Efforts Toward the Syntheses of Natural Products:
Part A: Paeoniflorin
Part B: (+)-Taxusin
A thesis presented by
Rebecca J. Carazza
B.S. Chemistry
University of Massachusetts, Amherst, 1993
Submitted to the Department of Chemistry in partial
fulfillment of the requirements for the degree of
Doctor of Philosophy in Chemistry
at the
Massachusetts Institute of Technology
June 1998
© 1998 Massachusetts Institute of Technology. All rights reserved.
Sinature
of
Author:
Signature of Author:
T-
-~-
-
- ..
-u
-
--
I-
-
-
-
-
-
D4pdrtment o('ihemistry
May 26, 1998
Certified by:
,Scott C. Virgil
Thesis Advisor
Acceuted bv:
Dietmar Seyferth
Chairman, Departmental Committee on Graduate Students
O-V
.Z\ .
JUN 1 51998
UR PAES
Science
This doctoral thesis has been examined by a committee of the
Department of Chemistry as follows:
Professor Rick L. Danheiser
Chairman
Professor Scott C. Virgil
/
Professor Peter H. Seeberger
Th/sis Supervisor
Efforts Toward the Syntheses of Natural Products:
Part A: Paeoniflorin
Part B: (+)-Taxusin
by
Rebecca J. Carazza
Submitted to the Department of Chemistry on May 26, 1998
in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy in Chemistry
Massachusetts Institute of Technology
ABSTRACT
Part A
Efforts toward the synthesis of the monoterpene glycoside
paeoniflorin (1) are discussed. Optimization of the previous synthetic route
was successful. Synthesis of the key cc-diazo intermediate 30 was achieved
and the construction of the carbocyclic frame was completed. Key reactions of
the strategy involve a ring contraction via a Wolff rearrangement, and
formation of the lactone 78 which undergoes diisobutylaluminum hydride
reduction followed by acid catalyzed cyclization to the paeoniflorin ring
system 80.
A new synthetic strategy was initiated to prepare the key
[3.2.1]bicyclooctanone 81 using a palladium mediated olefin cyclization of the
acyloin substrate 82.
CH 3
1, Paeoniflorin
OH
O
BnO
O
TBSO
TCH
O
TMSO
3
CH 3
TMSO
0O
OH
78
Efforts toward the synthesis of the diterpenoid natural product
Part B
(+)-taxusin (110) are discussed. An alternative route to the key intermediate
photoprecursor 130 was achieved employing a cerium trichloride mediated
addition of an aryl lithium 132 to an aldehyde 141.
A mechanism for the
exclusive formation of a cis 150 or trans 149 B-C ring system was proposed.
Attempts were made to cyclize the A-ring of both cis and trans ring fused
intermediates.
AcO
0l
OAc
Ac
OCH 3
OAc
Taxusin, 110
130
OCH 3
OCH3
0O
150
Thesis Supervisor: Scott C. Virgil
Title: Assistant Professor of Chemistry
149
132
Acknowledgments
I would like to take this opportunity to thank all of the people that
have been a major part of my life during my stay at MIT. First and foremost, I
am grateful to my mentor, my friend Professor Scott Virgil. The enthusiasm
he has for chemistry is matched by none.
Scott has been an inspirational
advisor who constantly offers positive encouragement.
I would like to thank all of the members of the Virgil lab both past and
present for their guidance and friendship.
Many thanks to Dr. Paige
Mahaney, Dr. Richard Allen (mind bomb. mind bomb, mind bomb!), Dr.
Edcon Chang, and Dr. Jeffrey Eckert all of whom taught me the important
aspects of total synthesis.
Justin Miller has taught me all the tricks to
ChemDraw, which helped tremendously in writing this thesis.
Teaching
with Justin has been fruitful and fun. MIT undergraduates that have worked
on my projects, or who just can't be left out are Federico Bernal, Junko
Tamiya, Sarah Folscraft, Juliet Midgley and Joseph Lee.
Not only did the
group offer support and guidance, they provided a friendly atmosphere to
work in.
Thanks to Chris Garrett for making my first two years here enjoyable. I
would like to thank Matt Martin for his friendship and for editing my thesis.
Evan Powers, may your team always win!
I would like to acknowledge the financial support that I received from
the Chemistry Department.
I am grateful for having such a supportive and encouraging family.
They believed in me and helped me maintain my sanity when things got
rough. Thanks Mom, Dad, Mike and Chandler. I would like to dedicate this
thesis to all of you.
Table of Contents
Part A: Paeoniflorin
Chapter I. Introduction
1.1 B ioactiv ity ...................................................................................................... 7
1.2 Degradation Products of Paeoniflorin ................................................. 9
1.3 Synthetic Strategy........................................... ....................................... 11
Chapter II. Formation of the Carbocyclic Framework
2.1 Retrosynthetic Analysis.........................................................................
2.2 a-Diazoketone Synthesis...........................................................................17
16
Chapter III. Attempts to Form the Paeoniflorin Fing System
3.1 Aldehyde Formation Promoted Side Reactions..................................26
3.2 Successful Construction of the Paeoniflorin Ring System ............... 33
Chapter IV. Revised Strategy
4.1 Novel Approach to Carbocyclic System..............................................38
4.2 Oxygenation of the C-3 Position.......................................42
4.3 Future Prospects with the Barton Reaction..............................45
Part B: (+)-Taxusin
Chapter V. Introduction
5.1 Biological Activity..................................................47
5.2 Stru ctu re .................................................... ............................................. 53
5.3 Synthetic Strategy...................................................55
Chapter VI. Synthetic Modifications
.................
6.1 Retrosynthetic Analysis............................
Route......................
Synthetic
Original
6.2 Modifications to the
60
61
Chapter VII. B-Ring Formation
7.1 Previous Work .......................................................... 68
7.2 New Proposed Mechanism..........................................70
7.3 Oxidative Cleavage Attempts...........................................................72
Chapter VIII. A-Ring Cyclization Attempts
74
8.1 Swindell's A-Ring Cyclization......................................................
8.2 A-Ring Cyclization Attempts with the trans-Fused
............ .............. 75
Ring System ......................................................
8.3 A-Ring Cyclization Attempts with the cis-Fused
R ing System ................................................ ........................................... 79
Experimental Section and Selected Spectra..........................
...........
83
Chapter I:
Introduction
1.1 Bioactivity
Paeoniae Radix i (Shaoyao) is an important herbal drug widely used in
traditional Chinese medicine.
It consists of a crude mixture of substances
derived from the roots of several species of Paeoneaceae; major harvests are
from Paeonia lactiflora and Paeonia Suffruticosa.2 Shaoyao has been used for
centuries as an analgesic, antispasmodic, astringent and sedative. The
interesting bioactivity displayed by this drug sparked interest in identifying
the components responsible for the therapeutic behavior. Efforts began in the
1960's and several highly oxygenated
characterized.
terpenoids were isolated and
3
HOCH 2
PhCO 2
/O
HO~
OH
CH 3
-OH
1, Paeoniflorin
Paeoniflorin (1) was the most abundant of the components and it was
determined to be a highly oxygenated, complex, cage-like monoterpene
Nojirna, H.; Takashi, K.; Hayashi, T.; Shimizu, M.; Morita, N. Jpn. J.
l(a) Kimura, M.; Kimwla. I.,
Pharmacol. 1984, 35, 61. (b)Hikino, H.; In Economic and Medicinal Plant Research; Wagner, H.,
55 85
Hikino, H., Farnsworth, N. R, Eds.; Academic Press, Inc.: London, 1985, pp. - .
