m o n molecules,
such as the cyclohexenes employed in our experiments.
I
I
NJ
O
Figure 21.
Oxymercuration and Epoxidation Reactions of
8-Oxatricyclo-[4.3.3.0]-undec-3-ene
-
21
-
With the successful completion of the. synthesis and deployment
of the propellane (12), the preparation of modhephene (13) utilizing
the dianion strategy presented itself as the next fertile application
of the method.
To achieve this goal, the synthetic scheme shown on
the following page was devised (Figure 22).
The extraordinary utility of this method for forming the bicyclic
intermediate QQ) was readily apparent from this analysis.
If the
ester functionality was a suitable electrophile for this reaction,
consecutive dianion mediated annelations could be used to produce (29)
in t w o steps from dimethylsuccinate.
Moreover, the back to back
annelations could conceivably be achieved by adding I,3-dibromopropane
to the dianion of dimethylsuccinate, as shown in figure 22, or alter­
natively, by successful addition of 3-bromoethy!propionate to the
dienolate of dimethylsuccinate followed by addition of 1,3-dibromopropane.
This would result in the desired cis-diester arrangement as
well; therefore, this approach w a s flexible, stereoselective, and
direct.
Wittig olef!nation of the ketone group would provide the alkene
(30) which could be stereospecificallv. catalytically hydrogenated to
(31) .
Construction of the final ring was then anticipated via
crotonization of the dimethyl ketone (32.), to the propellane (33)»
Separation of isomers and alkylation would then provide the ultimate
target.
'S,
%
X
0
COOCH 3
COOCH 3
O
11
COCH
COOCH3
COCH
29
COOCH 3
0
30
x
22
HoC
C
COOR
COOR
P
COOCH3
COOCH3
/
COCH
Proposed Synthesis of Modhephene
31
-23As a test for the serviceability of esters in the dianion method,
3-bromoethylpropionate was added to the dienolate generated in the
usual way from 3,4-dimethylcyclohexene dicarboxylate.
workup,
a respectable yield
Following
(60%) of 7-oxo-(cis)-l,6-dicarboxymethyl-
b i c y c l o - [4.3.0] - d e c - 3 - e n e (34) was obtained (Figure 23).
COOR
ROOC
CC'
COOR
COOR
34
R - CH 3
Figure 23.
Synthesis of 7-Oxo- (cis)-1,6-dicarboxymethylb i c yclo-[4.3.01-non-3-ene
An interesting discovery w as noted that although the dienolate of
dimethylsuccinate reacted with 1,3-dibromopropane to give (22): when
it was exposed to 3-bromoethylpropionate a complex mixture resulted
which contained no 2,3-dicarbomethoxycyclopentanone
(35) (Figure 24).
Apparently the dimethylsuccinate dienolate existed in a transoid
geometry and was less reactive than the cisoid dienolate of the cyclic
diester systems.
In an attempt to examine this hypothesis, N-methyl
succinimide was prepared and employed as the dianion in the reaction
—24—
with 3-bromoe thy !propionate.
Once again, the resulting complex
mixture contained none of the desired cyclopentanone.
Thus, it was
concluded that the configuration of the dianion was not the major
factor contributing to the failure of the reaction.
In an article
published subsequent to our investigation of this reaction, Yamamoto
29
reported the successful condensation of the dianion of diisopropylsuccinate w i t h 2- (bromomethyl)ethylacrylate to provide 5-methylene2,3-diisopropy!cyclopentanone dicarboxylate.
Yamamoto also reported
difficulty in employing 3-bromoetty!propionate in condensations with
the dianion of diisopropy!succinate30.
___ COOCH3
C
'OEt
^CO O CH3
Br
-H-
/\-C 0 0 C H .
^"COOCH-i
Figure 24.
Attempted ^ n t h e s i s of
2,3-dicarbomethoxycyclopentanone
By repeating this procedure for the dianion of I,2-dicarboxymethylcyclopentane,
the ketodiester (22) was synthesized in 61% yield
following purification.
Unfortunately, all attempts to convert the
ketone group of (22) to a methylene by Wittig olefination m e t with
failure.
-25Even under forcing conditions that had been employed success­
fully by other workers31 in sterically hindered ketones,
unreactive.
(2£) proved
In a related propellane ketone. Smith32 overcame a similar
obstacle by employing methyltriphenylphosphoniumbromide in a preheated
toluene solution of potassium t-amylate to provide the olefin CM) in
49% yield (Figure 25).
Figure 25.
Smith's Wittig Reaction
As can be seen in the diagram below,
this Wittig reaction was
the ultimate step in Smith's total synthesis of modhephene; he was
therefore committed to its success (Figure 26).
W e w e r e not bound by the same constraints, so rather than
repeating the procedure of Smith, an attempt was made to circumvent
the problem entirely.
—26~
a.b.c.d
e
h
Lg.
i.j
Modhephene
H2C
V \
(a) 1,2-dichloroethylene, hv. Corex, 5 hr., 67%.
(b) ethylene glycol,
acid catalyst, azeotropic removal of water,
(c) sodium, ammonia, -30
C, 78%.
(d) 2% aqueous sulfuric acid, 91%.
(e) p-toluene sulfonic
acid, benzene, heat, 4 hr. 93%.
(f) methyllithium.
(g) Jones
oxidation, combined yield: 88%.
(h) dimethyl homocuprate, ether,
boron trifluoride etherate, -78 C, 70%.
(i) methyl Wittig, 49%.
(j) chromatography,
(k) p-toluene sulfonic acid,
dichloromethane, 87%.
Figure 26.
Bhiith1s Synthesis of Modhephene
A major asset of the dianion technique is the flexibility
afforded by prudent choice of the electrophile.
Hence,
if introducing
-27-
the methyl group onto the bicyclic precursor for modhephene w as an
inconvenience, perhaps a bromomethylketone could accomplish the
annelation and introduce the methyl group in one step.
test this hypothesis,
In order to
4-bromo-2-butanone was prepared by addition of
gaseous IBr to methylvinylketone.
When the dianion of the cyclo­
pentane dicarboxylate was combined with this bromoketone, a fair yield
of the desired bicyclic alcohol (IZ) w as isolated
(Figure 27).
0
Il
/-^/C-OCH3
-O C H 3
Il
0
J
Figure 27.
Synthesis of 2-Hydroxy-2-methyI-(cis)I ,5-dicarboxymethylbicyclo-[3.3.01-octane
Although the yield of the reaction w as somewhat less than
spectacular (-30% following purification),
the task in one step,
the reaction accomplished
and was easily reproducible on a larger scale.
Since the starting materials w e r e readily available, the low yield was
-28-
not a hindrance to our efforts.
Dehydration of the epimeric alcohols
using phosphorous oxychloride in pyridine33 gave a 60% yield of the
isomeric alkenes (3 8 ) and (30)
(Figure 28).
The formation of this
isomeric pair of products was of little concern since both were
readily reduced to the requisite alkane
COOCH-
(31).
C 00CH-
(37)
COOCH-
C 00CH-
Figure 28.
Dehydration of 2-Hydroxy-2-methyl-(cis)I ,5-dicarboxymethylbicyclo - [3.3.01-octane
The keystone of the proposed synthesis of modhephene rested
upon the next step in the sequence,
the bicyclic alkenes
(30) and
(38).
that being the hydrogenation of
In the previous syntheses of
modhephene, esoteric methods had been used to obtain the desired
orientation of the C-8 methyl group,
(see appendix B).
Based upon our
understanding of the nature of the catalytic hydrogenation reaction34,
-29-
w e felt confident that reduction would proceed from the ester face of
(.31) in the manner shown below (Figure 29).
11
Figure 29.
Proposed Mechanism of Hydrogenation of 2-methylene-(cis)1 ,5-dicarboxymethylbicycl o- [3.3.01-octane
Due to the affinity of the catalyst surface for the lone pair of
electrons present on the oxygen atoms, the hydrogen delivery would
occur so as to place the methyl group in the correct orientation
between the t w o carbocyclic rings.
A supporting argument could be
proposed in terms of steric reasoning, as the carbomethoxy face might
be more open and thereby permit more facile attack by the reducing
system.
In practice,
when the alkenes were hydrogenated at 60 psi over
palladium on alumina, the resulting product showed only one set of
-30-
signals by 13C n m r w i t h no trace of olefinic carbons.
Other
spectral data as well as inspection of the product by TLC and
capillary GLC were consistent with the supposition of isomeric
purity.
The hydrogenation reaction had therefore occurred
stereospecifically (Figure 30); however, since this material was a
n e w compound, there was no way to make an unequivocable assignment
of the configuration of the methyl group at this stage of the
synthesis.
H 3Q
H2
(3&
) +
(3&
)
Pd
COOCH3
Cd
COOCH3
31
Figure 30.
Stereospecific Hydrogenation to 2-methyl-(cis)-1,5dicarboxymethylbicyclo-[3.3.01-octane
Based upon the reasoning outlined above,
it was assumed that the
proper stereochemistry had been achieved and the material was carried
on to the next step without further concern.
Final confirmation of
the structure of (31) awaited conversion to a known product.
-31-
The completion of the synthesis rested upon forming the final
carbocyclic ring from the diester residues.
To this end simple
methods w e r e sought to convert the ester groups to methyl ketones
however following a few initial disappointments in this regard,
the
dimethyl ketone (32) was abandoned in favor of a more amenable
intermediate.
To conclude the synthesis of modhephene from (21) required
fabrication of the five membered ring as well as the regioselective
introduction of three methyl groups.
Consequently an expedient method
of accomplishing this became a priority.
An acid catalyzed cycli-
zation of (39), analogous to a polyene cyclization3®, appeared to be
the simplest such reaction
(Figure 31).
Figure 31. Proposed Synthesis of Modhephene via Acid Catalyzed
Cyclization of 2-Methyl-(cis)-[1-dimethylmethylol-5(1-methylethenyl)Ibicyclo- [3.3.01-octane
-32-
The conformation of (39) appeared to be ideally suited to this
approach, as the cyclization would expectedly be facilitated by the
close locality of the olefin and alcohol groups in the transition
state.
However, procurement of (39) presented a serious stumbling
stone to the implementation of this idea.
The most direct synthesis of (39) from the diester
(H) w as
envisioned as the straightforward addition of four equivalents of
methyl lithium followed by dehydration of one of the alcohols to an
alkene.
This approach w a s fraught w i t h problems.
dehydration of the diol (40) could be realized,
Firstly, if the
it would undoubtedly
provide a complex mixture of isomeric hydroxy-alkenes along with some
diene.
Secondly, since the proposed diol could cyclize to a tetra-
hydrofuran propellane, the ultimate yield of hydroxy-olefin would be
dismal at best.
To overcome these difficulties, it w as hoped that the
alkoxide generated fcy addition of methyl nucleophile could be trapped
as the diacetate, or some other suitable intermediate, which could
then be pyrolyzed to the olefin.
In practice,
the concern over the side reactions of the diol (JO)
became a m o o t point.
In an experiment employing the diester (31), it
w a s discovered that due to the constraints of the system,
(21) could
not be alkylated fcy ordinary methyl nucleophiles to give the diol (JO)
(Figure 32).
-33-
Figure 32.
Attempted Synthesis of 2-Methyl-l,5-Dimethylmethylolbicyclo- [3.3.0]-octane
Product analysis of the reaction of four equivalents of methyl
lithium with the diester
(31) showed primarily the vinyl ether (45),
along with a trace amount of the tricyclic lactone (43).
Three equi­
valents of methyl lithium produced 90% vinyl ether in addition to
about 5% of the lactone.
added to the diester,
When t w o equivalents of the nucleophile were
an excellent yield of the lactone resulted.
One equivalent of the alkylating agent gave predominantly unreacted
diester
(31) along with varying amounts of the lactone (43)
Based upon the results of these experiments, the reaction
sequence shown in figure 33 was proposed.
The proximity of the ester
group to the tertiary alkoxide in (42) precluded the formation of any
alcohol.
0
^
Cl-OCH3
H3C CH3
C -O C H
C -C H
(42)
( 43)
(31 )
OLi
(45)
(44)
Figure 33.
Mechanism of Sequential Addition of Methyllithium to 2-Methyl-(cis) 1 ,5-dicarboxymethylbicyclo- [3.3.0] -octane
-35-
As outlined in this diagram, following initial formation of the
methyl ketone (41), subsequent attack by the methyl nucleophile
occurred predominantly at the ketone carbonyl to give the alkoxyester
(42).
which cyclized to the lactone
(43).
In the presence of excess nucleophile, the lactone presumably
underwent further reaction to the hemiketal (44). which due to steric
congestion with the beta-methyl group on ring 1B 1, dehydrated during
workup to the vinyl ether (45).
The hemiketal itself w a s not observed
under any of the conditions studied.
With the direct preparation of (39) at an obvious impasse,
synthetic utility of the vinyl ether (45) w as examined.
olefin
the
The keto-
(46) depicted in figure 34 was the proposed product of an acid
catalyzed ring opening of the vinyl ether moiety.
Figure 34.
Proposed Isomerization of 2-Methylene-3-oxa-4,4,8trimethyl tricyclo-[ 3. 3. 3. 0] -decane
-36This intermediate was sought on account of the ease with which
the vinyl ether could be obtained from the diester, and the manifest
resemblance of (46) to the hydroxy-olefin
proposed cyclization to modhephene.
(39) requisite for the
However, all efforts to affect
this isomerization w e r e frustrated? gas phase as well as solution,
chemistry w e r e equally ineffectual and in every case only unreacted
vinyl ether was recovered.
The results of this attempted isomerization, in concert with the
thwarted synthesis of the diol, portended an inauspicious end to the
pursuit of the synthesis of modhephene via the intermediacy of the
hydroxy-olefin (39); therefore another avenue of synthesis was
examined.
The inherent simplicity of utilizing a nucleophilic addition of
methyl lithium to add the required carbons to the diester (31) prompted
a consideration of the virtues of the lactone (42) as an intermediate
for the synthesis of the target.
This impulse was greatly reinforced
w h e n exhaustive characterization of a sample of the lactone revealed
that it was greater than 95% isomerically pure!
This regioselective
formation of the lactone (Figure 35) inspired a closer scrutiny of the
reaction leading to its formation.
On scale-up of this reaction, when 2.0 equivalents of methyl
lithium w e r e slowly injected into a stirred IHF solution of the
diester (31) at 0°C, a flocculent white solid formed.
After a few
minutes, the reaction w a s quenched fcy adding a few drops of 5% HC1,
-37-
and following extraction, a 60% yield of the lactone wa s obtained.
Figure
35.
Synthesis of 2-oxo-3-oxa-4,4,8-trunethyltricyclo-[3.3.3.0]-decane
Mass balance considerations indicated that the aqueous phase had
retained some product, so it w a s strongly acidified with concentrated
HCl and extracted with ether.
This yielded the remaining mass as an
off-white colored powder, which was subsequently characterized as the
beta-diketone
(4Z) (Figure 36).
Figure 36.
6-methy1-2,4-dioxotricyclo-[3.3.3.01-undecane
-38In a related experiment, the reaction described above was
duplicated in detail with one exception:
the methyl lithium was
injected into a solution of the diester (21) a n d 10 equivalents of
lithium methoxide generated from methyl lithium and methanol.
This
experiment provided about 50% of the lactone and 45% of the 1,3diketone, and was interpreted as implicating the lithium methoxide
formed by displacement by the methyl nucleophile at the methyl ester
as a base which could then catalyze the condensation to (42) shown in
figure 37.
The methyl lithium could also act as a base in this
context.
0
48
47
Mechanism of Formation of
Figure 37.
6-methyl-2,4-dioxotricyclo-(3.3.3.0]-undecane
-39-
An additional aspect of the discovery of (47) was the opportunity
presented for understanding the regioselectivity of the lactonization
reaction.
By inspection of Dreiding models it was apparent that the
C-5 methyl group of Q l ) experienced a gauche butane interaction with
an hydrogen on C-8, and that the ester groups were sterically eclipsed
(Figure 38).