2
yu, J.; Elix, J.A.; Iskander, M. N. Phvtochemistrv 1990, 29, 3859.
3
(a) Hattori, M.; Shu, Y. Z.; Shimizu, M.; Hayashi, T.; Morita, N.; Kobayashi, K.; Xu, G. J.; Nanba, T.
Chem. Pharm. Bull. 1985, 33, 3838. (b) Akao, T.; Shu, Y. Z.; Matsuda, Y.; Hattori, M.; Namba,
T.; Kobayashi, K. Clihemn. Pharm. Bull. 1988, 36, 3043. (c) Shibata, S.; Nakahara, M. Chem.
Pharm. Bull. 1963, 11, 372.
ChapterI: Introduction * 8
gylcoside. 4 Other components included lactiflorin (2)2, albiflorin (3)4c and
aglycones paeonisuffrone (4)5 and paeonilactones A (5) and C (6), (Scheme 1).6
Scheme 1: Minor components of the herbal drug Paeoniae Radix.
0
0
HOCH 2
0
0
HOCH 2
H
0N
HOHO
PhCO
O
0
2
OH
OH
BzO
CH
H
3, Albiflorin
2, Lactiflonn
HO
HO
HH
CH3
HO
O
R
5, Paeonilactone A: R=Me
6, Paeonilactone C: R=CH 20Bz
4, Paeonisuffrone
Many
research
groups
conducted
paeoniflorin's therapeutic potential.
experiments
to
evaluate
Paeoniflorin has provided positive
results in a wide range of studies. Recently paeoniflorin has been reported to
exhibit anti-inflammatory, anticoagulant and sedative activities.la
Paeony
root extracts have been found to exhibit protective effects against neuron
damage in the hippocampus when induced by metallic cobalt (an epilepsy
4
(a) Shibata, S.; Aimi, N.; Watanabe, M. Tetrahedron Lett. 1964, 20, 1991. (b) Aimi, N.; Inaba, M.;
Watanabe, M.; Shibata, S. Tetrahedron Lett. 1969, 25, 1825. (c) Kaneda, M.; litaka, Y.; Shibata, S.
Tetrahedron 1972, 28, 4309.
5
(a) Hatakeyama, S.; Kawamura, M.; Mukagi, Y.; Irie, H. Tetrahedron Lett. 1995, 36, 267. (b)
Yoshikawa, M.: Harada, E.; Kawaguchi, A.; Yamahara, J.; Murakami, N.; Kitagaqa, I. Chem. Pharm.
Bull. 1993, 41, 630.
6
(a) Hayashi, T.; Shinbo, T.; Simizu, M.; Arisawa. M.; Morita. N.; Kimura, M.; Matsuda, S.; Kikuchi,
T. Tetrahedron Lett. 1985, 31, 3699. (b) Yoshikawa, M.; Harada, E.; Kawaguchi, A.; Yamahara, M.;
Murakami, N.; Kitagawa, I. Chem. Pharm. Bull. 1993, 41, 630. (c) Hatakeyama, S.; Kawamura, M.;
Shimanuke, E.; Takano, S. Tetrahedron Lett. 1992, 33, 333. (d) Kadota, S.; Takeshita, M.; Makino, K.;
Kikuchi, T. Chem. Pharm. Bull. 1989, 37, 843. (e) Richardson, D. P.; Smith, T. E.; Lin, W. W.; Kiser,
C. N.; Mahon, B. R. Tetrahedron Lett. 1990, 31, 5973.
ChapterI: Introduction * 9
model).7
Another Chinese medicine, Shimotsu-to, contains a mixture of
herbs from various plant roots, one of which is the paeony root.
This
medicine has been reported to improve spatial working memory in rats, and
paeoniflorin was listed as a candidate for a cognitive enhancer. 8 TokiShakuyaku-San, an herbal medicine prepared from Paeoniae Radix, was
found to exhibit therapeutic potential in Alzheimer's disease by diminishing
cognitive disruption caused by cholinergic dysfunction. 9
A study on the absorption and excretion of paeoniflorin found that
paeoniflorin has low bioavailability.
The amount absorbed is mainly
excreted. 10 This suggests that the metabolites may be responsible for the
pharmacological action of the paeony root. This result was intriguing because
one of the degradation products of paeoniflorin resembles ibuprofen.
1.2 Degradation Products of Paeoniflorin
Often times, natural products are so complex that in order to determine
their structure, they are broken down into smaller, more easily defined
subunits.
During these initial reactions to determine the structure of
paeoniflorin, an interesting rearrangement was observed. When aglycone 7
was treated with acid, an aromatic acid (aglycone F) was isolated (Scheme 2).
Notice the resemblance of 8 to the anti-inflammatory drug ibuprofen.
It is
possible that this compound, or one similar, is a paeoniflorin metabolite and
1l
exhibits the anti-inflammatory behavior reported by Takagi and Harada.
7
8
Tsuda, T.; Sugaya, A.; Ohguchi, H.; Kishida, N.; Sugaya, E. Expt. Neurology 1997, 146, 518.
Watanabe, H. Behav. Brain Res. 1997, 83, 135.
9
Fujiwara, M. Jpn. J. Neuropsychopharmacology 1990, 12, 217.
10 Takeda, S.; Isono, T.; Wakui, Y.; Matsuzaki, Y.; Sasaki, H.; Amagaya, S.; Maruno, M. J. Pharm.
Pharmacology 1995, 47, 1036.
11Takagi, K.; Harada, M. Yakugaku Zavshi, 1969, 89, 887.
ChapterI: Introduction * 10
Scheme 2: Acid catalyzed rearrangement product resembles ibuprofen.
CH 3
CH 3
H3 C
HO
BzO
H®
OH
OH
OCH 3
H3C
OH
H 3C
8, Aglycone F
Ibuprofen
A series of reactions was performed that could give insight into the
mechanism by which the aromatic aglycone was formed (Scheme 3).
First,
paeoniflorin pentaacetate was oxidized with chromium trioxide to afford
lactone 10. Treating this keto lactone with hydroxide ion afforded the keto
acid 11. Exposure of keto acid 11 to aqueous acid afforded aglycone F.
Scheme 3: Stepwise procedure to obtain the aglycone F 8.
RO
0
0
SCH 3
OAc
9
BzO'
BzO
0
BzO
Cr0
3
OH"
RC
OH
CH 3
H+
CH 3
O
10
The proposed mechanism of the rearrangement is depicted in Scheme
4. The first step involves the hydrolysis of the glucose substituent and the
oxygen bridges to afford aldehyde 12. Following hydrolysis, the cyclobutane is
cleaved (most likely not concerted) to afford intermediate 13 which readily
tautomerizes and oxidizes to the aromatic product 15. There were several
ChapterI: Introduction * 11
other experiments on similar molecules to test the consistency of this
mechanism, and each one led to the same result.
Scheme 4: Proposed mechanism for the rearrangement.
Hydrolysis
CH 3
Fragmentation
CH 3
H3
OAc
130
CH 3
CH3
HO
HO
Tautomerize
Oxidize
H
OH
OH
Because of the high degree of oxygenation, treating paeoniflorin or its
derivatives with acid can lead to interesting rearrangement products, most of
which are initiated through the cleavage of the cyclobutane ring.