Figure 38. Conformational Equilibrium of
6-Methyl-(cis)- I ,5-dicarboxymethylbicyclo-[3.3.01-octane
It was therefore expected that the bicyclic skeleton of the
diester Ql) would be constrained to a skewed conformation.
Once
again, by scrutiny of models, the most likely such distortion placed
the methyl in a psuedo-equatorial orientation (Figure 39) which could
plausibly serve to discourage attack at the C-I carbomethoxy group.
— 40-
In order to account for the formation of the beta-diketone
(AD
it was proposed that the methyl ketone (48) formed by displacement at
the C-2 ester, due to the buttressing effect of the neighboring betamethyl group, underwent deprotonation in preference to suffering
another attack by a nucleophile (Figure 39).
By a similar mechanism,
(42) could also be formed from the C-I ester.
Nu:
<
H
R=OCH3
COCH
R=CH3
Figure 39.
Steric Differentiation of Ester Groups in
6-Methyl-(cis)-l,5-dicarboxymetly lbicyclo-13.3.01-octane
It could also be argued that the abstraction of a proton from the
methyl ketone (4£) would be much favored on a kinetic basis.
The
enolate thus formed would rapidly condense with the adjacent C-I
ester.
Loss of one of the very acidic methylene diketone protons
would then give the enolate of (42) which would be inert to further
alkylation^.
In an attempt to verify this reasoning,
the diester
Ql) was
-41-
qrystal for X-ray structure analysis.
Initial efforts to this end m e t
w i t h failure, as the diacid exhibited a verminous predilection to form
a powdery solid.
The analysis of the lactonization reaction provided useful
insight concerning the nature and mechanism of lactone formation; but
it now bec a m e essential to find a suitable method to convert the
lactone ring into a carboqyclic system.
As demonstrated above, c o m m o n
nucleophilic addition of another methyl group at this stage of the
synthesis seemed dubious.
Inspection of the literature revealed that
gamma-lactones of the type under scrutiny were dehydrated by a reagent
prepared from methane sulfonic acid and phosphorous pentoxide38 to
give 3-methylcyclopentenones.
When the propellane lactone (il) was subjected to the conditions
of this reaction a complex mixture was obtained.
Flash chromato­
graphy39 failed to separate these compounds, however GLC (13% DECS,
10!xl/4") resolved the mixture into three peaks: A-44%, B-22%,
33%, thereby allowing collection of analytical samples.
and C-
Compound 'B'
was subsequently identified as the enone (5Q) (Figure 40), while
compounds 'A' and 'C' remained enigmatic despite concerted efforts to
solve their structures.
— 42—
(a) P2O 5, CH3SO3Hf 70°C, 16 hr., 30%.
Figure 40.
Synthesis of 4,8-dimethylbicyclo- [3.3.0] -oct-3-enone
The l o w yield and the presence of other products implied that
rearrangement of the propellane skeleton might have occurred.
In sub­
sequent reactions, the yield of the enone wa s reproduced at 30-35%
based on the weight of the mixture obtained and integration of the GL£
trace.
As stated above, the lactonization reaction had occurred regiospecifically.
Therefore, a single isomeric enone w as expected from
the dehydration of the lactone (43), and based on the steric reasoning
already proposed, the expected isomer w as identical to an intermediate
in Smiths' synthesis of modhephene.
This w as confirmed by comparison
of our product, which proved to be identical in all respects, to an
authentic synthetic sample generously provided by Professor Smith.
Hence,
this constituted a formal synthesis of (*) modhephene.
41 summarizes these results.
Figure
— 43—
/C O O C H 3
C
a,b,c,d
TO O CH3
Modhephene
(c) r e a g e n t (a),
(a) 2.5 LDA, T H F f - 7 8 °C.
(b) I f3 - d i b r o m o p r opane.
(d) 4-bromo-2-butanone.
(e) FOCl3 pyridine, cold.
(f) hydrogen,
Pd/alumina.
(g) 2 eq. M e L i f TOFf cold,
(h) P9Ocf methane sulfonic
acid, 70°C.
Figure 41.
A Formal Total Synthesis of Racemic Modhephene
— 44—
The lactone was therefore proven to be a useful intermediate in
the formal synthesis of the target; however the yield of the dehydra­
tion w a s disappointing.
In light of this fact,
the beta-diketone (42)
was considered for employment as an intermediate in a n e w total
synthesis of modhephene
Figure 42.
(Figure 42).
Proposed Total Synthesis of Modhephene
Accomplishing this goal presented a major obstacle though.
As is
evident in the reaction shown above, conversion of the diketone to the
natural product required regioselective introduction of the three
missing methyl groups.
Based upon the behavior of the diester Ql) in the lactonization
reaction, it was known that the C-8 methyl (modhephene numbering)
could be exploited to achieve regiospecificity at the beta-carbonyl.
However, as this effect w a s postulated to arise from a conformational
bias in the bicyclic geometry, it remained uncertain whether the same
reactivity would be observed in the tricyclic diketone (47).
-45-
Models indicated as expected, that the propellane skeleton
greatly increased the rigidity of the carbon framework in (41),
thereby reducing the degree to which the 0 8
methyl group could serve
to shield the beta-carbonyl.
Another obstacle to the proposed synthesis exposed itself in the
conversion of the beta-diketone to the 1 ,3,3-trimethyl-l-propene
system.
The most convenient manner of accomplishing this emerged as
the conjugate addition of dimethyl homocuprate^
to the vinyl acetate
of the diketone (51), followed by 1,2-addition of methyl lithium and
dehydration (Figure 43).
Mesylate esters have also been employed
successfully in this reaction^.
However, as reported by Smith in his
synthesis of modhephene, conjugate additions to this type of hindered
ketone required special conditions and failed to go to completion4^.
b
(a) dimethylhcmocuprate
(b) methyl Grignard, then -H2O
Modhephene
Figure 43.
Proposed conversion of 4-Acetoxy-8-methyItricyclo13.3.3.0]-undec-3-ene to Modhephene
— 46“
To obtain a regioselective alkylation, a selective formation of
the vinyl acetate (51) w a s required,
If this could not be achieved,
chromatographic separation of the acetate isomers and recycling would
bec o m e a toilsome necessity.
as the requisite isomer,
Moreover, the acetate (51) w as demanded
as (S) could be converted to the target only
by lengthy and circuitous avenues.
Thus,
specific regioselectivity to
the proper enol-acetate loomed as a substantial obstacle to be sur­
mounted if the 1,3,3-tri m e thylpropene w a s to be had via this m e t h o d
With these imposed constraints, a study of the formation of the
vinyl acetate (51) from d i k e t o n e .(Al) w a s undertaken.
Acetic
anhydride with a trace of tertiary amine as a catalyst produced a Isl
mixture of the t w o a c e t a t e s ^ .
A drop of 5% HCl catalyzed the
reaction of (Al) with acetic anhydride to yield a 1:1 mixture of
acetates as well.
ineffectual.
Cooling the reaction to -30°C wa s equally
The reaction of isopropenyl acetate with (Al) under the
standard c o n d i t i o n ^ also provided a 1:1 mixture of the acetates
(Figure 44).
The t w o acetates proved to be inseparable by TLC.
These results indicated that the C-8 methyl group w a s indeed
less important in directing the chemistry of the propellane system
t^an it had been for the diester, and seemed to forebode disappoint­
ment concerning the desired goal.
Since the effects of the methyl
group w e r e obviously greatly diminished in the propellane (AZ) nny
attempt to take advantage of its presence would require a sensitive
assay.
-47-
OAc
(
4_7 )
+
O
OAc
1 :1
53
(a) acetic anhydride,
51
(b) isopropenyl acetate.
Figure 44. Nonselective Acetylation of
6-methy 1-2,4-dioxotricyclo-[3.3.3.0]-undecane
The best hope of such a reaction wa s deemed the thermodynamically
controlled O m e t h y l a t i o n of the enolate of the diketone with methanol
under equilibrating conditions (Figure 45).
By this strategy it was
hoped that the small thermodynamic differences between the methoxy
ethers
(M)
and
(55) could be observed.
(
54
Figure 45.
47
)
55
Conversion of 6-methy1-2,4-dioxotricyclo-13.3.3.0I-undecane
to the vinyl ethers under equilibrating conditions
-48Implementation of this hypothesis resulted in a very gratifying
result.
One vinyl ether w a s obtained in excess of 98% purity by
refluxing
HCl
(47) overnight in absolute methanol with 2 drops of cone.
(Figure 46).
(a) I drop H C l , methanol, reflux 18 hr.
Figure 46.
Synthesis of 2-Oxo-4-methoxy-8-methy 1tricyclo-[3.3.3.01-undec-3-ene
As shown above, based on the reasoning already presented, the
isomer expected from this reaction was (M) which does not suffer the
steric congestion between the O-methyl and C-8 methyl groups which (.55)
experiences.
Structural confirmation of which isomer had been
obtained w a s determined by conversion of the methoxy ether to the
enone (5£) by the action of methyl lithium in refluxing toluene
(Figure 47).
Milder condition provided only unreacted (4Z).
-49-
(a) 5 equivalents M e L i r toluener reflux.
Figure 47.
Synthesis of 4,6-dimethy 1-2-oxatricyclo-[3.3.3.0]-undec-3-ene
Spectral data were consistent with the structure shown for
(5£).
The product was proven to be dissimilar to the alternative (5Q) by
direct comparison with an authentic sample obtained as already stated.
To consummate the total synthesis,
the C-2 ketone had to be
elaborated to a geminal dimethyl function.
This transformation had
been previously reported by the German chemist Reetz45; but had
attracted little attention from the synthetic community,
apparently
owing to the exotic nature of the reagent employed to accomplish the
reaction.
More specifically,
in the paper published by Reetz,
dimethyltitanium dichloride had been used for the conversion of
ketones to their corresponding gem-dimethyl derivatives in 58% to 86%
purified yields.
The reagent was also reportedly efficacious in the
m e thy lation of tertiary alcohols and halides.
The experimental pro­
cedures for these reactions were extraordinarily simple and the
-50reaction w a s rapid, usually reaching completion in less than 30
minutes.
The pitfall to this reaction w as found in obtaining the
reagent.
Dimethyltitanium dichloride is a pyrophoric, volatile, red
solid w h i c h is reportedly sensitive to heat, light and halides46. . In
apparent conflict w i t h this information is the report that the reagent
can be prepared fcy the action of methyl magnesium iodide on titanium
tetrachloride4?.
Other reports indicate that alkyl lithiums and alkyl
grignards yield black resins w h en exposed to titanium tetrachloride48.
This is in agreement w i t h the results of experiments conducted in our
lab.
An alternative preparation of dimethyltitanium dichloride
involved addition of t w o equivalents of dimethyl zinc to titanium
tetrachloride in methylene chloride49.
This report w as substantiated
by an independent article employing the synthesis of the reagent5^.
This therefore w a s adopted as the method of choice.
Although dimethyl zinc wa s available commercially, ary procedure
requiring m o p e than a few milligrams proved financially unreasonable
in the academic setting.
Since it w as certain that model compounds
wo u l d be subjected to the reagent before commitment of the enone (Sg);
a cost effective synthesis of dimethyl zinc w a s investigated,
Such a
procedure w a s found in a note published in 1954 by Krug and Tang
In their synthesis, methyl iodide wa s added slowly to a zinccopper couple prepared by heating a homogeneous mixtupe of cupric
-51citrate and zinc powder over an open flame until evolution of gases
had ceased.
After standing 24 hours, dimethyl zinc w a s distilled, in
vacuo, under nitrogen in 60% yield (Figure 48).
Zn + Cu7CfiH4O7
- L U ---- >
2 6 W .
2) CH3I
Figure 48.
Zn(CH3),
32
Synthesis of Dimethylzinc
Reproduction of their method proceeded without incident, however
the material obtained in our lab w a s contaminated by 33% Mel,
apparently resulting from an excess addition of the halide*.
%
nmr
(CDCl3) exposed the methyl resonance of the dimethyl zinc at -0.41 ppm
relative to TMS.
Mass spectral analysis confirmed the presence of
dimethyl zinc, showing the parent ion at m/z=96, with the expected
methyl fragmentation pattern.
When this material was added at 0°c to a methylene chloride
solution of titanium tetrachloride a yell o w precipitate w a s formed.
Addition of a trace of diethyl ether provided a brilliantly colored
red solution.
1H nmr analysis of this material showed an intense
resonance at -1.90 p p m relative to TMS, and no trace of the dimethyl
zinc signal.
dichloride.
Figure 49 outlines this preparation of dimethyltitanium
-52-
TiCi4 + ZntCH
Figure 49.
Isophorone
Ti(C H3)2Cl2
Synthesis of Dimethyltitanium Bichloride
(4,5f5-trimethy 1-2-cyclohexenone)
(57) was added to
the yellow slurry just described and allowed to stir 18 hours while
w a r ming from O0C to room temperature.
The reaction was then quenched
by the cautious addition of dry ice, followed by excess a m m o n i u m
carbonate.
Extraction with methylene chloride and chromatography of
the crude syrup on silica gel, eluting with petroleum ether, afforded
a hydrocarbon which was subsequently characterized as 1,3,3,5,5-tetramethylcyclohexene (58)
(Figure 50).
Z
0
Figure 50.
Geminal Dimethylation of Isophorone
-53-
The geminal dimethyl compounds obtained from 3-methylcyclohexenone, 3-methylcyclopentenone, and cyclohexanone w e r e prepared in a
similar fashion.
The yield in each case was greater than 90% based
upon recovered starting materials.
instance w a s about 60%.
The percent conversion in each
It w a s concluded from this study that the
methyl iodide impurity in our dimethyl zinc did not detract from the
potency of dimethyl titanium dichloride as an alkylating reagent.
The
proposed mechanism for the geminal dialkylation reaction is given
below in figure 51.
57
\
Z
58
Figure 51.
Proposed Mechanism of the Dimethyltitanium Bichloride
Mediated Geminal Dimethylation of Isophorone
— 54-
A r m e d with this initial success, the application of the reaction
to the precious enone (_5£) was deemed feasible.
Exposure of (_5£) to
the standardized conditions resulted in a clear oil which was purified
by flash chromatography to give a colorless liquid which proved in all
respects identical to authentic (-)-modhephene.
Figure 52 summarizes
the total synthesis of modhephene.
H 3C
COOCH
15 LiOMel
2 M eLi 1
4 Steps
COOCH
T H R O 0C
COOCH
COOCH
Figure 52.
Total Synthesis of Racemic Modhephene
— 55—
This synthesis provided racemic modhephene in an overall yield of
34% from the tricyclic beta-diketone
the diketone from diester
(Al).
An enhanced synthesis of
(Jl) should be possible by employing the
method of House52 which would proceed through the half-acid ester
(59), and employ the high yield condensation of the keto-ester
(47) (Figure 53).
COOR
COCH3
48
31
59
R = CH3
R= H
47
Figure 53.
Proposed Alternate Synthesis of
6-methyl-2,4-dioxotricyclo-[3.3.3.01 - undecane
(AS.) to
—56—
A proposed synthesis of the optically active modhephene is also
possible by- this route.
Proceeding from the readily available
optically active (+)-3-methy!cyclohexanone, Favorski rearrangement of
the bromo-derivative wou l d provide the optically active ci8-1,2dicarbomethoxy-3-methylcyclopentane (60b).
Routine annelation of this
dianion w i t h 1,3-dibromopropane wo u l d provide the optically active
analog of the diester
(31).
shown as (61) in Figure 5 4
This is potentially a m u c h higher yield synthesis than the total
synthesis already demonstrated, as the mediocre alkylation with 4bromo-2-butanone is avoided,
are required as well,
Fewer manipulations of the intermediates
since the chemistry dealing with configuring the
C-8 methyl group is obviated.
One possible problem is found in the alkylation with dibromoprppane.
The planar nature of the dienolate involved will m o s t likely
exhibit no facial preference for attack by the electrophile.
will result in a diastereomeric mixture of the two products,
(62). illustrated below.
61.
This
( E U and
Chromatography should, however, provide pure
-57-
O
COOEt
COOR
g.b .c.d
COOR
600
60 b
R=H
R=CH3
e,f
f
\
COOCH3
+ isomer
Modhephene
COOCH3
62
61
(a) bromine,
(c) reflux,
THE, -78 0C.
Figure 54.
(b) alcoholic
alcoholic KOH, O0C.
methylene chloride,
(b)
H+
, reflux,
(e) 2.5 L D A l
(d) a b s o l u t e m e t h a n o l , H ,
reflux.
(f) 1 ,3-dibromopropane.
Proposed Synthesis of Optically Active Modhephene
-SB-
EXPERIMENTAL
Reported boiling points and melting points are uncorrected.
Nmr
spectra w e r e recorded on either a Varian A-60 nmr spectrometer using
CCl4 as a solvent and T M S as an internal standard or a Bruker WM-250 MHz
spectrometer using CDClg as a solvent and an internal standard.
Chemical shifts are reported in delta units relative to TMS.
spectra w er e obtained using a B eckman IR-S spectromenter.
frequencies are reported in c m --*-.
Infrared
Absorption
GLC analyses were carried out using
a Varian 1400 gas chromatograph equipped with a thermal conductivity
detector.
Mass spectra w e r e obtained using a V G 7070 high resolution
mass spectrometer in the EI m o d e at 70 ev and in the Cl m o d e using
isobutane at 70 ev.
Compound numbers containing decimals refer fo
page number and notebook number of raw data records
to page 93 of notebook number 2).
(e.g.,
93.2
refers
— 59-
Preparation of ethy 1—6 —broino~2~cyclohexanons cgptppxyXstS
Bromine (23.5 grams) was added over about 30 minutes to a
magnetically stirred solution of 25.0 grams of ethy1-2-cyclohexanone
carboxylate in 75 m L of chloroform at 0®C.
After stirring overnight,
a stream of moist air w a s bubbled through the solution for 60 minutes.
This removed most of the HBr and isomerized the bromine from the I- to
the 6— position.
The chloroform solution wa s then rinsed with
saturated sodium bicarbonate,
followed by a rinse with brine, and then
dried over anhydrous m a g nesium sulfate.
Jeft 35.1 g r a m s of a crude,
Evaporation of the solvent
highly colored product.
This material was
used in the next step without further purification.
The proton N M R
spectrum showed a broad triplet at 4.71 p p m indicating the presence of
the bromine atom.
Preparation of 1 .2—cvclopentanedicarboxvIic $CJld (2^1.
The crude ethyl-6-bromo-2-cyclohexanone carboxylate w a s added
slowly to an excess of ethanolic KOH solution (4M KDH,
EtCBZH2O 11/1).
The reaction flask was cooled by an external ice-water bath, and the
reaction was maintained under these conditions for 1.5 hours.
this time, the reaction w a s refluxed for 8 hours.
reaction to room temperature,
After
After cooling the
it w as acidified w i t h cone. HG1.
The
alcohol w a s removed by rotary evaporation and the remaining aqueous
slurry was extracted repeatedly with diethyl ether.
After drying the
combined organics over anhydrous magnesium sulfate, filtration, and
-60-
removal of solvents, 15.3 grams of a sticky, solid material w as
obtained.
Recrystallization from ethyl acetate afforded 11.8 grams of
the diacid as white crystals,
imp, 135-140°C
{Additional diacid
could be obtained from the mother liquor, or if the diester was
desired, the yield could be augmented by esterifying the crude diacid
directly.}
1 .2-cyclopentanedicarboxvlic acid
IR:
(KBr) 3200-2500 (broad), 1700,
1H N M R :
13C N M R :
MS:
J33b
1425,
1220,
940 c m "k
(D2O) 3.38 [2H, (m)3; 2.32-1.85 [6H, (m)].
178.9 (s); 46.7 (d); 28.2 (t)? 23.4 (t).
(No Mt) 140 (Mt-H3O ) , 122, 117, 1 12 (base), 99, 95, 87.
Analysis:
53.32; H,
C a l c d for C 7H 10O 4 :
C,
53.16;
H,
6.33;
Found:
C,
6.39.
Dimethyl-1 .2-cvclopentane dicarboxvlate
1221
Esterification of 4.0 grams of the diacid by the standard pro­
cedure using diazomethane gave 4.5 grams (93%) of dimethyl-1,2-cyclopentane dicarboxylate
(22),
which w as distilled (68-70°C at 0.28 Torr)
to obtain an analytical sample.
di mehhvi-.i .2-cvclopentane dicarbogylafcg
IR: 1740, 1445, 1210, 1190, 1040 c m " 1.
122k
-61-
-lH N M R
(tra'ns):
(m)]; 1.80
2.01 [6H,
3.70 [6H, (s)]; 3.14 [2H, (dd)]; 2.08
t4Hf (m)]:
(cis);
12E,
3.65 [6H, (s)]; 3.05 [2H, (dd)];
(m)].
(Cl) MHt=187, 1 5 5 (-MeOH).
ni niphbvl-1 .2-rvclopentane dicarboxvlatg
Dimethylsuccinate
(1.50 grams,
S22L
0.01 mole) was added via syringe
to a magnetically stirred solution of 100 m L of dry tetrahydrofuran
containing 2.2 equivalents of LDA under a dry nitrogen atmosphere at
-780C.
After stirring for about 15 minutes, the solution formed a
thick orange-colored slurry, and the dry ice/isopropanol bath was
replaced w i t h an ice/salt bath (-5°C).
The reaction mixture was
stirred for an additional 10-15 minutes,
then 2.28 grams (1.1
equivalents) of 1,3-dibromopropane w as added via syringe.
After the
addition, the slurry dissolved to give a pale orange solution which
w a s stirred for an additional t w o hours while slowly warming to room
temperature.
The reaction w a s quenched w i t h dilute H d , and the
aqueous phase w a s extracted with ether, followed by several
extractions w i t h dichloromethane.
The combined organic extracts, were
dried and rotovapped to give an orange liquid which distilled at 8790°C,
0.35 Tofr to give 0.78 gram
(51%) pure diester,
identical in all
respects to that obtained by the diazomethane esterification of 1,2cyclopentane dicarboxylic acid.
—62—
A small amount ("3%) of the butylmethyldiester (105.2a) was also
obtained w h i c h resulted from transesterification of the dimethyl
diester.
l-carboxvbutYl-2-carboxymethvlcvclopentan_e:
%
NMR:
4.09 [2Hf (t)]; 3.69 E3H, (s)l ? 3.11 [2H,
(m)]; 1.90-1.20
MS:
[8H,
(m)l; 0.93
(m)]; 2.05 [2H,
[3H, (t)].
^
|
Mf=228, 197, 196, 168, 1 5 5 (base), 141, 127, 126, 113, 95, 67. |
Diniothvl-1.2-cyclopentene dicarboxvlate J M L
A 0.10 a solution of lithium cyclohexyli sopropyl amide w a s
prepared by. reacting cyclohexyl isopropyl amine
(1.50 gram,
and one equivalent (7.5 ml, 1.44 a) of n-butyl lithium.
j
10.0 mmol)
After
i
j
stirring for about 10 minutes, a vacuum was employed to remove the
j
hexane and isolate the amide as a white solid which w a s then
I
redissolved in 54 m L of anhydrous tetrahydrofuran.
j
i
This solution w a s cooled to -78°C and stirred while 1.0 gram (5.4
i
mmol) of the vicinal diester w a s added slowly via syringe.
After IOp
15 minutes 1.36 grams (5.4 mmol) of iodine dissolved in 15 m L tetra-|
hydrofuran w a s injected.
This resulted in a faintly pink solution
j
which w a s stirred briefly and then quenched by adding excess dilute ;
HC1.
Following extractive workup, drying, and removal of solvents, a
light y e l l o w oil (1.3 grams, 87%) w a s obtained.
6,x3/4"r
dimethyl
GLC
(13% DECS,
175°C) showed t w o major products which were identified as the
(85%) and butylmethyl
(15%) 1,2-cyclopentene diesterS.
—63—
aimAthvl-l.2-cvclopentene dicarboxvlate
1H N M R :
3.78 t6H, (s)3; 2.75 [4Hf (t)l; 2.01 t2H, (ddd)l.
13C N M R :
165.7
(s), 139.6
(s), 51.3 (q), 34.0 (t), 21.6
(t).
IR: 1720, 1640, 1340, 1290, 1150, 1085, 1030, 955, 770, 750 c m " 1 .
MS:
M t =184, 153, 152
Analysis:
Found:
(base), 125, 124, 93, 79.
C a l c d for C g H 1 2 O 4 :
C,
58.70 ; H,
6.53.
C, 58.87 ; H, 6.75.
i-hnhvi-2-TTtpthvlcvclopentene djcarboxvlatg1H N M R :
4.18 [2H, (t)3? 3.77 [3H, (s)]; 2.74 [4H, (t)]; 2.00
E2H, (pentet)]; 1.62 I2H, (pentet)l; 1.39 [2H, (pentet)]?
0.94 [3H,
MS:
(t)].
(No Mt), 1 9 5 & 194 (- M e O H ), 171, 154, 153 (base), 152, 140, 139,
138, 126, 111, 98, 93.
nimethyl-i .2-cyclohexene dicarboxvlate .142*21
Using the same procedure as for '(16), 2.0 grams
(10.0 mmol) of
' dimethyl-1,2-cyclohexane dicarboxylate produced 1.97 grams of a dark
liquid which was shown by GLC to be > 90% (49.2) and its double bond
isomer
(approximately 2:1, respectively).
This mixture,
after
refluxing overnight in acidic methanol w as converted almost
quantitatively to (49.2).
after distillation
The yield of purified (49.-2) was about 70%
(94-98°C at .35 Torr).
—64—
dimethyl-1.2-cyclohexene dicarboxylate
1H N M R :
IR:
3.73
.(JMLZk
[6H, (s)]; 2.31 [4H, (fine ddd)] ? 1.65 [4H, (fine ddd)].
2850, 1725, 1650, 1440, 1250, 1200, 1178, 1100, 1070, 1055, 770,
755, 680 c m - -1-.
MS:
(No M t ) ,
167, 166 (- M e O H ), 138, 137, 123, 107, 105, 79 (base),
77, 67, 59.
P r e p a r a t i o n of ?.-oxo-(cis)-l.5-dicarboxvmethvlbicvclo-[3.3.0]-octane
(29)
Dimethyl-1,2-cyclopentane dicarboxylate (L00 gram,
5.40 mmol)
w a s added by syringe to a cooled (-78°C), stirred solution of 2.5
^ q u i v a i J L i t h i u m diisopropyl amide in 54 m L anhydrous tetrahydro—
furan under nitrogen.
After stirring for about 15 minutes,
the
solution w a ? w a r m e d to — 5°C and 1.1 equivalents (1.07 grams) of ethyl3-bromopropionate
w a s injected.
The reaction was stirred for an
additipnal 2-3 hours and quenched with excess dilute HC1.
After the
usual work up, the product w a s subjected to flash chromatography (7:3
hexane/ethyl acetate) to provide 0.78 gram (61%) of pure (211)°
I
A minor product (0.15 gram, 10%) w a s obtained which w a s sub­
sequently identified as the monoalkylated tfiester
( I H aZ).
2-oxo-(cis)-l,5-dicarboxvmethylbicyclo- [3.3,0] -QCtflRfi
iZSJj
IR; 1750, 1725, 1440, 1245, 1200, 1100 c m -1.
1H N M R :
3.69 [3H, (s)l; 3.62 [3H, (s)l; 2.80-1.40 U 0 H ,
(m)].
—65—
1^ C N M R :
. 214.0 (s), 175.0 (s), 169.0 (s), 70.5 (s), 62.0 (s), 52.5
(c|)t 52.4
MS:
(g),
38.0
(t), 36.5 (t), 34.0 (t), 29.5 (t), 24.9
(t).
Mt=240, 209, 180, 153 (base), 152, 137, 121, 120, 111, 93.
Analysis?
Celled for C 1 2 H 1 6 O 5 :
59.85 ; H,
6.80.
C, 60.00 ; H, 6.67.
Pounds
C,
jl,2-dicarbomethoxy-l-(3-ethylpropionatyl)-cyclopentane (111.2):
1H N M R :
4.12 [2H, (q)l; 3.65 (3H, (s)]j 3.63
[3H, (s)]; 2.72
flH,
(dd)l; 2.50-2.10 [4H, (m)]; 2.05-1.80 (4H, (m)]; 1.75-1.55 [2H, (m)];
1.23
t?H,
13C N M R :
(t)].
175.0 (s), 174.1 (s), 173.0 (s), 60.3 (s), 56.3 (s), 53.2
(t),
51.6 (q),
51.5 (q), 34.4 (t), 33.0 (t), 30.5 (t), 28.6
(t), 22.7
ft),
JL4.0
NS:
(No Mt), 241, 240 (- E t O H ), 226, 212, 199, 194, 181, 180, 167, 153
(q).
(base), 141, 139, 125, 121, 93.
Analysis:
Fqund:
C a f c d for C 1 4 H 2 2 O 6 :
C, 58.74 ; H, 7.69.
C, 58.55 ? H, 7.58.
Preparation of cis-1.5-dicarboxymethylbicyclo- [3.3.0] -octane
(85.2)
A solution of 2.5 equivalents lithium diisopropyl amide
(.068
cjram diisopropyl amine and 4.70 m L 1.44 M n-BULi) in 30 ml, dry
tetrahyd^ofuran was stirred at -78°C under nitrogen wh i l e 0.50 gram
(2.68 mmol) of 1,2-dicarboxymethylcyclopentane was added via syringe.
After stirring for about 10 minutes, the reaction w as w a r m e d to -5°C
-66-
and 1.36 grams (6.70 mmol) of 1,3-dibromopropane w as added.
reaction wa s stirred for one hour while w arming
The
slowly to room
temperature and then quenched by pouring the reaction into excess
dilute P^l1
Epctragtive wor k u p with dichloromethane and removal of
solvents, in vacuo, provided 1.25 grams of a yellow oil.
Chromatography
(7:3 hexane:ethyI acetate) afforded 0.30 gram
the pure bicyclic diester.
(60%) of
No starting material w as recovered.
c i s - 1 .5-dicarboxymethvlbicyclo-[3.3.01 -octane iS5s2.:)
1H N M R :
NMR:
IR:
3.59 [6H, (s)]; 2.23 [4H, (m)l; 1.80-1.55 [8H, (m)l.
176.9
(s), 64.3
(t), 51.6
(q), 38.6
(t), 25.0
(t).
2850, 2700, 1725, 1440, 1280, 1235, 1195, 1140, 1050, 1015,
900, 820 cm"1 .
MS:
Mt=226, 195, 194, 185, 166, 153, 135, 107
(base), 79.
Attempted Preparation fi£ 2-methvl- (cis)-l,5-dicarboxvmethvlbfcyclo%
(1.1.01-octane (311
^
the usual procedure,
5.0 grams of 1 ,2-dicarboxymethyIcyclo-
pentane (27 mmol) w e r e added to 2.5 equivalents of L D A at -78°C in 250
m L dry THE.
After stirring 10 minutes,
1.5 equivalents of
1,3-dibromobutane w e r e injected into the reaction pot.
The reaction
was allowed to stir for one hour, and then terminated and worked up.
This afforded an orange liquid wh i c h w a s distilled (110-140%, 0.35 m m
Hg) to provide 1.39 gra m s
(21%) of a colorless liquid.
GLC (13% DECS,
-67-
10'x
1/4”, 165°C)
revealed only a trace of starting material and at
least five other peaks.
The major peak
submitted for analysis.(80.2).
(about 50%) was collected and
None of the desired product was
Obtained.
I .2-dicarboxymethyl-l-(3-propenvl)-cyclopentane (80.2):
1H N M R :
[3Hf
.5.88 U H ,
(s)];
3.62 I3Hf
(m) I .