1.3 Synthetic Strategy
The first total synthesis of paeoniflorin was achieved by Corey in
1993.12
Shortly thereafter, Hatakeyama and coworkers published their
synthesis, which produced paeoniflorin in its natural form. 1 3 Each of these
groups used radical reactions to generate the paeoniflorin skeleton, but in
different fashions.
There is a great deal of similarity between an intermediate in Corey's
sequence 16 and the natural product paeonilactone A (5).
12
13
Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871.
Hatakeyama, S.; Kawamura, M.; Tekano, S. J. Am. Chem. Soc. 1994, 116, 4081.
This molecule
ChapterI: Introduction * 12
contains the cyclohexane portion of the natural product as well as one of the
ether linkages. This synthetic route first focuses on bridging the second ether
linkage then forming the strained cyclobutane ring via a novel samarium
iodide radical reaction.
Scheme 5: Corey's intermediate resembles paeonilactone A.
OTIPS
H3 O
H
HO
H
0
H
0O
H CN
R
5, Paeonilactone A: R=Me
6, Paeonilactone C: R=CH 2OBz
16 Corey's
intermediate
Corey and co-workers began their synthesis by employing a manganese
(III) promoted annulation between the silyl ether double bond and
cyanoacetic acid. 14 Intermediate 16 contained the 10 carbons that are present
in the final terpenoid product.
Scheme 6: Corey's approach to obtain the caged frame.
CH3
CH 3
CH 3
MnO 3(OAc) 7
OTIPS
3 steps
H...
NCCH2CO 2H
48%
.-. OTIPS
-- OTIPS
44%
NC
OH
18
NC
TMSOTf
35%
0
1. PCC
2. Sml 2 , TH F
.
CH 3
93%
HO
O
-
CH 3
OTIPS
OTIPS
20
14(a) Corey, E. J.; Gross, A. W. Tetrahedron 1985, 26, 4291. (b) Corey, E. J.; Ghosh, A. Chem. Lett.
1987, 223.
ChapterI: Introduction * 13
Generating epoxide 18, followed by a Lewis acid mediated epoxide opening
and intramolecular cyclization afforded 19 with the complete oxacyclic
framework intact.
After oxidation with PCC, samarium iodide radical
mediated ring closure provided the complete cage-like frame. In five steps,
they were prepared for the gylcosylation reaction.
Intermediate 21 in Hatakeyama's synthesis resembles a natural product
This synthetic approach
isolated from Paeoniae Radix, paeonisuffrone (4).
was designed to provide the carbocyclic cage-like structure before cyclizing the
ether bridges.
Scheme 7: Hatakeyama's intermediate is similar to paeonisuffrone (4).
HO
CH3CO2
0
0
H3 C
OH
3
O
0
21
Hatakeyama
0
4, Paeonisuffrone
and co-workers began their synthesis by employing a
photochemical [2+2] enone-olefin cyclization of 22 (which was prepared in
four steps). This reaction provided cyclobutyl ketone 21, which contained the
complete carbocyclic frame. Functional group interconversion afforded 23,
which upon generaton of the hypoiodite, underwent a radical reaction which
led to the formation of 24. After five additional steps, they were prepared for
the gylcosylation reaction.
ChapterI: Introduction * 14
Scheme 8: Hatakeyama's approach.
0
[2+2], hv
CO 2CH
3
C
64%
,H 3
2 steps
H3
kCH3
74%
NC
O
21
OH
23
Phl(OAc) 2
12, hv
92%
Both groups had essentially the same structure (25 and 26) for the
glycosylation reaction, but employed different coupling reactions (Scheme 9).
Corey and co-workers chose to couple a 1-dimethylphosphite derivative of
the tetrabenzyl ether of 1-glucose (27) with 25 in the presence of zinc (II)
After deprotection, paeoniflorin was
chloride and silver perchlorate.
obtained in 18% yield (3 steps).
Scheme 9: Glycosylation reactions by Corey and Hatakeyama.
BnO
BnO
B nO
BzO
0
\
OP(OCH 3 )2
. _ - \ -OBn
27
0
Orey
Deprotection
BnO
OR
25 R=TIPS, Corey
26 R=CO 2Bn, Hatakeyama
BnO
BnO
1
0
BnO 0
28
\a 01Aa
OO
CC3
ChapterI: Introduction * 15
Hatakeyama and co-workers employed the use of an imidate derivative
of the tetrabenzyl ether of 1-glucose (28) for the glycosylation.
They
successfully achieved the exclusive formation of the 1-glycoside.
After
deprotection (-)-paeoniflorin was obtained in 67% yield (2 steps).
Chapter II:
Formation of the Carbocyclic
Framework
2.1 Retrosynthetic Analysis
The two ether bridges of paeoniflorin make it sensitive to acid as
described in the previous section. Because of this, it was decided that these
ether linkages would be installed at the end of the synthesis. Thus our initial
focus was on the carbocyclic framework.
Scheme 10: Retrosynthetic analysis of paeoniflorin.
HOCH 2
HO
HO
PhC(
Glycosylation/
Ring Closure
CH 3
Ring
Contraction
OH
TBSO
CH3
CH 3
/
/-0 O
Ring
Expansion
OCH 3
TBSO-
CH3
OTBS
OTBS
Diels-Alder
33
O
OCH 3
30 X=N 2
31 X=H 2
Starting with paeoniflorin, removal of the glycoside and interconversion of
the benzoyl functional group and opening of the oxacyclic rings affords
aldehyde 29. The oxidation state of the aldehyde is consistent with the closed
system, and the structure appears to be a reasonable candidate to produce the
desired cyclized product. The cyclobutyl aldehyde is a Wolff rearrangement
retron, and cyclobutyl carbonyl 29 can be synthesized from a ring contraction
of oc-diazocyclopentanone 30. Bicyclic ketone 31 should be available from
-
ChapterIH: a-Diazoketone Synthesis * 17
cyclohexene 32 via a ring expansion and functional group interconversion.
Cyclohexene 32 is a Diels-Alder retron available from methyl acrylate and the
novel bis-silyloxy diene 33.
2.2 a-Diazoketone Synthesis
Dr. Richard Allen
15
began this project and was successful in completing
the synthesis up to, but not including, oa-diazoketone 30. Modifications of the
original synthetic route were made and those changes will be discussed. The
reactions leading to the ring expansion are depicted below (Scheme 11).
Scheme 11: Synthesis of the ring expansion precursor.
0
O
i. 10 equiv. Et3N, THF-Hexane
1.0 equiv. TBSCI, 0 o' 23 0C
CH3
TBSO
CH 3
ii. 1.0 equiv. TBSOTf,
O
-78
0C
34
OTBS
--- 0 oC
87%
OCH 3
Toluene, rt
88%
O
CH 2 0H
OCH 3
LiAIH 4, THF
TBSO
\
OTBS
-78
oC
--4 0 0C
TBSO
\
CH3
OTBS
1. 03, -78 oC
CH 2 CI2 . MeOH;
then Me 2S
2. Mel, K2 CO 3,
DMF
90 %
36, 37
(based on recovered
starting material)
endo:exo [3 : 1]
32, 35
O
HOH,
II
OH
TBSO
CO 2 Me
- CH 3
OH
CO 2Me
LiCH 2 P(OMe) 2
3 equiv. THF
-78 0C
97 %
"P(OMe) 2
O
II
O
39, 59%
15 Allen, R. D. Studies Towark the Synthesis of Lactiflorin and Paeoniflorin. Ph.D. Thesis, Massachusetts
Institute of Technology, Cambridgy, MA, June 1996.