MS:
(ddd)l; 5.08 [1H,
(dd)3? 5.00 Q H f (s)l; 3.69
(s)]; 2.90-2.70
E3Hf (m)]; 2.10-1.20 [6Hf
)
(No M t ) ,
195, 194 C-NeQH), 166, 135, 134, 107
(base), 106,
91, 79.
Epoxidation of 3.4-dimethL
y l-8-oxatricyclo-[4.3.3.03-undec-3-ene IZSsZL
at elevated temperature
To 100 nq
(0.52 nmol) of (70.2)in about 15 mL CHClg was added 100
m g of m-chloroperbenzoic acid dissolved in 5 mL CHClg-
The reaction
was stirred at 20? C for one hour, after w M c h time G LC analysis
(10%
DECS on Chromasorb W - M ; 10' x 1/4", 170°) showed only unreacted
(70.2).
After heating the solution to reflux for 1.5 hours, the
reaction was cooled to room temperature and allowed to stand
overnight.
The reaction mixture was then worked up by rinsing the
CHClg solution with saturated sodium bicarbonate solution, followed by
saturated brine.
The organic phase was then dried over anhydrous
magnesium sulfate and filtered, then the solvent was removed by rotary
evaporation-
This afforded 90 mg of a clear liquid (83%).
GLC
-68-
analysis revealed that no starting material remained and two new .pa
peaks in the approximate ratio of 1:1 were present.
Samples of each
were collected and submitted for analysis.
I ,4 -dimethvl-8-oxatricvclo-[4.3.3.Q]-undec-2,4-diene 111=21:
1NMl: 5.39 I2H,
J=8.6]; 1.83
(s)]; 3.79 E2H,
(d), J=8.63? 3.53 [2H,
[2Hf (m)l; 1.79 [6H,
(d),
(s)l; 1.65-1.32 [4H,
(m)3.
MS: M t =190, 175, 145 (base), 131, 115, 105, 91.
3-methvl-4-methvlene-8-oxatricvclo- [4.3.3.03 -undec^2=ene lffis2sl:
1NMR: 5.45 [1H,
(br s ) 3 ; 4.98 [1H,
(br s)]; 4.85 [1H,
(d), J=2.93?
[1H,
(d), J=8. 5 3 ; 3.70 [IR,
(d), J=8.53; 3.61 tlH,
3.58 [1H,
(d), J=2. 1 3 ; 2.34 [1H,
(br d), d=12.73; 2.26 E1H,
3.77
J=12.73; 1.84 [3H,
(d), J=1.53; 1.80-1.55 L6H,
(d), J=2.13;
(br d),
(m)3.
MS: M t =190, 175, 158, 145 (base), 131, 117, 105, 91.
Rpoxidation s £ 3.4-dimethvl-8-oxat ricvclo-[4.3,3.03-undec-3-ene
(70.2) a t 20°C
To 20 mg of (70.2) in 15 m L methylene chloride at O0 C under a
dry nitrogen atmosphere was added 20 m g of MCEBA in 5 m L of the same
solvent.
The reaction mixture was stirred at 20° for; 72 hours, then
worked up as outlined above.
GLC demonstrated that all of the
starting material Iiad been consumed, and that only traces of the
dienes
(6 0 . 2 ) and (60.2a) were present.
again formed in a 1:1 ratio.
The
major products were
Collection of the two peaks by GLC and
-69-
subsequent analysis revealed their identity as the desired epoxides
(70.2a) and
(70.Zb). .
1 .4-dimethyl - (avn)-3»4-ePOXV-8-oxatricvclO- [4,3,3,03 -rVhdecam
IpiMR;
3.69 [2H,
(d) J = 7 .5]; 3.27
J=15.0]; 1.88 [2H,
1.27 [6H,
MS:
l2Ur
;
(d), J=7.5]; 2.01 I2Hf (d),
(d), J=15.0J; 1.85 (2H,
(m)]? 1.55-1.33
[4H,
(m)];
(s)].
Mt=208, 193, 177, 163, 151, 145 (base), 135, 121, 109.
Analysis:
(HPMS) calcd for C 13H 2QO2 208.1463, Found 208.1476
1 .4-d-imfithyi - (anti)-3. 4-epoxv-8-oxatrigycloIn M R :
3.73 [2H,
(d), J=7.5]; 3.57 t2H,
Cd), J-15.03; 1.67
[2H,
3, Q] -undecan^
{7Q.«2feL°-
(d), J=7.5l; 1.96 I2H,
(d), J=15.0]; 1.70-1.40 [6H,
(p))l ? 1°29 ^6Hf
(s)3,
MS:
Mt=208, 193, 177, 163, 151, 145 (base), 135, 121, 109.
Analysis:
HRMS calcd for C 13H 20O 2 208.1463, Found 208.1443
Kpoxidation of 8-oxatricv c l o - [4,3,3,03- u n d e c - 3 - ^ m li 2
Treatment of 60 mg of
02)
with 65 mg of MCEBA for 24 hours at
20° in 20 m L of chloroform gave 66 mg
(100%) of a clear liquid that
was analyzed by GLC (13% D E G S , 10' x 1/8", 180%), demonstrating the
presence of two products,
m
and
W
in the ratio of 53.1:46.9,
respectively (based on GLC peak integrals).
■—70—
sy n - 3 .4-epoxv-8-oxatr icyclo- [4,3.3.Q] -undecane
1H N M R :
3.66 [2H,
(ddd)]; 2.10 [2H,
I.§2
[2%,
(d), J=IO.03; 3.37 [2H,
(d), J=IO.0]; 3.14 [.?Hf
(ddd), J=14.5,2.7,1.0];
(m)I; 1.65-1.45 [4H,
12M-'-
1.93 [2H,
(br d), J=14.5];
(m)3.
MS: 180, 162, 149, 132, 117, 91, 79
(base).
Analysis: HRMS calcd for C 11H16O 2 180.1150, Found 180.116
ant i - 3 ,4-eix)xv-8-oxatricyclo-(4.3.3.0]-undecane 1251?
1H N M R :
3.73 [2H,
(ddd)]; 2.19 [2H,
l.p]; 1.70-1.40
MS:
(d), J=7.8]; 3.57
[2H,
(d), J=7.81; 3.13
(ddd), J=17.2, 3.1, 0.9]? 1.77 E2H,
[6H,
[2H,
(dd), J=17.2,
(m)].
180, 162, 149, 132, 117, 91, 79
(base).
Analysis: HRMS calcd for C 11H16O 2 180.1150, Found 180.1155.
Methoxvmercuration of 8-oxatricyclo-[4.3.3.0]r m d eCrSreGe
Tto a magnetically stirred solution of m e
equivalent
-021
(0.29 gram)
of mercuric acetate in 10 m L methanol was added 0.15 gram of the
propellane
(IS), followed by one drop of concentrated nitric acid.
After stipring for 18 hours at roan temperature, one equivalent of
sodium methoxide
(48.6 mg) was added and the solution was stirred for
one additional hour.
Then 5 mL of 0.5 M NaCH was added, followed by
excess solid sodium borohydride.
The reaction was stirred briefly,
during which time it became a homogeneous gray slurry, then allowed to
settle before being vacuum filtered through celite.
Ranoval of
-71-
solvent at reduced pressure afforded 0.17 gram (95%) of a yellow
liquid that showed two peaks
1/8" y JrSO0O
(26) and (2%) by GLC (10% D E G S y 10' x
which were present in a 1:1 ratio.
Kyn-3-inethoxv-8-oxatricyclo- [4.3.3.0] -undecane
%
NMR:
3.81 [2Hr (d), J=7.0J; 3.69 [2H,
J=20.4y 7.3J; 3.32 [3Hy (s)]; 2.00-1.20
MS:
196, 168, 166, 149, 137
Analysis:
J2&L?
(d), J=7.01; 3.67 Q H y (dd),
Q2H,
(m)].
(base), 119, 93, 91, 79.
HRMS calcd for C ^ H 20O 2 196.1463, Found 196.1456
anti-3-methoxv-8-oxatricyclo- [4.3.3.01 -undecane iZil:
1H M ® :
3.72 E2H,
(d), J=6.9J; 3.65 [2H,
Jp8.2, 7.5]; 3.31 E3H,
MS:
(d), J=6.9] ; 3.61 ElH,
(s)l; 2.00-1.10 Q 2 H ,
(dd),
(m)].
196, 168, 166, 149, 119, 93, 91, 79, 49 (base).
Analysis:
HRMS calcd for C 12H 20O 2 196.1463, Found 196.1466
Dreparat-inn of 3.4-dimethvl-(cis)-l-6-dicarboxvmethvlbicyclo-(4,3.PJnon-3-ene (50.2)
Tten grams (0.044 imle) of 1 ,2-dime thy 1-4,5-dicarboxymethy lcyclohexene were added to a solution containing 2.5 equivalents of lithium
dii^opropyl amide (generated from 76.8 m L of 1.44 M n—butyllithium and
11.2 grams of diisopropyl amine) in 360 m L of tetrahydrofuran which
had bean freshly distilled from sodium benzophenone ketyl.
The
reaption was conducted under a dry nitrogen atmosphere at no more than
-IO0C.
After allowing tne dianion of the diester to form (about one
-72-
or t w o minutes suffices)» 1.5 equivalents (13.3 grams) of 1,3-dibromo
propane in a m i n i m u m amount of dry tetrahydrofuran were injected into
the reaction mixture.
The dark red solution usually lightened to a
pale yell o w at this point, and the cooling bath was removed.
Stirring
w a s continued for about one hour, during which time salts were usually
observed precipitating from the solution.
If the reaction w as allowed
to stir overnight, yields w e r e lower and the product w a s m o r e highly
colored.
The reaction was worked up by either injecting three equivalents
of cone. HCl, in which case the amine salts which formed w e r e filtered
off; or alternatively,
the reaction could be poured into excess dilute
HCl and the product extracted from the aqueous layer w i t h methylene
chloride.
In practice,
the latter procedure proved easier to perform.
On a large scale, excess tetrahydrofuran w as evaporated prior to
extractive w o r k up.
After drying the combined organics over anhydrous
magnesium sulfate and removal of the solvent,
(b.p. 110-129°C,
short path distillation
0.5 m m Hg) resulted in 5.9 grams
(59%) of a semisolid
material (50.2). w h i c h w a s homogeneous by TLC and G L C
I.A_dimethyl - ( r .i s)-l.6-dicarboxVmethvlbicycljp-F4,3»0]-TWrc=3=fiD£
(50.2):
13C N M R :
176.0 (s), 123.3 (s), 54.0 (s), 51.4 (q), 34.0 (t), 29.9
(t),
19.Q(t).
MS:
iy|t=266, 235, 234, 206, 191, 175, 147 (base), 131, 119, 105, 91.
-73-
Preparation of 8-oxa-3,4-dimethyltricyclo- [43»3.01-undec-3-ene
The diester
(50.2)
(5.0 grams) was added to a tetrahydrofuran
solution of 0.5 g r a m lithium aluminum hydride at O0C. ,After 3 hours
the excess hydride w a s discharged by cautious addition of w e t ether.
The tetrahydrofuran w a s removed by rotary evaporation,
then the crude
diol was taken up in methylene chloride and washed three times with
saturated brine and dried over magnesium sulfate.
in
used
This material was
the next step without further purification.
T o 2.25 grams of the diol wa s added 1.9 grams of p-toluenesulfonyl chloride in dry gyridine.
The reaction mixture w as stirred
for 2 hours at 40-60°C, and then it w a s poured onto a slurry of ice
containing 28 m L of cone, sulfuric acid.
The aqueous mixture was
extracted w i t h dichloromethane, and the extracts were d p e d and
d i s t i l l e d Cb.p. 95-100°C, 0.5 T o r r ), t o g i v e 0.75 g r a m (36%) of the
purified propeliane.
8 ^ o x a - 3 .4— d i methvltricvclo- [A.3.3.01 -undec-3-enB 152*21:
^H NMRs
(ppm from TMS) 3.52 [2H, (d), J=8.5]; 3.46 [2H, (d), Jf 8.53;
1.93 E4fl, (br s)]; 1.68 E6H, (br s)]; 1.65-1.35 E6H, (m)].
13C n ^R:
19.8
M£|:
127,2 (s), 81.5 (t), 61.5 (s), 40.0 (t), 39.9 (t), 24.7 (t),
(q).
M ^ F l 92, 174, 161, 159, 147, 133, 117 (base), H O , 105, 91.
Analysis: calcd for
H,
10.46.
C13H20O=
C, 81.13 ,
H,
10.40.
Found:
C, 81.08 :
—
74
—
Preparation of cis—1..6—dicarbomethoxybicyclo- [4°3<>0]~non...3—SR£ ()-$)
A solution of 100 m L of dry tetrahydrofuran,
17.4 m L 1.44 M n-
B u L i f and 2.55 grams of diisopropylamine w as stirred under nitrogen at
-78°C for 15 minutes; then 2.0 grams of 3,4-dicarbomethoxycyclohexene
(10 mmol) w a s injected and the bright red solution w a s stirred for an
additional 10 minutes. The dry ice/isopropanol bath w as replaced by an
ice/salt bath and 2.40 grams
added.
(1.2 equiv.) of I f3-dibromopropane w as
This resulted in a lightening of the Color of the reaction to
a pale yellow.
After stirring for t w o hours the reaction was quenched by pouring
in into excess dilute HC1.
The phases were separated and the aqueous
was extracted three times w i t h 50 m L of dichloromethane.
The combined
organics were dried and evaporated to yield 2.39 grams of a light
yellow liquid.
GLC (13% D E G S f 10'xl/4"f 180°C) revealed that no
Starting material remained, and a ne w peak had appeared.
Short path
distillation (102-108°Cf 0.4 Torr) produced 0.70 gram of a clear
liquid.
Column chromatography of the distillation residue provided an
additional 0.71 g r a m of a yellow liquid homogeneous and identical to
the distillate by GLC.
The combined yield w a s 60%.
cis-1.6-di carbomethoxvbicyclo-[4.3.01-non-3-.e.ne iiiLb
1H N M R :
5.64 [2Hf (fine triplet)]; 3.70 [6Hf (s)]; 2.50 I2Hf (ddd)f
J 1 = I 7 ^ f J 2 a n d J 3 s m a l l ! ; 2.35-2.18 t2Hf (m) I ; 2.19 [2Hf (ddd)f
j=17.5 H z ] ; 2.87-2.53 [4Hf (m)].
-75-
13C N M R :
176.2 (s), 123.1 (d), 51.8 (s), 51.4 (q), 34.2 (t)f 31.4
(t)r I?.5 (t).
IR:
2900, 1730, 1690
916, 733
MS:
(shoulder),
1440, 1320, 1280, 1205, 1176, 1105,
(str) an-1.
(No M t ) , 207
(-OMe), 206, 178, 163, 152, 119 (base), 105, 91.
Preparation of 8-oxatricyclo-[4.3.3.01 -undec-3-ene (121
T h e diester
(JS), (0.70 gram, 3.0 mmol) was added to 0.05 grams
of LiAlH4 in 50 m L tetrahydrofuran.
The solution was stirred for one
hour and then the excess hydride was discharged by addition of a small
amount, of w e t ether.
The solids were filtered off and the solvents
removed to give the diol
(71.2).
The residue was taken up in pyridine
and stirred at 0°C while one equivalent
sulfonyl chloride was added.
(0.60 gram) of p-toluene-
This solution was stirred overnight ap^
then dumped into 20 m L of cone, sulfuric acid on crushed ice.
Following extraction with dichloromethane and evaporation o f .solventsf
0.69 grams of a clear, fragrant liquid w as obtained.
Flash chromatography (1:1 hexane:chloroform) afforded 0.28 gram
(57%) of a fragrant yellow liquid which was shown to be the desired
propellane.
/
ci s - 1 »6-dimethylolbicvclo- [4.3.03 -hon-3-ene
%
N M R : 3.64 E2H,
2.82
(d), J=12.5 Hz]; 3.47 E2H,
E2H, broad humpl; 2.16
J t=16.3]; 1.62 E6H,
E2H,
(d), J=12.5 Hz];
(br d), J=16.3]; 1.87 E2H,
(br s)]; 1.70-1.50 E6H,
(m)].
(br d),
-
IR:
3300
76
—
(broad -OH), 2850, 1695, 1440, 1380, 1048, 1018 cm- 1 .
8-oxatricyclo-[4.3.3.Q]-undec-3-ene (12):
1H N M R :
5.86 [2H,
(t), J=4.2 H z l ; 3.57 [4H,
(s)]j 2.03 E4H,
(br s)l;
1.70-1.45
E6H,
13C N M R :
128.5 (d), 81.4 (t), 55.1 (s), 40.0 (t),. 32.5 (t), 24.1 (t).
MS:
(m)].
Mt=164, 146, 133, 119, 105, 91 (base), 79, 77.
Analysis:
Calcd for C 11H16O:
164.1197.
Found:
164.1149.
Preparation of the ditosylate of I ,6-dimethvlolbicyclo-[4.3.01-non-3ene (20.3)
To a cooled (ice/salt), stirred solution of 6.40 grams p-toluenesulfonyl chloride in 50 m L pyridine was added 3.0 grams
the diol in a small volume of pyridine.
(16.5 mmol) of
The solution was stirred
overnight and then quenched by pouring it into excess cone, sulfuric
acid on crushed ice.
Following extraction of the aqueous with
methylene chloride, 6.30 grams
(100%) of a yellow oil was isolated.
I ,6-dimethylolbicyclo-[4.3.01-non-3-ene ditosylate (20.3):
1H N M R :
7.78 [4H,
(s)]; 2.45 [6H,
IR:
(d)3; 7.36 [4H,
(s)]; 1.91
[4H,
(d)]; 5.45 [2H,
(br s)]; 1.58 [6H,
(s)3; 3.81 [4H,
(m)].
2900, 1730, 1600, 1360, 1190, 1180, 1100, 955, 835 & 815, 735,
660 cm"1 .
MS (Cl):
MHf =319, 165, 147 {-HOTs} (base), 146, 133, 119, 105, 92.
-77-
Prgparation of N-methvl-3 P -S-fi-hgtrahydropthalimide ..(gJLlI
Tto a well stirred suspension of NaH in glyme (6.40 gra m s 50% oil
suspension) at ice bath temperature w e r e added 20 grams (133 mmol) of
the imide.
evolved
The reaction w a s stirred until no more hydrogen w as
(about 24 hours) and then 19.0 grams
dripped into the pot.
reaction
(1.1 equiv.) of MeI w as
The cooling bath w as then removed and the
w a s refluxed for 24 hours.
The reaction w a s work e d up by removing the glyme and recrystal­
lizing the solids from hot water.
This gave white crystals which were
recrystallized from hexane to give clear, white needles mp: 67-7O0C.
N-Tnmthvl-1.2.5.6-tetrahydropthalimide.
1H N M R :
1& L21
5.89 (2H, (d)3; 3.10 [2H, (d)l; 2.95 t3H, (s)3; 2.61 I2H,
(dd)]; 2.24 [2H, (dd)].
NMR:
IR;
180.1 (s), 127.7 (d), 38.9 (d), 24.7 (q), 23.2 (t).
3010, 2895, 1765, 1 6 7 0 (broad!), 1440, 1380, 1320, 1280, 1190,
1120, 1050, 1025, 970, 940, 900, 875, 770, 695, 650, 640 c m
MS:
Mt=165, 136, 107, 80, 79, 77, 58.
Prgparation
of
N-methy1-7,9-dioxo-8-azatrievclOrJA3.3?0] ~,undec-3~.gh£
(93.2)
N-methyltetrahydropthalimide (4.12 grams, 25 mmol) w as added in
50 m L tetrahydrofurah to a tetrahydroftiran solution of 2.5 equivalents
of lithium diisopropylamide under nitrogen at -78°C.
This produced a
-78-
The solution was stirred for
6
hours at -5°Cr then 6.0 grams
(1.2
equivalents) of I ,3-dibromopropane was added and the solution was
stirred 18 hours.
{Addition of the dibromopropane caused the slurry
to dissolve.}
The reaction was terminated by pouring it into excess dilute
hydrochloric acid.
Extractive workup (MeClg) an^ removal of solvents
afforded 6.41 grams of a brown liquid which was placed on a silica gel
column and eluted with 8:2 hexane:ethyl acetate.
grams
This produced 4.4
(86%) of an orange tinted oil which was submitted for analysis.
N-methyl-7.9-dioxo-8-azatricvclo-[4.3.3.Q]-undec-3-ene (93^21:
1H M R :
2.24 [2H,
tlH,
5.88 [2H,
(fine doublet)],- 2.94 [3H,
(dd)]; 2.05 [2H,
(s)]; 2.67
[2H,
(d), coupled to 2.673; 1.67 [3H,
(dd)];
(m)3; 1.30
(m), coupled to 1.67 & 2.241.
13C N M R :
182.5 (s), 128.4 (d), 55.8 (s), 37.8
(t), 31.0
(t), 24.8
(t), 24.2 (q).
IR:
'2850, 1765 & 1710 (imide), 1680
(alkene), 1440, 1380, 1335, 1290,
1090, 1025, 900, 730, 650 cm"1 .
MS:
Mt=205, 176, 164, 162, 147, 138, 120, 119, 105, 91.
Preparation of N-methvl-8-azatr icyclo- [4.3.3.03 -undec-3-ene
To a stirred, cooled tetrahydrofuran suspension of 0.30 gram
lithium aluminum lydride was added 1.63 grams
(8.0 mmol) of the
tricyclic imide in a few m L tetrahydrofuran.
This solution was
-79-
ref luxed for one hour following the final addition of Imide? and then
stirred at room temperature overnight.
After discharging the excess LAH by dropwise addition of water
the salts w e r e filtered and rinsed with methlyene chloride.
The
organics w e r e wash e d w i t h dilute a m m o n i u m chloride, then brine, and
dried over anhydrous m a g nesium sulfate.
Evaporation of solvents
produced 1.33 grams (94%) of a golden liquid with a distinct amine
odor.
This liquid wa s passed through a basic alumina column using 5%
ethyl acetate in hexane.
The amine (1.15 gram) obtained from this
chromatography was used for an analytical sample.
KHTnpthvl-ft-azatricyclo- [4jt3.3.Q] - undec-3=gn£
1H N M R :
J3An2h
5.84 [2H, (t)3 ? 2.35 t4H, (dd)]| 2.23 I3H, (s)]; 2.00
14H,
(ddd), coupled to 5.84 by J=2-3 H z 3? 1.70-1.40 [6H, (m)3.
13C N M R :
24.8
(t).
IR:
3000,
130,0 (d), 71.1 (t), 60.2 (s), 43.3 (q), 41.2 (t), 34.9 (t),
2850,
2800
(shoulder), 2750, 1645, 1480, 1440, 1360, 1265
(doublet), 1220, 1190, 1150, 1075, 990, 910, 890, 880, 830, 735, 700,
665 c m -1.
MS:
Mt=177, 162 (-Me), 148, 134, 122, 105, 86, 84 (base), 57, 45.
Analysis
(HRMS):
Calcd for
C12H19N5
177.1512.
Founds
177.1515.
-80-
Prpparation of N.T^-dimethvl-8-azafcricvclo-[4«3?3.eP3-vmdec-jr isne I M M e
(95.2)
Ihe N -methyl proj^llane (0.63 gram,
3.56 mmol) was added dropwp.se
in a m i n i m u m volume of diethyl ether to a two-fold excess of methyl
iodide in 20 m L ether and then stirred for 10 hours.
The excess
methyl iodide and solvent w a s then removed and the remaining solids
w e r e recrystallized by dissolving in a m i n i m u m amount of ethanol and
then adding diethyl ether dropwise until the first perceptible, but
temporary cloudiness w a s observed.
Cooling yielded 1.03 gra m s (91%)
of impressive, fluffy white needles mp;
242-2440C.
This salt was
soluble in chloroform.
N . N - d i m e t h v l - 8 - a z a t r i c v c l o - [4.3.3.0J -undec~3r£ne iodide _(&5«21:
1H N M R :
[3H,
5.95 [2H, (t), J=3.1 H z l ? 3.79 L2H,
(s)]; 3.65
(d), J=12.9 Hz]; 3.71
(2H, (d), J=12.9 Hz]; 3.61 [3H, (s)]; 2.23 [4H, (br
s)]; 2.00-1.50 £6H, (m)]»
13C n m R:
128.3
23.2
(d), 77.3 (t), 55.8 (q), 55.3 (q), 54.3 (s), 41.7 (t),
34.2
(t),
(t).
IR:
3500, 2950, 2800, 2675, 1613, 1488, 1453, 1440, 1380, 1120, .1070,
1000, 965, 930, 912, 850, 7 1 0 c m - 1 .
-81-
Pre-paration of w-methyl-N-deuteromethyl-8-azatricyclo- [4,3.3.,Q]
3-ene Iodide
(96o2)
A 50 m L t w o necked roundbottom flask w a s flame dried, fitted wi,th
a septum,
and placed under nitrogen.
Then 100 m g (0.5$ mmol) of the
N-methyl propellane dissolved in 10 m L of anhydrous diethyl ether was
injected into the flask, followed by excess deuteromethyl iodide.
The
reaction was stirred for 2 hours at 20°C following wh i c h time the
reaction w a s wor k e d up as outlined above for the dimethyl salt.
B y recrystallization, 171 m g (96%) of a white crystalline solid
w a s isolated mp: 244-246%.
N M R analysis revealed that this compound
consisted of a mixture of epimeric amine salts.
T^methvlnN-deuteromethvl-8-azatricvclo- [4.3.3.03 -undec-.3=aD£ iPflldg
(96.2):
1H N M R :
5.96 [2H, (t), J=3.0 Hzl,- 3.82 E2H, (overlapping doublets),
J=12.9, 3.9 Hz]; 3.71 B H ,
(s), (N-Me)]; 3.63 B H ,
(overlapping
doublets), J=i2.9, 3.9]; 3.60 [3H, (s), ( N - M e ) I; 2.23 [4H, (br s),
(allylic methylenes)];
2.00-1.60
(6H,
(m)].
Preparation of 4-bromobutan-2-one (
A dichloromethane solution of 50.0 grams (0.71 mole) of
mefhyIvinylketone w a s stirred at 0°C wh i l e 26.65 grams of gaseous JHBr
w e r e bubbled into the flask at a rate such that little or n o HBr w a s
detected by w e t litmus paper at the exit port of the reaction flask.
- —82—
The reaction w a s deemed complete when HBr w a s evidenced above the
reaction.
The reaction w a s worked up by transferring the
dichloromethane solution to a separatory funnel and rinsing repeatedly
with saturated sodium bicarbonate solution.
If this rinse procedure
w a s omitted, the distilled product became highly colored and rapidly
polymerized.
After removal of the dichloromethane in vacuo, the
reddish residue w a s distilled (75-79°C at 18 m m Hg) to provide 85.8
grams
(80.1%)
of pure product.
4-bromobutan-2-one
IR:
(114.2):
2900, 1710, 1410, 1360, 1335, 1265, 1175, 1160, 1010, 910, 733
cirfI.
1H N M R :
13C NMR:
MS:
152
(18.8%),
3.51
[2H, (t)l; 3.00 t2H, (t)]; 2.15 [3H, (s)J.
204.9 (s), 45.4 (t), 29.6 (q), 25.0 (t).
(1.6%), Mf= I S O (1.6%), 137, 135, 123, 115, 109, 107, 81, 71
43 (100%).
P r e p a r a t i o n of 2-methyl-(cis)-l, 5-dicarbomethoxybicyclo- [3.3.0]-octan2-oi (37)
A t w o liter, three necked roundbottom flask wa s flame dried,
placed under a nitrogen atmosphere and charged with 2.5 equivalents of
lithium diisopropyl amide in one liter of tetrahydrofuran wh i c h had
been freshly distilled from sodium benzophenone k e t y L The solution
was magnetically stirred wh i l e cooled to -78°C, and 1,2-dimethylcyclopen tanedicar boxy late (24.60 grams,
0.132 mole)
w a s added slowly
-83-
via syringe.
After stirring for 30 minutes, excess 4-bromobutan-2-one
(1.5 equivalents, 29.0 grams) was added at -40°C.
The reaction was then stirred for an additional 3 hours wnile it
was allowed to warm slowly to roan temperature.
After this time, the
reaction was quenched by cautiously adding H 2O.
Following removal of
most of the IHF by rotary evaporation, the reaction mixture was recon­
stituted with dichloromethane and rinsed repeatedly with 5% aqueous
H C l , once with brine, and then dried over magnesium sulfate.
This
gave 36.0 grams of an orange syrup which was passed through a silica
gel column (5cm X 45cm, 9:1 hexane:ethyl acetate) to provide 6.10
grams of the starting material, 7.00 grams of the desired alcohol, and
1.71 grams of an intermediate, lew boiling material.
The yield of
purified product, based on recovered starting material, was 27.5%.
A emaiI amount
(about 0.7 gram) of the monoalkylated product,
I ,2-dicarbomethoxy-l-(3-oxobutyl)-cyclopentane
(118.2), was also ob­
tained.
9-TnPhhvl- (p .i r )-I. 5-dicarbomethoxvbicvclo- [3.3.QJ--QCtan-2r.p l 1311:
In m r
(epimeric m i x ture):
3.71, 3.70, 3.64, 3.63 (methyl ester sing­
lets ); 2.50-1.45 (aliphatic multiplets); 1.46, 1.36 (methyl singlets).
IR:
3500, 3400 (-0H), 2900, 1725, 1440, 1375, 1200, 1110, 1080, 1055,
1000, 930, 870, 750.
MS:
Mt=256, 224 (- C M e ), 207, 196, 185, 179, 164, 153
121, 93, 79.
(base), 137,
-84-
l.2-dicfiT-hoxymethyl-l- (3-oxoWtYl)"Cyclopentane
NMR:
3.65
3,9.9%!:
[3H, (s)3; 3.63 I3H, (s)l; 2.73 ElHf (t), J=8.71 ? 2.49
[2H, (t), J =8 .2]; 2.15 [3H, (s), m e t h y l ketone]; 2.10-1.50 [8 H f (m)l.
IR:
2850,
1725
(broad), 1670
(shoulder), 1430, 1350, 1200, 1030, 720
cm--*-.
13C N M R :
(q);
207.9 (s); 175.1 (s); 174.1 (s); 56.0 (s); 53.0 (d); 51.5
51.4 (q); 39.5 (t); 34.9 (t);31.6 (t); 30.0 (q); 28.5
(t);
22.3
(t).
MS:
225, 224, 213 (-C2H 3O), 199, 186, 185, 165, 164, 154, 153, 137,
126, 121, 95, 79, 67, 55, 43 (base).
An a l y s i s :
C a l c d for C 13H 3 0 O 5 :
61.08
7.68.
; H,
C, 60.94 ; H, 7.81.
Found:
C,
Prpparation nf 9-mAt^yi-(cis)-I,s-djcatbomethokybicyplo- [3,3,03-QCt-Ir
ene (381
A 250 m L roundbottom flask w a s charged with 5.25 gr a m s (20 mmol)
of the alcohol and 75 m L of dry pyridine.
The solution w a s cooled to
-5°C w i t h an ice salt bath and the flask w a s placed under nitrogen.
Then TOCl5 (6*2 grams,
2.0 equivalents) w a s added dropwise by syringe.
After stirring overnight the reaction w as quenched by pouring the dark
solution into a beaker containing excess concentrated HCl and about 50
grams of crushed ice.
Following an extractive work u p and filtration
of the dried organic residue through a silica gel column (6:4
hexane:ethyI acetate),
1.94 grams of the alkene was obtained as a
f-85—
golden colored liquid (57.0%) along with 1.48 grams of unreacted
alcohol which could be recycled.