ChapterII: a-DiazoketoneSynthesis * 18
Formation of bis-silyloxy diene 33 can be achieved in a one pot
sequence using tert-butyldimethylsilyl trifluoromethanesulfonate, but it was
in our best interest to employ a more cost effective approach.
The
incorporation of the first silyl enol ether was achieved using tertbutyldimethylsilyl chloride in the presence of triethylamine. Silylation of the
second enol ether required tert-butyldimethylsilyl trifluoromethanesulfonate,
again with triethylamine as the base. Using this modified procedure, large
quantities of bis-silyloxy diene 33 were obtained in 86% yield.
At this point, the previous strategy involved a Diels-Alder reaction of
bis-silyloxy diene 33 with methyl propiolate to afford the unsaturated ester
product.
Sodium borohydride reduced the unsaturated ester forming
exclusively the desired endo isomer 32 in excellent yield (Scheme 12).
Scheme 12: Previous route to endo-ester 32.
0
TBSO
H3 CO
OCH 3
OCH3
CH 3
OCH 3
OTBS
Toluene, rt
33
NaBH 4
MeOH, 25 C
OTBS
93%
CH 3
\
TBSO
_
TBSO
41
CH 3
\
OTBS
32
However, the mixture of endo and exo isomers 32 and 35 could be obtained
directly using methyl acrylate as the dienophile (Scheme 11).
Dr. Allen
discovered that theendo isomer underwent the ring expansion, but the exo
isomer led to a complex mixture of products. Previously it was decided that
the amounts of the desired endo isomer were unacceptable, but recent
modifications increased the endo to exo ratio as well as the yield, and made it
a worthwhile procedure.
-ChapterII:
a-Diazoketone Synthesis * 19
Esters 32, 35 could be reduced using lithium triethylborohydride but
scaling up the reaction proved problematic, possibly because of the slow
reaction and complications with dissociation of the boron complexed from
A moderate scale reduction (1.4 g 32, 35) using lithium
the alcohol.
aluminum hydride produced the alcohol in 98% yield.
Unfortunately, the
large scale (7.4 g 32 and 35) version was not as successful, as the desired
reaction was accompanied by cleavage of the TBS enol ether. To employ this
method on large scale, it was necessary to terminate the reaction prematurely
to prevent this unwanted side reaction. Alcohols 36 and 37 were isolated in
71% yield (90% yield based on recovered starting material).
Because the
previous reactions were performed on such a large scale, it was sensible to cut
steps and employ the use of less expensive reagents.
Although the yields
were slightly lower than those previously reported, we were able to produce
large quantities of material quickly and cost effectively.
Scheme 13: Previous route to enone 45.
H
H
H
OTBS
SOTBS
H3
TBSO
P(OMe) 2
O
Imidazole
CH3
THF, rt
CH3
TBSO
75%
DMF
86%
P(OMe) 2
O
11
O
O
O
43
42
40
SeCN
1.
OH
aq. HF,
CH 2 C12, CH 3CN
-22 0C
86%
CH 3
TBSO
H2C
n-Bu 3 P, THF, rt
CH 3
TBSO
2. aq. H20 2 , THF
o0
80%
O
O
ChapterII: a-Diazoketone Synthesis * 20
The next sequence involved
the ring expansion to form the
[3.2.1]bicyclooctane system followed by the preparation of the ring contraction
precursor, c-diazoketone 30. The ring expansion did not require modification
and was performed as previously described (Scheme 13).
The ketalization, however, presented room for improvement.
This reaction
was sensitive; it had to be refluxed for at least three hours, but too much time
allowed an undesired rearrangement to take place.
Scheme 14: Formation of ketal 46 and rearranged product 50.
H2 C
H 2C
TBSO
CH3
O
45
(CH20H) 2, TsOH
Benzene,
reflux
77%
(90% based on
recovered enone)
CH
H3
CH 3
TBSO
2
O
O
L
O
46
50
Ketal 46, along with many other synthetic intermediates in this synthesis, was
sensitive to acid.
Running the reaction overnight led to the formation of a
rearranged product that was determined to be the [2.2.2]bicyclooctane system
50; the proposed mechanism for its formation is depicted in Scheme 15.
Opening the ketal led to the allylic oxonium ion. The partial positive charge
at the allylic carbon promoted vinyl group migration to give the oxygen
stabilized cation 49. Loss of the TBS group from this oxonium ion to ethylene
glycol converted 49 to a ketal affording bis-ketal 50 in as much as 47% yield.
Because of the unsaturation in the position oa,
to the ketal, it is
extremely sensitive to acid and precautions must be taken or the system selfdestructs.
ChapterII: a-DiazoketoneSynthesis * 21
Scheme 15: Acid promoted vinyl migration.
H 2C
H 2C
C
TBSO
CH 3
Ketal
H3
C
TBSO
H3
Protonation
0-
H
O- H
o6
.
.OH
OH
CH 2
CH 3
Formation of
Vinyl
CH 3
migration
bis-ketal
0
Continuation of the sequence involved conversion of the exo
methylene
ketal
46 to a ketone via a two step process involving
dihydroxylation with osmium tetroxide and oxidative cleavage with lead
tetraacetate.
Yields obtained for the dihydroxylation were 92-98% using a
stoichiometric amount of osmium tetroxide.
This was certainly not ideal,
due to the cost and toxicity of the reagent, especially on large scale.
Scheme 16: Formation of the ca-diazoketone.
0
H2 q
CH 3 TrisN 3 , Benzene
60 % KOH-H 20
CH 3 1. Os0 , THF, py
4
2.
Pb(OAc) 4
92% (2 steps)
CH 3
phase tran. cat.
O
/O
65%
Running this reaction with catalytic amounts of osmium tetroxide (5-10
mol%) in the presence of excess quantities of 4-methylmorpholine-N-oxide
- ChapterII: a-Diazoketone Synthesis * 22
(NMO) as the catalyst regenerating agent, resulted in yields ranging from 5682%.
An unusual byproduct was isolated from the reaction, and was
determined by NMR analysis to be the osmate dimer 51. This result was
peculiar because we did not observe a dimer of both terminal methylenes 52,
which was clearly the reaction site preferred by the bulky reagent.
Scheme 17: endo-exo Osmate dimer 51 vs. exo-exo osmate dimer 52.
CH
H2C
SCH
3
TBSO
0
O
CH
0
3
O
3
O- Os- O0
TBSO
HH
51, Observed
OTBS H
CH 3
52, Not observed
Due to the large steric requirements of the reagent, preferential addition to
the less hindered exo face of the terminal methylene is favored.
Oxidative
hydrolysis of the osmate ester by NMO was apparently the slow step, as the
formation of dimer 51 competed with it. The osmium bound to the terminal
methylene preferentially formed the dimer with the more substituted double
bond, as the addition to another terminal methylene 52 (on the exo face)
would cause the cyclopentane rings to collide (Scheme 17).
Attacking the
internal double bond from the exo face did not elicit the same unfavorable
steric interaction.
With large quantities of NMO in a dilute reaction solution we were
able to increase the yield to 82%; unfortunately, the dimer was still observed.
With five mole percent of osmium tetroxide present, a loss of 10% to dimer
formation was observed.
Additional amounts of osmium tetroxide were
- ChapterII: a-Diazoketone Synthesis * 23
necessary to make up for the loss of catalyst, which in turn formed more
dimer. It was clear that using stoichiometric amounts of osmium tertoxide
was preferable to catalytic osmium tetroxide since the loss of 20-40% material
at this step would hinder our progress in the synthesis. Oxidative cleavage of
the diol was achieved in excellent yields using lead tetraacetate.
With ketone 31 in hand, preparation of a-diazoketone
accomplished as previously described (Scheme 16).16
30 was
Monitoring this
reaction was quite difficult because the intermediate of the reaction and the
product had nearly the same Rf by thin layer chromatography.
However,
color could be used to indicate the conversion of the intermediate to the
product as the intermediate was magenta and the product pink-orange after
staining with p-anisaldehyde.
Also, the product exhibited a strong UV
absorption via thin layer chromatography.
Interestingly, the NMR spectrum
of the isolated product did not match that obtained previously.
We
determined that a-diazoketone 30 was indeed the product of the reaction but
we were unable to determine the product isolated previously. A byproduct
isolated was concluded to be the triisopropylbenzene sulfonamide 54, and the
mechanism of its formation is depicted below.
Enolate attack of the trisyl
azide can proceed either via path A or B. The internal nitrogen of the azide is
more sterically hindered, and intermediate 53 of path A is less stable due to
the proximity of the bicyclic ring to the bulky aryl substituents. These factors
combined to make this pathway higher in energy, both in the transition state
and the intermediate, therefore producing only small quantities of 54 after
loss of nitrogen. On the other hand, in path B attack can occur at the more
easily accessible terminal nitrogen, and the intermediate formed has the
bicyclic ring four atoms removed from the aryl substituents. This distance
16
Lombardo, L.; Mander. L. N. Synthesis 1980, 368.
ChapterII: a-DiazoketoneSynthesis * 24
dramatically lessens the steric interference displayed in the intermediate of
path A. Loss of the triisopropylbenzene sulfonamide afforded o-diazoketone
30 in 65 % yield.
Scheme 18: Reactions with trisyl azide.
00
NN
N= N N- S-
tA
N=
B
A
N=N
H
0
O
SN- S-Ar
N- S-Ar
0
A
CH3
TBSO
Loss of N2
Protonate
amine
O
O
54
53
O0
O
N= S- Ar
B
TBSO
CH 3
TBSO
CH3
N2
Loss of
H2NSO 2 Ar
TBSO
CH 3
0--30
In summary, modifications were made to the previous procedure to
obtain alcohols 36 and 37 in a more efficient and practical manner. This was
achieved by altering the conditions of the first three reactions in the sequence.
In the subsequent reactions, the goal was to increase product yields. Although
the ketal formation reaction was the only reaction which exhibited an
improved yield, the increase was more than 20%. Finally, close monitoring
ChapterII: ac-Diazoketone Synthesis * 25
of the diazo transfer reaction allowed for the isolation of a-diazoketone 30,
which had not previously been synthesized.
With the a-diazoketone in hand, we were one step away from
obtaining the complete carbocyclic frame.
Dr. Allen had successfully
completed the ring contraction of molecule 56, so we were hopeful that our
system would also undergo the transformation.
Scheme 19: Previous Wolff rearrangement.
O
CO02CH 3
N2
hv, 23 'C
Rayonet, 254 nm
CH 3
TBSO
MeOH
50%
MOMO
TBSO
CH 3
MOMO
2:1 endo:exo
56
Thus, irradiation of a-diazoketone 30 at 0 OC in a mixture of dichloromethane
and methanol afforded the desired Wolff rearrangement providing cyclobutyl
ester as a mixture of endo and exo isomers in excellent yield.
Scheme 20: Formation of the a-diazoketone.
0
C0
2 CH 3
N2
TBSO
CH 3
-
0
0
30
0 C hv
--
CH 3
CH 2C1 2 , MeOH
95%
57, 58
1.5:1 endo:exo
Chapter III: Attempts to Form The
Paeoniflorin Ring System
3.1 Aldehyde Formation Promotes Side Reactions
With the synthesis of the carbocyclic ring system complete, the focus
was now directed toward the alkylation of the cyclobutane ring and bridging
of the cyclic ether functionalities to form the cage-like ring structure.
Our
strategy involves the Wolff rearrangement to provide esters 57 and 58, and
then alkylation of the cyclobutane followed by closure of aldehyde 29 to form
the ether bridges.
Although it would have been ideal to incorporate the
benzoyl moiety onto the cyclobutane ring at this point, this functionality was
incompatible with the subsequent reduction step. We chose to alkylate with
benzyloxymethyl chloride, 1 7 then convert it to the benzoyl functionality once
the oxygen bridges were installed.
The mixture of endo and exo isomers formed from the Wolff
in order to perform
the alkylations
rearrangement
was separated
independently.
We believed the alkylation of the mixture would lead to
problems due to the differences in reactivity between the two isomers. Endo
isomer 57 had a more accessible hydrogen and the deprotonation would likely
be more facile than the deprotonation of exo isomer 58. The reactions were
slightly different, with endo isomer 57 giving a slightly higher yield. Both
reactions afforded alkylated ester 59 in 65-71% yield. An interesting byproduct
of the reaction was determined to be 60. This byproduct was peculiar as ketals
are usually uneffected by base.
This product actually gave insight to an
alteration in the synthetic plan that will be discussed later in this chapter.
17
Fang, C., Suganuma. K.; Sucmune, H.; Sakai, K. J. Chem. Soc. Perkin Trans. 1 1991, 1549.
ChapterIII: Attempts to Form the PaeoniflorinRing System * 27
Scheme 21: Alkylation of ester affords desired exo alkylation product 59.
0
OCH 3
CH3
TBSO
LDA, THF-HMPA
-20
then BOMCI
40. n
.o
BnO
CO 2 CH 3
BnO
TBSO
CH3
TBSO
C O 2C
O
o
-78 oC
.o
OH
59
60
71%
17%
57
H3
Reduction of esters to the corresponding aldehydes can be achieved
using diisobutylaluminium hydride (DIBAL) at -78
Cooling the DIBAL
oC.18
by adding it along the side of the flask is necessary to avoid any increase in
temperature.
It is crucial to run this reaction at -78 'C as warming would
allow for an additional reduction to take place.
A critical aspect of this
procedure is the stability of the aluminum complex formed after the first
hydride transfers to the ester. If the complex is unstable, the reaction can be
driven to dissociation. Once dissociated, another reduction can easily occur.
Because the ester is located in close proximity to the ketal, we believed that an
unfavorable interaction between the aluminum complexed acetal and the
ketal would promote the dissociation, so we felt it was necessary to reduce the
ester completely to the alcohol then oxidize it to the aldehyde.
Scheme 22: Reduction of ester 59 to alcohol 61.
TBSO
CH3
DCHiBAI-H, -30
Hexane, 99%
O
59
18
OH
BnO
CO2CH3
BnO
Garner. P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
CH
TBSO
3
O
61
61
ChapterIII: Attempts to Form the PaeoniflorinRing System * 28
Completely reducing the ester to the alcohol successfully afforded
alcohol 61 in 99% yield. This product, like many others in this synthesis, was
extremely sensitive to acid. Glacial acetic acid was used to quench the reaction
and during one experiment too much acid was added which caused
deprotection of the ketal.
The alcohol immediately cyclized into the
unsaturated ketone affording cyclic ether 62.