2-methyl-(c i s )- I ■5-dicarbomethoxybicyclo-[3.3.01-oct-lren£ JJSls
NMRs
4.80 [1H,
(s)]; 3.71 [3H,
[2Hf (m)I; 2.08 Q H ,
IR:
(s)l; 3.69 t3H,
(m)]? 1.90-1.50 (5H,
(s)]; 2.52-2.40
(m)]; 1.44 [BH,
(s)].
2900, 1725, 1425, 1210, 1100, 1085, 1030,, 800 cm"1 .
MS(CI):
Mflt=239, 207
MS(EI):
K(t=238 , 206, 178, 149, 119 (base), 91.
Analysis
(HRMS):
(base), 179, 178, 159, 119,92.
calcd for C 13H18O 4 :
238.1205,
Found:
238.1210.
Preparation of 6—methyl— (cis) — 1,5—dicarbomethoxvbicvclo~ [3.°.3 .0) ~QQt^Qg.
(31)
The alkene
(38)
(1.85 grams, 7.70 mmol)
was hydrogenated at 60
psi in 50-0L00 iriL of absolute methanol over a PalladiumZAl2O 3 catalyst
with vigorous shaking for 72 hours.
Following vacuum filtration of
the catalyst and removal of the solvent, 1.87 grams (100%) of a sweet
smelling golden colored liquid was obtained.
The alkene and the
alkane product were inseparable by GLC on packed columns, so
H NM R
was used to determine the extent of reaction.
After 72 hours, no
olefinic proton signal was observable by NMR.
Sequential addition of
Resolve-Al E u F O D ™ indicated the reduction had occurred stereospecifically from the carbomethoxy face, as only one methyl doublet was
evidenced.
This conclusion was confirmed in a later experiment.
UXh
fi-Tnettyl-(cis)-l»5-dicarbomethoxybicyclo-[3.3nQ 3 - o c t a n e
NMR:
.[3H,
3.59 [6 H, (s)l; 2.76 [1H, (ddd)l; 2.3-1.3 H O H ,
(m)I; 0.89
(d), J = 6 .7 Hz].
13C N M R :
177.2 (s); 175.0 (s); 69.0 (s); 64.1 (s); 51,7 (q); 51.0
(q); 45.6 (d);
40.9 (t); 35.2 (t); 34.3 (t)? 33.0 (t)?
23.6 (t); 14.7
(q).
IR: 2900, 1725, 1450, 1430, 1240, 1190, 1135, 1010, 7 50 c m ” 1 .
MS:
Mt=240, 209, 208, 185, 180, 167, 153 (base), 138, 121, 105, 93,
91, 79.
Analysis
(HRMS):
calcd for C 13H20O 4:
240.1362, Found:
240.1370.
Attempted synthesis of 1.6-di-(l~methylethenyl)-bJ.cyclo~lA.-3-j.QJji
non-3-ene (29.3)
'
A tetrahydrofuran solution
(50.0 mL) of 6.20 m L 1.5 M. MeLi (4.4
equivalents) w a s stirred at 0®C while 0.5 g r a m (2.1 mmol) of the
bicyclic diester w a s slowly added via syringe.
The reaction was
stirred for 4 hours and then 0.72 g r a m (2.5 equivalents) of BOCl3 w a s
injected in 10 m L triethylamine.
The reaction w as stirred overnight,
and in the morning a white precipitate w as present.
The reaction wa s
terminated by cautiously adding w e t ether, followed by dilute aqueous
HC1.
After w o r k u p and removal of the solvents 0,42 g r a m of a yellow
solid w a s obtained,
GLC (13% DECS, 10' x 1/4", 200°C) provided three
peaks ("A"-75%, "B"-15%,
nC - 1 0%, respectively),
determined to be starting material.
the last of which w a s
None of the desired product was
-87-
obtained,
After standing in chloroform for one week peak 1B 1 had
disappeared;
presumably,
being equilibrated by trace acid to 1A 1.
eA" 7-methylene-8-oxa-9.9-dimetlyItricyclo^[4p3 o3 o03-und_ec-3rjaP.£
(29.3a):
1B N M R :
5.70 [2H, (m)l; 4.12 [1H, (d), J=1.8 Hz]; 3.79 tlH, (d),
j = l „8 Hz]; 2.40-1.30 flOH, (m)]; 1.30 [3H, (s)]; 1.18
IR:
2890, 1665,
1450, 1385
[3H,
(s)].
(doublet), 1280, 1225, 1140, 1125, 995,
885, 795 c m ™ 1.
MS:
Mtp204, 189, 161, 147, 145, 135, 131, 119, 105, 91 (base), 84,
77,
43.
Analysis
(HRMS):
Calcd for C 14H2QO:
204.1552.
Found:
204.1533.
I-acetyl-6- (1-Tnethvlethenvl)-bicyclo- [4.3.PlrDOn-3c^n^
1H N M R :
5.70 [2H, (m)]; 4.80 (1H, (fine doublet)]; 4.69 ElH, (fine
■ doublet) ]; 2.54 I1H, (m) ]; 2.43 [1H, (t) ]; 2.17 [3H, (s), (Me
ketone)]; 2.15 [4H, (m)]; 1.80 E3H, (fine doublet)]; 1.75 [4H, (m)].
MS:
Mt=204, 189, 180, 179, 178, 161, 146, 145, 133, 131, 111, 117,
HS,
105, 92, 8 6 , 84 (base), 43.
A t t e m p t e d synthesis of 1 ,6- d i - (I,l-dimethvlm&thvl o D r b i c y c J.Q~ E4.3,.0J ~
non-3-ene (30.3)
A dry 250 m L t w o necked flask w a s put under nitrogen and charged
w i t h 50 m L of freshly distilled tetrahydrofuran followed by 1.00 gram
(4.2 m m o l ) of 1 ,6 -dicarbomethoxybicyclo- E4.3.0] -non-3-ene.
This
—88~
solution w a s stirred at 0°C wh i l e 11.20 m L of 1.5 H MeLi
equivalents) was slowly added via syringe.
(4.0
After the addition of MoLi
was completed, the cooling bath w a s removed and replaced by a heating
mantle.
The reaction was stirred at reflux for 60 minutes; after
which time the reaction was cooled and 1.68 grams of acetic anhydride
w e r e injected to guench the unreacted MeLi and trap the alcoxide.
The
reaction w a s stirred for 30 minutes and then poured into, excess dilute
HCl, and extracted w i t h dichloromethane.
and drying procedures 1.13 grams
Following the usual rinses
(84%) of a red liquid w a s isolated.
GLC analysis of the product (13% DECS,
5' x 1/4", 17O0O
revealed
three peaks; each w a s collected and characterized by instrumental
methods.
NOne of the desired diol or its acetate derivative was
produced.
Product 0A 8 (major product):
7-mf>fchvl
1H N M R :
o-a-nxo-g.9-dimet^yltr icvclo- [4.3,3 ^ -undec-.3z£n g ( 3 W a l:
5.70 [2H, (m)l; 4.12 & 3.79 Q H each, (d), {vinyl C H 2 ^ ?
2.40-1.30
IR:
2890,
QOH,
(m)]; 1.30
[3H, (s)l; 1.18 I3H, Cs)],
1665 (sharp), 1450* 1385 & 1375 (gem dimethyl), 1280,
1225,
1140, 1125, 995, 985, 7 9 5 c m - 1 .
MS: Mt-204, 189 (-Me), 161, 147, 135, 131, 119, 105, 91 (base), 84,
77,
43.
,Analysis: Calcd for P ^ H 2QO:
204.1552.
Found:
204.1533
-89-
Product 'B's
NMR: 5.90
(unidentified)
[2H,
(m)]; 1.12 I2H,
pi:
(m)]; 2.15 [4H,
(ddd)I ; 2.00 [3H,
(s)];1.46
[4H,
(m)].
3000, 2850, 2680, 1690
(strong), 1615 (sharp), 1440, 138Q, 1?8Q,
11^0, 860, 730, 700, 640 cm"1 .
MS
(Cl):
M H t =229, 189 (base, -40), 173, 159, 145, 129, 117, 115, 103,
92.
Product 0C 8 (minor product):
7-oxo-8-oxa -9 ,9-dimethvltricvclo^[4.3.3.03-undec-3=fine (3Q?3pl:
1R N M R :
[6H,
5.79 [2H,
(ddd)I, 2.46 E2H,
(m)I; 1.38 & 1.30 [3H each,
NS (Cp):
(dd)l; 2.19 E2H,
(brd)]? 2.00-1.50
(s)l.
Mgt=207 (base), 189, 161, 147, 133, 120, 105, 92.
Prpparation fi£ 2-oxo-3-oxa-4.4.8-trimethvltxigyclQ - E3.,.3,3,QJr d e caoe
(43)
Po a cooled, stirred solution consisting of 25 m L THF and 300 mg
pf the diester (31) under nitrogen w as added 2.11 m L 1.3 I MeLi via
syringe.
The reaction was allowed to stir overnight and then quenched
by cautious addition of water.
The volume was reduced by rotary
evaporation and the residue was taken up in dichloromethane.
This
organic phase was washed repeatedly with brine, and then dried over
magnesium sulfate.
Removal of solvent afforded 240 m g
desired propellane lactone.
(80%) of the
-90-
The aqueous phase was strongly acidified with cone. HCl and
extracted with ether.
After drying over magnesium sulfate, 130 m g of
a golden gum was obtained which crystallized upon standing.
Flash
Chromatqgraphy (5:5 hex a n e :ethyl acetate) of this solid provided 22^
mg
(95% recovery) of a white crystalline solid which was identified as
the 1 ,3-dione propellane 2 ,4-dioxo-6-methyltricyclo-[3.3.3.0]-undecane
i£L).
2-oxoT-3-oxa-4.4.8- t rimethvltricvclo- [3.3.3.01 -decane I A l l :
1H N M R :
5.08 [1H, (s)]? 2.05 ElH,
(m)]? 1.35 [2H,
i^C N M R :
(m)l? 1.04 [3H,
(m)l; 1.83 [5H,
(m)]? 1,52 E4H,
Cd), J=6.6 Hz].
205.8, 203.9, 105.9, 68.7, 42.8, 35.2, 35.1, 34.6, 33.2,
27.3, 15.6.
IR:
29Q0, 1750, 1460, 1380
(doublet), 1340, 1260, 1100, 1025, 990,
910 CitT1 .
MS:
Mt=192, 164, 151, 135, 119, 107, 86 (base), 84, 47.
analysis:
Calcd for C 12H 16O 2 :
192.1128.
Found:
2.4-dioxo-6-methvltricvclo- [3.3.3...03-undfiSSPe
1H N M R :
7.60 tlH,
192.1139.
iML'
(broad hump)]? 2.20-1.30 T12H,
(m)3? 1.08 [3H,
( s) ] .
11C N M R :
205.8, 203.9, 105.9, 68.7, 67.2, 42.8, 35.2, 35.1, 34.6,
33.2, 27.3, 15.6. .
MS:
Mt=192,. 164, 151, 135, 119, 107, 88
(64.5%), 47.
(26.7%), 86 (100%), 84
—91—
Analysis:
Calcd for c i2H 1 6 ° 2 '
192.1128.
Found:
192.1139.
Ciyn^hPRia of 4,8-dimsthyltricvclo- [3.3.3.03 -undee - 3 - m - 2 r A D e I M l
A 100 m L three necked roundbottom flask was equipped with a
mechanical" stirrer, flame dried, and placed under nitrogen.
The flask
was then charged with 50 m L of 1:10 phosphorous pentoxide/methane
sulfonic acid solution, which was heated to 85°C before 280 mg of the
lactone propellane (38) w a s injected via syringe in a minimum volume
of methane sulfonic acid.
The solution darkened immediately and alter
stirring for 24 hours the reaction was quite dark.
A n additional gram
of P2O 5 was added after about 30 hours and the reaction was stirred an
additional 18 hours.
The reaction was quenched by cautiously pouring tne contents of
the flask into a beaker containing 300 m L saturated bicarbonate
solution.
This mixture was then extracted three times with 100 mL
dichloromethane.
The combined extracts were washed with brine and
dried over anhydrous magnesium sulfate.
This produced a dark, viscous
liquid which w a s filtered through a short silica gel plug to give 120
itg (47%) of an amber colored liquid.
I/A”, 170°C)
revealed three peaks (44%, 22%, 33%) and no remaining
starting material.
desired product.
Analysis of the second peak showed it: to be the
The first peak showed only aliphatic protons by 1H
NMR, and analyzed for
analysis.
GLC analysis (13% DECS, 10' x
by high resolution mass spectral
Kugelrohr distillation removed this material.
-92-
4 .fi-dimehhvltricyclo-[3.3.3.Q]-undec-3-en-2=one (.501:
1H W :
5.74 [IH5 (brs)]; 2.03
1.55 [SH5 (m)]; 1.25 [2H,
MS (El):
[3H,
(brs)]; 1.80 [GH5 Cm)];
(m)]; 0.98 [3H,
M t =190, 175, 162, 147, 136
Analyses: Calcd for CjgH^gO:
(d)5 J=7.65 Hz].
(base), 108, 91.
190.1335.
Found:
190.1346.
Spectral data for this material was IDENTICAL to that obtained from &
synthetic sample obtained from Professor A.B. Smith III.
S C Peak #3 (Unidentified!:
1H N M R :
2.80
Hz]; 2.22 [1H,
[2H,
(brdd)l, 2.45 [1H,
(brs)], 2.32 [1H,
(d), J=6.3 Hz]; 2.19 [1H,
(m)]; 1.00 [3H,
(d), J=6.3
(brs)]; 2.10-2.00 [3H, (m)];
1.70 [3H,
(s)]; 1.55 [4H,
(s)]; 0.62 I3H,
(s)].
MS (EI):
Mt=178 (analyzed for C-^Hjg0 ) • ^3., 135, 121, H O
(base,
^ H i o O ) , 93rf 69.
Preparation of 2-inethvlene-3-oxa-4.4,8- t rinethvItricyclo- [3,3,3?.
QJ ~
decane (45)
In the preparation of the propellane lactone
(43), if an excess
of methyllithium was present, a small amount of the vinyl ether was
obtained as a mixture of the 6-methyl and 8-methyl isomers.
A nearly
quantitative yield of the vinyl ether propellane could be obtained by
addition of 3 equivalents of MeLi.
It was characterized as follows;
—93—
2-methylene-3-oxa-4»4.8— trlntsfchyltyxcyclo— [3«3»3_*0 1—dsconfi
I
1H N M R :
[SR,
4.25 [1H,
(s)]y 3.66 Q H ,
(m)3? 1.29 [3H,
13Q
1$5.7
(s)]; 2.12 t2H,
(s)3; 1.24 [3H,
(s)3? 1.00 [3H,
(s) {quaternary vinyl ether); 85.7
(methylene); 69.9 (s); 66.6
(dd)],- 1.90-1.60
Cd), J = 6 . 5 H z 3 .
(s); 83=4 (t)
(s); 44.9 (d); 39.4 (t); 36.4 (t); 36.3
(t); 34.9 (t); 28.9 (t); 27.4 (q); 25.3 (q);
22.5 (t); 16.1
(q); 14.0
(q).
MS:
M t =206, 191, 177, 163, 151
(base), 149, 133, 121, 109, 107, 105,
?!, 43, 41 t
IR:
2850, 2690, 1655, 1450, 1380, 1250, 1120, 980
Prpparation M
(doublet), 805.
a-mPthvl-4-acetoxvtricvclo-[3.3.3.0Jj=13nde<?-3-en-?-.on£
(51) and 6-methvl isomer j M l
Method
hr-
A 50 ItiL two necked round bottom flask was equipped with a
magnetic stir bar, flame dried, and flushed with nitrogen before being
charged with 80 mg
(0.42 mmol) of the 1,3-dione dissolved in 3-5 m L of
isopropenyl acetate.
The reaction was stirred and heated to about
40°c, then one drop of cone, sulfuric acid was injected, at which
point the reaction became slightly darkened.