This intermediate closely
resembles intermediate 21 in Hatakeyama's synthesis (Scheme 23). Although
forming the cyclic ether was unfortunate, it was encouraging in that it was the
type of cyclization we wanted the hydrated aldehyde to undergo. Because of
this favorable cyclization, the ketal cannot be removed before the aldehyde is
formed.
Scheme 23: Acid promoted cyclization affords cyclic ether 62 which is similar
to an intermediate in Hatakeyama's Synthesis.
BnO
OH
TBSO
- CH3
O
61
BzO
BnO
H
TBSO
CH3
0
62
CH 3
-
0
Hatakeyama's intermediate
21
Because of its high sensitivity towards acidic solutions, we chose to
oxidize alcohol 61 to the aldehyde using a neutral reagent. We felt that if the
ketal was removed, the molecule would instantaneously cyclize, not allowing
the aldehyde to be isolated, or if the ketal was removed before the oxidation
cyclic ether 62 would be obtained. The Dess-Martin periodinane is a strong
oxidizing agent that oxidizes under neutral conditions. 19 After the oxidation,
19 Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
ChapterIII: Attempts to Form the PaeoniflorinRing System * 29
crude NMR analysis of the isolated product showed a surprising mixture of
two compounds, one of which was an aldehyde.
Because of the solvents
interfering in the crude NMR, the sample was placed under reduced pressure
for a few hours with hopes that a clearer NMR could be obtained. Indeed that
was the case. Unfortunately this time the aldehyde product was no longer
evident. A single compound was present which was determined to be retroClaisen rearrangement product 64.
Scheme 24: Oxidation to the aldehyde is followed by the retro-Claisen
rearrangement.
H
OH
AcO
, ,OAc
OAc
-CH3
O
facile
CH 3 rearrangement
0
':
(Dess-Martin
reagent)
BnO
61
CH 3
O
OTBS
61
We did not expect the aldehyde to readily rearrange because Monti and
co-workers synthesized 65, a similar compound that was stable at room
temperature.20
Scheme 25: The tert-butyldimethylsilyl ether facilitates the retro-Claisen
rearrangement.
Retro-Claisen
CH 3
rearrangement
20
Larsen, S. D.; Monti, S. A. J. Am. Chem. Soc. 1977, 99, 8015.
CH 3
ChapterIII: Attempts to Form the PaeoniflorinRing System * 30
Claisen rearrangements are concerted [3,3]-sigmatropic rearrangements
that occur through a six-membered transition state. These rearrangements
provide y,6 unsaturated carbonyl compounds from the corresponding allyl
vinyl ethers.
In our system, the reverse was favored thermodynamically.
The rigid conformation of the bicyclic system cannot easily adopt the favored
chair transition state usually seen in these rearrangements.
By assuming the
boat conformation, aldehyde 63 would adopt the orbital overlap necessary for
the retro-Claisen rearrangement to occur.
Although this reaction is usually unfavorable in this direction, there
are three factors which contribute to the driving force in the conversion of
aldehyde 63 to rearranged product 64.
The predominant thermodynamic
driving force is the cleavage of the cyclobutane ring which relieves -26
kcal/mol of strain energy. Secondly, the tert-butyldimethylsilyl ether plays a
key role in the rearrangement process as it is located in the position at which
the newly formed double bond can be stabilized as a vinyl ether. The silyloxy
group also stabilizes the transition state and facilitates the rearrangement at
room temperature.
Without its presence, isolation of the aldehyde would
likely have been possible, as it was for Monti's synthetic studies. It may also
be important that the large tert-butyldimethylsilyl ether and the methyl
benzyl ether which in the cyclobutane were adjacent to one another become
far removed from each other in the product. This is best depicted in Scheme
24.
We found it worthwhile to attempt the oxidation with PCC on
alumina with delayed addition of acid in hopes of deketalizing the ketone,
making the [-position a more desirable site for the aldehyde to attack.
Unfortunately
this
oxidation
attempt
generated
the
retro-Claisen
ChapterIII: Attempts to Form the PaeoniflorinRing System * 31
rearrangement as well.
Apparently the double bond could not be present
within the bicyclic ring system when the aldehyde was being generated.
A new approach was investigated to generate the cyclobutyl
By
carboxaldehyde without undergoing a retro-Claisen rearrangement.
protecting the enone, as a silyl dienol ether similar to the byproduct 60
discussed earlier, perhaps the retro-Claisen would not occur.
The exo
methylene carbon would be far enough away from the aldehyde that it would
be very difficult to achieve a retro-Claisen rearrangement.
Treatment of the alkylated product 59 with 1% hydrochloric acid in
acetone afforded in nearly quantitative yield the enone 66. Silyl dienol ether
was prepared under kinetic enolate trapping conditions.
To a mixture of
enone 66 and 1.2 equivalents of tert-butyldimethylsilyl trifluoromethanesulfonate at -78 'C was added lithium diisopropylamide.
After work-up,
diene 67 was obtained and was used in the next step without further
purification.
Scheme 26: Synthesis of silyl dienol ether 67.
BnO
OCH 3
TBSO
CH 3
HCI, Acetone
98%
O
59
O
O
O
BnO
OCH3
TBSO
CH 3
OCH 3
BnO
LDA, TBSOTf
TBSO
ZTHF
0
OTBS
66
67
Silyl dienol ether 67 would next be converted to the aldehyde and
deprotected to test this new strategy for the oxacyclic ring system synthesis.
Instead of reducing the ester to the alcohol then oxidizing it to the aldehyde,
we chose to form the aldehyde directly. The tert-butyldimethylsilyl enol ether
ChapterIII: Attempts to Form the PaeoniflorinRing System * 32
67 was not expected to pose the same steric effect which we felt was present in
the ketal compound 59.
Two equivalents of diisobutylaluminum hydride
solution were added to the silyl dienol ether 67 at -78 'C and after quenching
at -78 oC, the aldehyde 68 was isolated in 18% yield (51% based on recovered
starting material). It may have been best to employ the sequence used on the
other system after all. Because of the presence of two tert-butyldimethylsilyl
ether moieties in aldehyde 68, we chose aqueous hydrogen fluoride as
selective deprotection conditions. Surprisingly, the reaction of aldehyde 68
with aqueous hydrogen fluoride proceeded at 0 'C to afforded a 2:1
diastereomeric mixture of aldol products 69 and 70. The facile protonation of
the aldehyde made it susceptible to attack by the tert-butyldimethylsilyl enol
ether in a Mukaiyama-type aldol reaction.
Scheme 27: Successful formation of aldehyde 68 and Mukaiyama-type aldol
reaction.
0
O
DiBAI-H, -78
OC
Toluene/Hexane
TBSO
TBSO
51% (based on
recovered 67)
OTBS
67
OH
HF aq., 0 C
BnO
CH 3CN/H20
TBSO
H
34%
OTBS
68
69, 70
Employing the use of an aldehyde to obtain the ether bridges was
unsuccessful because its high reactivity led to the generation of undesired
products. The aldehyde needed to be replaced by another functional group,
preferably with the same oxidation state. Of the possibilities, none were very
promising as the conversions to desired functional groups could likely lead to
complications.
The formation of lactone 10 and carboxylic acid 11 from the
ChapterIII: Attempts to Form the PaeoniflorinRing System * 33
degradation reactions discussed in Chapter I (Scheme 3) gave the insight for
the following sequence.
Scheme 28: Focus directed toward synthesizing carboxylic acid 71.
BzO
O
O
O
BzO
0o
RO
CH3
OH
BnO
CH
RO
CH 3
TBSO
3
O
OH
O
O
71
11
10
Perhaps an acidic solution would favor the closure of the acid 71 to
afford a lactone intermediate similar to 10.
Reduction of the lactone to a
lactol would then allow closure of the paeoniflorin ring system without
involving the intermediacy of an aldehyde.
Based on this literature
precedent we decided to direct our efforts towards the formation carboxylic
acid 71 instead of the aldehyde 29.
3.2 Successful Construction of the PaeoniflorinRing System
There were two competing choices available for the production of
carboxylic acid 71.
The Wolff rearrangement could be performed in an
aqueous mixture (instead of the methanolic solution) so that the ketene
generated from the rearrangement would provide the acid 72 and 73.
Alternatively, the methyl ester derived from the Wolff rearrangement could
be hydrolyzed.
Although these reactions seem straightforward, each led to
complications described below.
The Wolff rearrangement was attempted first and indeed was
successful.
The crystalline acid was obtained without optimization, in 58%
yield. Because of the difficulty in analyzing the aqueous mixture, the reaction
ChapterIII: Attempts to Form the PaeoniflorinRing System * 34
may have been exposed to the intense light source for a duration longer than
necessary, possibly causing undesirable side reactions.
The alkylation
optimized for the synthesis of ester 59 was employed using two equivalents of
lithium diisopropylamide in tetrahydrofuran-hexamethylphosphoramide
(HMPA) at -20 'C. After the addition of benzyloxymethyl chloride, only the
benzyloxymethyl ester 74 was obtained.
Unfortunately this O-alkylation
result was the only product observed suggesting that the expected dianion was
not formed.
Scheme 29: Wolff rearrangement provided acids 72 and 73, but O-alkylation
was observed
CO 2 CH20OBn
CO02 H
THF, BOMCI
H20
THF,
THF,H20O
.
L.O
LO
LO
58%
72, 73
30
0
74
If the acid was cyclized first, the alkylation would still be unsuccessful
as basic treatment of the lactone would afford the open form as seen with the
studies by Aimi (Scheme 3).4b
This dianion alkylation approach was
therefore abandoned, and the focus turned toward the hydrolysis of ester 59
obtained from the ester enolate alkylation.
Ester 59 was unreactive towards deprotection by standard conditions
including lithium hydroxide in aqueous dimethoxyethane 21 and lithium
iodide
in dimethylformamide.
22
Treatment with sodium iodide and
trimethylsilyl chloride resulted in deprotection of the ketal but not the
21
22
Corey, E. J.; Narasaka, K.; Shibaski, M. J. Am. Chem. Soc. 1976, 98, 6417.
Magnus, P.; Gallagher, T. Chem. Commun. 1984, 389.
ChapterIII: Attempts to Form the PaeoniflorinRing System * 35
methyl ester. 23
lithium
ethyl
Fortunately, the ester could not withstand the force of
mercaptide. 24
Preparation of 0.5 molar lithium ethyl
mercaptide in HMPA was followed by addition of the ester 59. After extended
reaction at room temperature, the acid 75 was isolated in 77% yield.
The
nucleophilic displacement of the methyl ester by ethyl mercaptan was
successful only with HMPA as the solvent.
Scheme 30: Ester hydrolysis with lithium ethyl mercaptide.
0
0
BnO
OCH 3
TBSO
CH3
HMPA, EtSLi
rt, 3d
O
O
OH
BnO
77%
59
CH 3
TBSO
O
O
75
We learned earlier that the allylic ketal was sensitive to aqueous acid
treatment therefore we chose anhydrous methanesulfonic acid for the lactone
formation.
With the ketal still present, the selective reduction with
diisobutylaluminum hydride would be possible immediately following the
lactonization.
Unfortunately, the reaction mixture was not completely
anhydrous, and we isolated two products from this reaction which were
determined to be 71 and 76. To our surprise, when the ketal was removed,
the equilibrium favored the open form 71, but when the ketal was present it
preferred to cyclize 76.
23
Heck, M. P.: Monthillcr, S.; Mioskowski, C.; Guidot, J. P.; Le Gall, T. Tetrahedron Lett. 1994, 35,
5445.
24
Vaughn, W. R.; Baumann, J. B. J. Org. Chem. 1962, 27, 730.
ChapterIII: Attempts to Form the PaeoniflorinRing System * 36
Scheme 31: Lactone cyclization of acid 75.
O
O
TBSO
CH3
O
CH3SO 3H
O
TBSO
CH3
o
71
75
0
OH
BnO
OH
BnO
BnO
TBSO
CH3
O
kO
76
Treatment of lactone 76, with diisobutylaluminum hydride at -78 'C in
dichloromethane afforded the lactol 77 as a 6:1 mixture of diastereomers in
50% yield with 50% recovery of lactone 76. Based on the downfield shift (5.81
ppm) of the hydroxyl proton in the 1 H NMR spectrum, it seemed reasonable
that the predominant product was the desired lactol 77. With the hydroxyl
group in close proximity to the ketal oxygen, intramolecular hydrogen
bonding would deshield the hydroxyl proton and lock the conformation
about the C-O bond. This interaction is consistent with a 13.2 Hz coupling
constant. The stereochemistry of the major isomer 77 is understandable based
on the less sterically hindered approach of diisobutylaluminum hydride from
the exo face of the lactone.
Reaction of the mixture of lactol isomers with
hydrochloric acid and acetone at 0-425 oC resulted in formation of a new
bridged acetal product.
After purification by column chromatography, the
NMR spectrum revealed that the paeoniflorin caged ring system had formed.
However, the presence of a CH 2 CH 20H group unexpectedly indicated that the
ketal group was only partially deprotected.
The oxacyclic acetal 78 was
therefore obtained and this reaction is currently under optimization.
ChapterIII: Attempts to Form the PaeoniflorinRing System * 37
Scheme 32: Successful synthesis of the oxacyclic acetal 78.
BnO
TBSO
CH 3
DiBAI-H, CH 2C12
-78
-78 "C
CH3
0
76
HCI (aq)
e
O
CH
3
Acetone
OH
76
Perhaps, further treatment with acid may be successful in completing
the removal of the ketal protecting group.
Alternatively, elimination of the
hydroxyl ethyl group could afford a vinyl ether which could then be easily
hydrolyzed.
Chapter IV: Revised Strategy
4.1 Novel Approach to Carbocyclic System
Bicyclic ketone 31 was originally synthesized in thirteen steps as
described in Chapter II.
Several of the intermediates in this route were
sensitive and had a tendency to undergo undesired rearrangements and
cyclizations. Because of these potential problems, it was in our best interest to
obtain the bicyclic ketone 31 via a new sequence, preferably with fewer steps.
A new strategy was designed; the retrosynthetic analysis is described in
Scheme 33.
Scheme 33: Retrosynthetic analysis of key intermediate 31.
Functional
group
Heck
Reaction
Interconversion
TMSO
TMSO
0
Grignard
Acyloin
Condensation
H 3 CO
0
H3CO J
Addition
OCH 3
84
H 3CO
Functional group interconversion of the bicyclic ketone 81 was planned to
provide
the
key
intermediate
ketone
31.
Disconnection
of the
[3.2.1]bicyclooctanone ring system was envisioned to generate the symmetrical
bis-trimethylsilyl enol ether 82.