The reaction was allowed
to proceed for 16 hours, then the excess isopropenyl acetate was
removed by rotary evaporation and the residue was taken up in
dichloromethane.
This organic solution was washed repeatedly with
aqueous sodium bicarbonate, once with brine, and then dried over
sodium sulfate.
Removal of solvents gave 128 mg of an orange colored
-94-
liquid that w a s chromatographed on silica gel (8:2/hexane:ethyl
acetate) t o yield 74 m g
(75.2%) of pure vinyl acetate.
Subsequent
nmr analysis revealed that this material consisted of equal amounts of
the
8-methyl and 6-methyl isomers.
The isomers did not separate on
packed GLC columns, however w h e n G C M S w a s performed using a 30 meter
capillary column, the t w o isomers w e r e resolved in a Isl ratio.
Method B.:
A 25 m L round bottom flask w a s fitted w i t h a magnetic stir
bar, flame dried, and placed under a nitrogen atmosphere.
Then 10 mg
(0.052 mmol) of the 1 ,3-dione w a s injected into the flask in a m i n i m u m
amount of dichloromethane, followed qy 3 m L of acetic anhydride and
one drop of cone. H C L
After stirring for one hour,
the excess acetic
anhydride w a s removed by rotary evaporation, and the r e s i d e was taken
up ir> dichloromethane.
The usual w o r k u p afforded 12.2 m g
(100%) pf a
yel l o w liquid w h i c h w a s identical in all respects to the material
obtained by method A in all respects.
8 - m e t h v l - 4-acetoxvtricyclo- [3-.3.3.Q] -undec-3rgn-2~.
ong.15JU. S D d
fi-methvl isomer
MMR
(isomeric mixture):
6.18 & 6.13 [1H, s, vinyl protons) ? 2.29 &
2.28 [3H, s, acetate methyls) ? 2.15-1.20 [11H, m, aliphatic methane
and methylenes);
1.04 & 1.01 E3H, d, J=2.4 Hz,
isomeric methyls).
MS: (second peak) Mt=234, 192 (base), 164, 151, 138, H O , 69, 43.
(first peak) Mt=234, 192 (base), 164, 150, 137, H O , 69, 4j.
-95-
I£:
2915,
2833, 1783, 1692, 1590, 1453, 1376, 1340, 1188,
1168, 1124,
IOlOf 868, 840 c m -1.
Analysis
^!4.1244.
(HRMS): calcd for C 14H18O 2 S
(second peak)
Found;
234.1232,
(first peak) Found;
234.1244.
P r e p a r a t i o n nf A-m ^^-hnw-ft-niethvltric v c l o - [3P3,3.J )1-qndoc-3-en-2-.on£
(54)
A solution containing 20 m L of absolute methanol and 2 drops of
cqnceptrated HCl w a s stirred under nitrogen while 570 m g
the 1 ,3-dione w a s added in a m i n i m u m amount of methanol.
(3.0 mmol) of
This solu­
tion w a s stirred under reflux for 36 hours and then the solvents were
removed and a sample w a s taken for G C M S analysis.
The crude residue
.weighing 600 m g w a s subjected to flash chromatography (8?2
hexane ;ethyI acetate) wh i c h produced t w o fractions weighing 370 m g and
223 mg, both as golden colored liquids.
Subsequent analysis showed
the first compound w a s the desired methoxy-vinyl ether and the second
compound w a s unreacted 1,3-dione.
The yield of G A ) based on
recovered starting material w a s 100%.
The material obtained by this
method w a s homogeneous by TLC, GLG (on both packed and capillary
columns), and appeared isomerically pure by proton and carbon N M R as
well as by MS.
4-TnPt-Wv-a-methvltr.i cyclo- [3.3.3,01 -imdec-3-en"2rfiD£
1H N M R ;
5.14
(m)] • 3,.70-l*20
tlH, (s)l? 3.81 t3H, (s)l; 2.02 U H ,
tlOH,
(m)]; 1.02 B H ,
SMh
(m)l; 1.81[4H,
(d), J=6.7 H z L
-96-
13c N M R :
207.1 (s); 191.8 (s)? 104.1 (d), 69.9 (s); 64.4 (s); 58.3
(g);
(d);
42.6
14.9 (q)« (No
35.0 (t); 34.9 (t); 34.7 (t)? 33.0 (t); 26.9
(t);
evidence of an isomer w a s apparent.}
IR:
2800, 2720, 1680, 1585, 1450, 1357, 1233, 1145, 1010, 826 c m " 1.
MS:
M+=206, 191, 178, 163, 152, 137, 1 2 4 (base), 115, 105, 91.
Analysis
(HRMS):
Calcd for C 13HlgO 2.:
206.1307.
Found:
206.1320.
Preparation of 4.6-dimethvltrjlcyclo- [3.3n3.Q) =undoe-3-en-2r.one 1 5 6 1
A 50 m L t w o necked roundbottom flask w a s flame dried, flushed
w i t h nitrogen and fitted w i t h a septum.
Then 20 m l of dry toluene and
37Q m g of (54) were injected, followed by 5 equivalents of methyl
lithium.
The reaction w a s then refluxed under nitrogen for 24 hpy^s,
following w h i c h time the reaction w as quenched by cautious addition of
absolute methanol.
and brine.
The reaction w a s then rinsed w i t h 5% HC1, water,
Drying over m a g nesium sulfate and evaporation of solvents
gave 30$ m g of a yell o w oil.
Flash chromatography [7:3 hexanesettyl
acetate] afforded t w o fractions:
A— 45 m g and B
261 mg.
Fraction A
w a s identified as the isomeric dienes 6- and 8-methyl-2-methoxy-4methylenyltricyclo- [3.33.0] -undec-2-ene.
GLC analysis of flash
fraction B revealed 3 peaks, 21% consisting of 2,8-dimethyl-4-metbylenyltricyclo- [3.3.3.01 -undec-2-ene and the tricyclic ketone
(M)»
The
remaining 79% of flash fraction B w a s identified as 4,6-dimetbyltri,cyclo-[3.3.3.0]-undec-3-en-2-one
CS).
-97-
A.(\—c\impfchv-ihricvclo-[3.3.3.03-undec-3-en-^rQng
MS:
ISfiJ-*
Mt = 1 9 0 r 175/ 162/ 148 (base)/ 134/ 120/ 105/ 91/ 77.
1H N M R : 5.81 Q H ,
(d), J =
1.20 (!IjIH/ (m)] ? 0.97 [3H,
Analysis:
2.6 Hz]? 2.08 [3H,
(d), J = 2.6 Hz]? 2.00-
(d), J = 6.9 Hz).
Calcd. for C 13H 18O:
190.1355? Founds
190.1356.
Synthesis of 1.3.3.5,5 - t e t r a m e t M l c v cloh.e%me I M l
A 50 ml two-necked roundbottom flask was flame dried and placed
under argon, then 20 mis of freshly distilled methylene chloride was
injected and cooled to 0°C with an external ice bath.
Dimethyl-
titanium dichloride was generated by adding 2 equivalents of dimethyl
zinc to I equivalent (0.11 ml, 0.18 gram) in one portion.
The
presence of the dimethyl titanium compound was confirmed by
observing the new methyl resonance at -1.90 ppm,
resonance occurs at -0.41 ppm).
1H nmr by
(the dimethyl zinc
After stirring 15-30 minutes at O0C,
0.14 g ram (0.10 mole) of isophorone was injected neat.
The reaction
was then wrapped in aluminum foil to shield it from light and left to
stir overnight.
Workup:
The reaction was quenched by pouring the flask,contents
into a beaker, and then cautiously adding methanol, water, or dry ice
in small portions.
When the vigorous evolution of gases has ceased
the reaction is diluted with saturated ammonium carbonate and
extracted twice with methylene chloride.
Following drying and removal
of solvents, the yellow liquid was purified by chromatography on
-98-
silica gel eluting w i t h petroleum ether.
85 m g
(65%) of the product.
The first fraction afforded
Rinsing the column wi t h 10% ethyl acetate
in petroleum ether produced 50 m g of isophorone.
Ihe yield of product
based on recovered starting material was 99%.
1.3.3.5,.5-tetramethvlcvclohexene 1581:
IR;
2900,1450,1380
1H N M R :
5.25 IlH, (m) ] 1 . 6 4
(s)]; 0.93
MS:
(doublet), 1360, 845 cm™1 .
I6H,
BH,
(s)]; 1.27 I4H,
(s)l; 0.96 (6 H,
(s)].
Mt=I52, 137
(base), 121, 96, 95, 91, 98, 6 6 , 57, 41.
Analysis: Calcd for
C jj JE^Os
152.0554.
Found:
152.1554.
Synthesis of 2.4.4.8-tetramethvltricyclo- [3.3.3.iUzundsc=2z^m
(Modheohene)
(131
B y the procedure outlined above for isophorone, 239 m g of the
ketone (M) w a s injected into a methylene chloride solution of
dimethyl titanium dichloride at 0®C under argon*
After stirring
overnight and workup, 20 m g of a hydrocarbon product w a s obtained by
chromatography.
200 m g of unreacted starting material w a s also
recovered.
The hydrocarbon was further purified by GLC to provide an
analytical sample of modhephene which exhibited a mass spectrum and
elemental analysis identical to the natural product.
-99-
Modhephene (13):
MS:
M + = 2 0 4 (19%), 189 (100%), 16 1 (20%), 149 (38%), 147 (28%), 133
(10%), 119 (27%).
IR:
(crude product)
Analysis:
Calcd for
3000, 1460, 1380 cm
204.1122.
Found:
204.1822.
-100-
LITERATURE AND NOTES
-101-
1.
a) For a recent review see: Symposia-in-Print, Number 3, edited
b y L. A. Paquette, T e t r a h e d r o n , (1981), 37, #25.
b)
2.
L, A, Paquette, Topics j n Current Chemistry.
165.
(1979), 29, 41-
a) L. A. Paquette, G. P. A n n i s a n d H. Schostarez, J. Am. Chem.
Soc.. (1982), 1 0 4 . 6646-53.
b) S. Danishefsky, M. Hirama, K. Gombatz, T. Harayama, E. Berman,
P. F. Schuda, J. Am. Chem. Soc.. (1978), 1 0 0 . 6536; (1979), .
1Q1, 7020.
c) W. H. Parsons, R. H. S c hles s i n g e r , M. L. Quesda, ibid.. (1980),
1 0 2 . 889.
3.
a) S. D. Burke, C. W. M u r t i s h a w , J. O. Saun d e r s a n d M. S. Dike,
J. Am. Chem. Soc.. (1982), 1 0 4 . 872.
b) S. D a n i s h e f s k y , K. Vaughan, R. C. Gadwood, K. J. Tsuzuki, J,
Am. Chem. Soc.. (1980), 10%, 4262-4263: ibid.. (1981). 103,
4136-4141.
c) W. K. B o r nack, S. S. B h a g w a t , J. Ponton, P. J. Helquist, J.
Am. Chem. Soc.. (1981). 1 0 2 . 4646-4648.
4.
a) C. E x o n and P. M a g n u s , J. Am. Chem. Soc.. (1983), 1 0 5 , 2477.
b) T. Ito, N. T o m i y o s h i , K. N a k a m u r a , S. Azuma, M. Izawa, F.
Mayuyama, M. Yanagiya, H» Shirahama and T. Matsumoto,
Tetrahedron Lett.. (1982), 1721.
c) P. G. Schuda, H.-L. A m m o n , M. R. H e i m a n n and S. B h a t t a c h a r jee,
J. Ore. Chem.. (1982), il, 3434.
5.
a) E. W e n k e r t a n d T. S. A r rhenius, J. Am. Chem. Soc.. (1983),
1 0 5 . 2030.
b) L. H. Z a l k o w , R. N. Harris, D. v a n Derveer, J. A. Bertrand, J.
Chem. Soc.. Chem. Commun.. (1977), 456.
c) W. O p p o l z e r , K. Battig, T. Hudlicky, Helv. Chim. Acta..
(1979), £2, 1493; T e t r a h e d r o n . (1981), 32, 4359.
-102-
d) W, G. D a u b e n f D. M. W a l ker, J» Org. Chem., 1981,
1103.
e) P. A. W e n d e r, G. B. Dreyer, T e t r a h e d r o n . (1981), 37, 4445.
6.
See appropriate references in Professor Paquette’s recent review
articles listed as reference (I).
7.
R D. Otzenberger, Pinacol-Tetrahydrophthalans-Frontalin,
Thesis, Montana State University, (1971), p, 49.
8.
a) L. A. P a q u e t t e a n d P. C. S t orm, J. Am. Chem. Soc., (1970), 22.,
4295.
Ph.D.
b) R. F. G r a t z a n d P. Wilder, Jr., Chem. Commun.. (1970), 1449.
c) P. G a s s m a n , J. G. S c h a f f h a u s e n , a n d P. W. R a y n o l d s , J 2.M k .
Chem. Soc.. (1982), 104, 6408.
9.
P. W i l d e r , Jr., a n d C. V. A. Drinnan, J. Org. Chem..
414.
10.
R
11.
B. Testa, Principles of Organic Stereochemistry.
Inc., N e w York, N.Y., (1977), p. 115.
12.
a)
(1974), 12,
D. O t z e n b e r g e r , jap*, cit., p. 69.
L. H.
Z a l k o w , R N. Harris, III, D.
Soc.. Chem. C o m mun.. (1978), 420.
J. v an
Marcel Dekker,
Derv e e r ,
J2.Chem.
b) J. W r o b e l , K. T a k ahashi, V. Honkan, G. Lannoye, J. M. Cook a nd
S. H. B e n t z , J. Ora. Chem.. (1983), 48, 139.
c ) A. B. Smith, Pv J. Jerris, Org. Chem., (1982), 42, 1845; A. B.
Smith, P. J. Jerris, "Abstracts of Papers’1, 179th National
Meeting of the American Chemical Society, Houston, TX, March
24-28, 1980; American Chemical Society: Washington, DC, 1980,
O R G N 63.
d) M. K a r p f , A. S. Dr e i d i n g, T e t r a h e d r o n Lett.. (1980), 21, 4569.
e) H. S c h o s t o r e z , L. A. Paquette, J. Am. Chem. Soc.. (1981), .101.,
722.
f) W. O p p o l z e r , F. M a r a z z a, Helv. Chim. Acta,, (1981), M f
1575.
-103-
g) W. O p p o l z e r f K. B a t t i g f H e l v. Chiiru Acta.. (1981),
2489;
h) P. A, W e n d e r f G. B. D r e y e r f J. Am. Chem. Soc.. (1982), 104,
5805.
13.
L. H. Z a l k o w f R. N. Harris, III, D. J. v an D e r v e e r f J. Chem.
Soc.. Chem. C o m mun.. (1978), 420.
14.
See reference 12.
15.
R. D. O t z e n b e r g e r f op. cit.. p. 6 8 .
16.
S. B. Glancyf Ethereal Oxygen Influences on Solvomercuration and
Hydrtwenation Reactions. Ph»D. Thesis, Montana State University,
(1983), p. 48.
17.
a) R. N. M c D o n a l d a n d R. R. Reitz, J. Org. C h e m . , (1972), 24182422.
b) D. N. Harpp, L. Q. B a o , C. J. Black, J. G. Gleason, a n d R. A.
Smith, J. Org. C h e m . , 2 3 » (1975), 3420.
c) J. G. G l e a s o n a n d D. N. Harpp, T e t r a h e d r o n Lett.. (1970),
3431-3434.
18.
Although McDonald and Reitz (reference 17a) reported a 60% yield
of cyclopentene-1 ,2-dicaraboxylate when , '-dibromodimethyl
pimelate w a s exposed to base, attempted reproduction of their
method provided none of the reported product.
19.
a) $. C. Kl o e t z e l , Org. R e a c t i o n s . (1948), 4, I.
b) p. L. H o l m e s , Org. R e a c t i o n s , (1948), A, 60.
c) L. W. B u t z a n d A. W. Rytina, Org. R e a c t i o n s . (1949), jj, 136.
d) J. G. M a r t i n a n d R. K. Hill, Chem. Rev.. (1961), 6 1 . 537.
e) J. Sauer, A n a e w . Chem. Inter. Ed.. (1966), 5, 211.
f ) J. Sauer, Angew. Chem. Inter. E d . . (1967), £., 16.
20.
For references to dianions of vicinal diesters see the following:
a) P. J. Garrett, R. Z abler. T e t r a h e d r o n Lett.. (1979),
JL,
73-76.
b) P. J. G a r r e t t a n d R. Z a h l e r , J. Am. Chem. Soc.. (1978), 100.
7753-4.
-104-
c) K. G. Gilyard, P. J. G a r r e t t t f A. J. U n d e r w o o d a n d R, Z a h l e r f
Tetrahedron Lett,, (1979), 2Qj 1815-18.
d) K. G. B i l y a r d f P. J. G a r r e t t a n d R. Z a h l e r f Sy n t h e s i s . (1980),
5, 389-90.
<?
e)
G. B i l y a r d a n d P. J. Garrett, T e t r a h e d r o n Lett.. (1981),
IS7, 1755-8.
I
21.
See appropriate references in reference la and lb.
22.
a) B. J. B a r reirof Tetrahedron Le t t . . (1982), 3605.
b) A. P. K o z i k o w s k i a n d P. D. Stein, J. Am. Ghent. Soc.. (1982),
1 0 4 . 4023.
c) H. U m e z a w a , T. T a k e u c h i , K. Nitta, T. Y a m a m o t o , S. Y a m a o k a , J.
Antibiot. Ser. A,. (1953), 5., 101.
d) K. T o k i , Bull. Chem. Soc. J p n . . (1957), 3 Q f 450.
e) K. T o k i , ibid.. (1958), 31, 333.
f) J. N. Marx, G. M i n a s k a n i a n , T e t r a h e d r o n Lett.. (1979), 4175.
g) R. K. B o e c k m a n Jr., P. C. Naegely,
Chem.. (1980), 4£, 752. .
S. D. Arthur, J. Ore.
h) Y. K o b a y a s h i , J, T s u j i, T e t r a h e d r o n Lett.. (1981), 2 2 . 4295.
23.
a) A. B. Smith, III, S. J. B ranca, N. N. Pilla a n d M. A.
Guaciaro, J. Org. Chem.. (1982), 42, 1855.
b) A. B. Smith, III, S. J. Branca, J. Am. Chem. Soc..
1 0 0 . 7767.
(1978),
c) K. Umino, T. Furuma, R Matsuzawa, Y. Awetaguchi, Y. Ito and
T. Okuda, J. Antibiot.. (1973), 26. 506.
d) K. Umino, N. T a k e d a , Y. Ito, a n d T. Okuda, Chem. Pharm. Bull..
(1974), 21, 1233.
e) T. Date, K. A o e , K. K o t e r a a nd K. Umino, Chem. Pharm. Bull..
(1974), 21, 1963.
-I OS-
24.
a) A. B. Smith, III a n d D. B osc h e l l i , J. Org.. Chem., (1983), ig.,
1217.
b) A. B. Smith, III a n d D. B o sc h e l l i , T e t r a h e d r o n Lett.,
(1981), 22, 3733.
c) K. A s a h i , J..N a g a t s u , S. Suzuki, J. Antibiot.-, A19, (1966),
195.
d) K. A s a h i a n d S. Suzuki, Agric. BloJL,. Chem., (1970), M ,
25.
a) G. M. S t r u n z a n d G. S. Lai, Can. J. Chem.,
(1982), M ,
325.
2528.
b) D. C. B i l l i n g t o n , P. L. Pauson, O r g a n o m e t a l l i c s , (1982), I,
1560.
c) C. M. Mikolaiczyk,
Le t t . , 1982,
S. Grzejszczak and P. Lyzwa, Tetrahedron
2237.
d) Y. T a k a h a s h i , H. K o z u g i a nd H. Uda, Chem. Commun., (1982),
496.
e) T. S i w a p i y o s a n d Y. T h e b t a r anonth, J. O r g. C h e n w (1982), 47,
598.
26.
For reviews of the Favorski rearrangement see:
a) C. Rappe, in S. Patai, S m Chemistry, of t h e CariafiD Palogeh
B o n d , pt. 2, pp. 108 4 - 1 1 0 1, J o h n W i l e y & Sons, Inq., N e w York,
(1973).
b) D. R e d m o r e a n d C. D. Gutsche, Adv. A l i c y c l l c Chenh# (1971), 2,
1-138.
c) A. A. A k h r e m , T. K. U s t y n y u k a n d Yu. A. Titov, R h & & _ C h e m
Rev.. (1970), 21, 732-746.
d) A. S. K e n d e , Org. Rea c t . , (1960), 21,
261-316.
27.
The following catalysts were tried:
B F 3 OEtzO — all w i t h no success. .
AICI3, NaClg, SnClz'
28.
a) For a review of the Oxymercuration Reaction see:
Chem. Rev.. (1951), 48, 7-43.
J. Chatt,
b) For the H N O 3 catalyst reference see: A. M. Birks and
G. F. W r i g h t , J. Am. Chem. Soc., (1940), 62:2, 2412.
—106—
c)
29.
30.
For the basic procedure employed see: H. C. B r o w n and P.
Geoghegan J r . , J ju Am. Chem. Soc„, (1967), 89, 1524.
K. Furuta, A. M i s u m i , A. Mori, N. Ikeda, H. Y a m a m o t o ,
^Tetrahedron Lett.. (1984). 25. 669.
A. Misumi,
K. Furuta,
H. Yamamoto,
Tetrahedron Lett.,
(1984),
23., 571.
31.
a) A. W. Johnson, Ylide Chemistry.
N e w York.
b) . A. Maercker, Org. Reactions.
c)
s.
(1966), Academic Press,
(1965), M #
T r i p p e t t . 0. Rev. Chem. B-Qga-, (1963),
Inc..,
270-490.
12,
406-440,
d) J. March, Advanced Organic Chemistry. McGraw-Hill Book
C o m p a n y , N e w York, 1977, p. 8 6 4 ref. 369.
32.
A. B. Smith, III a n d P. J. Jer.ris, J. Org. Chem..
1845-1855.
33.
v
A. Butanandt and J. Schmidt-Thome,
2 2 , 182.
34.
a) B. P. Mundy and S. B. Glancy, personal communication.
Ber.,
(1982), 4%,
(1938), 22,
b) B. P. M u n d y a n d J. J. T h eodore, J. Am. Chem. Soc.,
1 0 2 . 2005.
1487;
1939,
(1980),
c) G. S t o r k a n d D. E. K a h n e , J. Am. Chem. Soc., (1983), 105,
2005.
35.
For examples of this conversion see:
a) J. A. P r i c e a n d D. S. Tarbell, Org. Synth. C o X L , ffpJL. I,
(1963), 285.
b) R. E. B o w m a n , J. Chem. Soc., (1950), 322.
36.
a) B. M T r o s t a n d D. E. K e e l e y , J. Am,. Chem, B o c su, (1976), 28.,
250 and references therein.
b) P. A. G r i e c o a n d R. S. F i n k e l h o r , T e t r a h e d r o n Lett^, (1974),
527.
-107-
c) G. S t o r k a n d P. A. G r i e c o f J. Am. Ghent. Soc,, (1969), 21,
2407, and previous papers in this series.
d) J. A. M a r s h a l l a n d G. L. Bundy, T e t r a h e d r o n Lett., (1966),
3359.
37.
When the diketone (47) was exposed to methyl lithium in THF at
room temperature for 8 hours and then quenched, only unreacted
(47) was recovered.
Even in refluxing toluene containing excess
MeLi, very little of the diene resulting, from dialkylation of
(47) was observed.
38.
a) P. E. Eaton, G. R, C a r l s o n a n d J. T. Lee, J. O r g. Chem.,
(1973), 2&j 4071.
b) L. A. Paquette, E. F a r k a s a n d R. G a l e m m o , J. O r gj,,Chem.,
(1981), 46, 5434-5436.
39.
W. C. Still, J. Ora. Chem., (1978), 43, 2933.
40.
a) B. P. Mundy, Concepts of Organic Synthesis,
Inc., N e w York, 1979, p. 163.
Marcel Dekker,
i?) C.
P. Casey, D. F. M a r t i n a n d R. A. Boggs, T e t r a h e d r o n Letf--.,
(1973), 2071.
c) G. R, Posner, Org. Rea c t ions, 19, (1972),
I.
41.
Personal ccnmunication, B. P. Mundy.
42.
a) A. B. Smith, III, P. J. Jerris, J. Org. C h e n w
1845-1855.
(1982), 41,
b) K. M a r v y a m a , Y. Y a m a m o t o , J. Am, Chenw Soc., (1977), 92, 8068.
c) K. M a r v y a m a , Y. Y a m a m o t o , ibid., (1978), 1 M , 3240.
43.
G. Hofle, W. S t e g l i c h a n d H. V o n b r ugqen, Anaew. Chem., I n t e r JEd^
Enal.. (1978), 12, 569.
44.
R. V i l l o t t i , H. J. R i n g o l d a nd C. Djerassi, J. Am. ChenL- Soc..,
(1960), BI, 5693.
45.
M. T, R e e t z , J. W e s t e r m a n n , R. Steinbach, J. Chenu S-O-Q^- CJiejLC o m mun.. (1981), 237.
-108-
46.
P. C. W a i l e s f R. S. P. C o a t e s a n d H. W e i g o l d f O r a a n o m e t a l lie
Chemistry
Titanium. Zirconium, and Halfnium. Academic Press,
N e w York, (1974), p. 11.
47.
D. F. Herman, U.S. patent 2,886,579
48.
a) R Feld, P. L. Cowe, The Organic Chemistry of Tita n i u m .
B p t t e r w o r t h a n d Co., Ltd., W a s h i n g t o n , D.C. (1965), p. I; see
also reference 2.
(1959).
b) R. G. Jones, Xowa St. Coll. J. Sci.. (1942), 12, 8 8 .
49.
C. Beermann,
Germ a n Patent,
1,089,382,
50.
a) M. T. Reetz and J. Westermann,
654.
(1960).
Synth. Commun..
(1981), 647-
b) Jti. T. Reetz, J. Westerman and R Steinbach, Angew. Chem.
Inter. Ed. Engl.. (1980), 1&, 900.
51.
R C. K r u g a n d P. J. C. Tang, J. Am. Chem. Soc.. (1954), 2 £l, P2262.
52.
G. S t o r k a n d F. H. Clarke, Jr., J. Am. Chem. Soc.. (1961), 83.
3114.
-109-
APPENDICES
APPENDIX A —
NMR SPECTRA OF HETEROATOM CONTAINING
250.1 MH2 1H nmr:
8-oxat ricyclo-[4.3.3.0]-undec-3-ene
BROAD-BAND DECOUPLED
H
H
M
*.4,
#4
t-
I
75
62.9 MHz
C nmr:
8-oxatricyclo-[4.3.3.0]-undec-3-ene
25
250.1 MHz
H nmr:
250.1 MHz
H nmr:
anti-3,4
epoxy
oxatricyclo
■unde cane
250.1 MHz
H mnr:
a n t i - 3 - m e t h o x y - 8 - o x a t r i c y c l o - [4.3.3.0]-undecane
250.1 MHz
nmr:
syn-3-methoxy-8-oxatricyclo-[4.3.3.0]-undecane
BROAD-BAND DECOUPLED
»Ul
62.9 MHz
JL
JUk
_|_
-J__ u_
125
25
nmr:
8-oxa-3,4-dimethyltricyclo-[4.3.3.0]-undec-3-ene
OFF RESONANCE DECOUPLED
-L
62.9 MHz
J
__ I_____ L
125
nmr:
I
I
I
■__ I
IJ
j__ L.
25
8-oxa-3,4-dimethyltricyclo-[4.3.3.0]-undec-3-ene
r
i
CO
4
nmr:
I
3
1
2
1 1 r
I
3 ,4-dimethyl-(syn)-3,4-epoxy-8-oxatricyclo-[4.3.3.0 ]-tmdecane
250.1 MHz
H nmr:
3 , 4 - d i m e t h y l - ( a n t i)- 3,4 - e p o x y - 8 - o x a t r i c y c l o - [4.3.3.0]-undecane
H
lx)
I
O
250.1 MHz 1H n m r :
N-methyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
-CH3
BROAD-BAND DECOUPLED
23
62.9 MHz
C nmr:
N-methyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
OFF RESONANCE DECOUPLED
250.1 MHz 1H nmr:
N-methyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
+
/CH3 r
xCH3
7
250. I MHz
nmr:
6
5
4
3
N,N-dimethyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
I"
JL
7
250.1 HHz "*"H nmr:
6
j
......... I
5
4
3
N ,N-dimethyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
BROAD-BAND DECOUPLED
C nmr:
N ,N-dimethyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
I
to
O
62.9 HHz
nmr:
N , N - d i m e t h y l - 8 - a z a t r i c y c l o - [4.3.3.0]-undec-3-ene
1
250.1 MHz
H nmr:
N-methyl-N-deuterometliyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
JU
O
250 MHz
nmr:
N-methyl-N-deuteromethyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
+ /C H 3
250.1 MHz
nmr:
N-methyl-N-deuteromethyl-8-azatricyclo-[4.3.3.0]-undec-3-ene
-130-
APPENDIX B —
LITERATURE SYNTHESES OF MODHEPHENE
Modhephene
Dreiding1s Synthesis
(a) KCNy 64%.
(b) m e thyltriphenylphosphonium bromide, base, 88%.
(c) hydrogen, 10% Pd/C, ethanol, 95%. (d) K O H , 93%.
(e) th i o n y l
chloride, then T M S C CTMS, aluminum chloride, then sodium
tetraborate, methanol, water, 86% mixture of isomers,
(f) vpc
(g) 6 2 0 C, p y r o l y s i s , 95%.
(h) v p c (three isomers),
(i) MeLi,
ether,
(j) Jcmes oxidation, 88%.
(k) methyl Wittig, 71%.
(I)
rhodium trichloride, ethanol, water, 80 C, 81%.
-131-
OCH'
a ,b
c
Modhephene
Oppolzer's Synthesis
(a) l-magnesio-3-butenyl bromide, TOF (no yield),
(b) I H HCl,
O C, 68%.
(c) 3-chloropropanal ethylene glycol acetal, Mg, THF,
CuBr-DMS, 50%.
(d) aqueous formic acid, sodium formate, room
t e m p . , 15 hr, (no yield),
(e) I M N a O H , ether, (no yield),
(f)
M s C l , pyridine, (no yield),
(g) CBN, ether, 45%.
(h) toluene,
250 C, sealed tube, 73%.
(i) hydrogen, 5% Eti/C, ethanol {no
yield),
(j) IDA, THF, -78 C, then phenyl selenium bromide, THF,
-78 C, (no yield),
(k) 15% aq. hydrogen peroxide, pyridine,
methylene chloride, 43%.
-132-
a.b
a . R = S i(C H 3)1
a.
b. R = H
b. R=CH-
Modhephene
Paquette's Synthesis
R =O
-133-
<ti5 °
e,f
A
W
/
g
Modhephene
Wender1s Synthesis
(a) hv, V y c o r , c y c l o h e x a n e , 35 hr, 21%.
(b) K O H , M e O H , 8 6 %.
(c) Bar i u m permanganate 95%.
(d) hydrogen U atm}, 5% Pd/C,
100%.
(e) KOH, hydrazine, ethylene glycol, heat, 54%.
(f)
Potassium t-butoxide {15 equiv.}, MeI U O equiv.}, THF, 5
min, room temp, 68%.
(g) Dimethyl homocuprate, THF, -78 C,
C l g P O (NMe2), dimethyl amine, 76%; then Li, ethylamine, THF,
0 C, 93%; and then hydrogen. Platinum oxide, 100%.
MONTANA STATE UNIVERSITY LIBRARIES
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Wiikening, d . w .
c o p .2
A n e w regiocontrolled and
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