Among many organometallic reaction
ChapterIV: Revised Strategy * 39
methods possible, the palladium mediated cyclization of the olefin to the enol
ether is well precedented. 25 The bis-trimethylsilyl enol ether 82 is a prochiral
precursor which could be investigated in enantioselective versions of the
intramolecular palladium mediated cyclization as well. The acyloin reaction
being the only recourse for the synthesis of bis-silyl enol ethers requires the 3alkyl gluterate precursor 83.26 Removal of the side chain gives the starting
materials for this synthesis, trans-dimethyl glutaconate (84) and 4-bromo-1butene.
Overman 27 developed a procedure to obtain 3-alkylated glutarate esters
from the copper-catalyzed addition of Grignard reagents to trans-dimethyl
glutaconate.
For the addition to proceed, they found it was necessary to
activate the unsaturated ester using excess amounts of trimethylsilyl chloride;
when no trimethylsilyl chloride was present, no reaction was observed.
Because of the acidity of dimethyl glutaconate's c-hydrogens, it is necessary to
form the silyl ketene acetal of one of the esters before the addition of the
Grignard reagent. If this is not accomplished, one equivalent of the Grignard
will be wasted on the enolization of the ester. Due to the expense of 4-bromo1-butene, we chose to form the trimethylsilyl ketene acetal.
An important improvement to Overman's procedure was achieved by
performing the reaction under inverse addition conditions.
glutaconate
(84)
was
Dimethyl
treated with triethylamine and trimethylsilyl
trifluoromethanesulfonate in tetrahydrofuran-hexane and removal of the
byproduct triethylammonium triflate afforded the moisture sensitive silyl
ketene acetal 85.
The solution of dimethyl glutaconate ketene acetal 85,
chlorotrimethylsilane
25
and
0.2
equivalents
of
cuprous
26
Kende, A. S.; Roth, B.; Sanfilippo, P. J. J. Am. Chem. Soc. 1982, 104, 1784.
Ruhlmann, K. Synthesis 1971, 236.
27
Leotta (III), G. J.; Overman, L. E.; Welmaker, G. S. J. Org. Chem. 1994, 59, 1946.
iodide
in
ChapterIV: Revised Strategy * 40
The dropwise addition of the
tetrahydrofuran was cooled to -35 -C.
preformed Grignard reagent to the solution of 85 was monitored via thin
layer chromatography until the complete consumption of starting material
was apparent. The reaction afforded diester 83 in 79% yield.
Scheme 34: Synthesis of 3-substituted glutarate diester 83.
O
O
H3 CO
NEt 3, TMSOTf, 0
OCH 3
THF/Hexane
OTMS
O
0C
H 3 CO
OCH 3
85
i. THF, Mg, 40
ii. Cul, -35 "C
O
0C
Br
iii. 85, 79%
H 3 CO
H3CO
With the diester in hand, we were prepared to perform the acyloin
Because diester 83 was similar to several molecules in the
condensation.
literature, we expected this reaction to run smoothly, and indeed it did,
affording the bis-silyl enol ether 82 in 97% yield. It was necessary to use this
product immediately because the compound undergoes hydrolysis readily.
Scheme 35: Acyloin synthesis of Bis-trimethylsilyl enol ether 82.
O
H3 CO
i. Na, Tol, A
H3CO
ii. TMSCI, 83
1 h, A 97%
TMSO
TMSO
It is well known in the literature that unsaturated silyl ethers can
undergo intramolecular cyclization with a pendant olefinic group in the
ChapterIV: Revised Strategy * 41
presence of palladium (II) if a five-, six-, or seven-membered ring can be
formed. 28 This method has been employed to obtain spiro and bridged bicyclo
ketones. The cyclization is thought to involve the nucleophilic attack of the
enol ether double bond onto the palladium-coordinated olefin. 29 In our
system, the silyl ether double bond can attack the olefin via a 7-endo or 6-exo
pathway (Scheme 36).
Scheme 36: Options available to the silyl ether double bond.
TMS O.
O
O
\ -OAc
A: 7-endo TMSO
-TMSOAc
TMSO,
TMSO
-HOAc, Pd
A
-Pd(OAc)
TMSO
TMSO
2
88
87
86
B
TMS.
+
\
82
B:-
\\
-OAc
Pd(OAc)
TMSO
-TMSOAc
-HOAc, Pd
TMSO
81
89
The 7-endo route leads to the formation of bicyclononenones 87 and 88
after P-hydride elimination of the palladium. With the 6-exo route, there is
only one option for P-hydride
elimination
leading
exclusively
to
[3.2.1]bicyclooctanone 81. Both entropy and enthalpy favor the cyclization to
proceed via the 6-exo pathway.
Addition of 1.5 equivalent of palladium (II)
acetate to an acetonitrile solution of bis-silyl enol ether 82 and dry sodium
acetate at room temperature for eight hours afforded the [3.2.1]bicylclooctanone 81 in 44-58% yield. The presence of sodium acetate in the reaction
28
Heck, R. F.; InPalladium Reagents in Organic Syntheses; Katritzky, A. R., Meth-Cohn, O., Rees, C.
W.; Eds; Academic Press Inc.: London 1985, pp 222-225.
29
Kende, A. S.; Roth, B.; Sanfilippo, P. J.;Blacklock, T. J. J. Am. Chem. Soc. 1982, 104, 5808.
ChapterIV: Revised Strategy * 42
mixture was found to buffer the acetic acid generated during the reaction.
Otherwise, the acidic solution could promote the cleavage of the trimethyl
ether, and exposure of the alcohol to acid may lead to complications in the
reaction. It is important to note that the low yield of ketone 81 may be due to
product loss associated with the isolation of this volatile product from the
reaction mixture.
Scheme 37: Palladium mediated cyclization affording 81.
0
Pd(OAc) 2
TMSO
NaOAc
CH 3CN, rt
44-58%
TMSO
TMSO
81
82
It is not uncommon to isolate olefin regioisomers that could not have
been formed directly from the initial P-hydride elimination.
Possibly the
short-lived palladium-bound olefin is responsible for such isomerizations.
NMR analysis of the crude product did in fact show the presence of a small
amount of a product with the double bond isomerized to the more stable
endo location.
This procedure provides the bicyclic ketone 81 in three steps from
dimethyl glutaconate in 44% overall yield.
This expedient synthesis of the
[3.2.1]bicyclooctanone ring system compares admirably with our previous
thirteen step sequence.
The overall yield could possibly be increased by
optimizing the isolation of product 81 from the Heck reaction.
4.2 Oxygenation of the C-3 Position
This new successful route was encouraging because we were able to
ChapterIV: Revised Strategy * 43
attain the desired ring structure in three steps. There was one problem with
this system-it lacked the correct oxygenation at the C-3 position. How could
we obtain this oxygenation, and in what part of the sequence would it be best
to incorporate it? Surprisingly, we found a case in the literature in which a
ketal could withstand the reductive conditions of an acyloin condensation. 24
This precedent gave us the initiative to functionalize the C-3 position before
the acyloin reaction (Scheme 38).
Scheme 38: Desired ketal precursor for acyloin condensation and the
numbering scheme for paeoniflorin.
0
8
O
H 3CO
H3CO
HOCH 2
HO
CO2CH2
O
HOO
10
-
o-)-
OH
O
0
/ o
,CH
5
4
2
3
OH
90
An umpolung approach would be required to add a masked ketone to the
glutaconate.
Perhaps a dithiane would provide the desired conjugate
addition to the glutaconate.
Because the dithiane would not be able to
withstand the acyloin conditions, it would be necessary to convert it to the
ketal after addition to the glutaconate.
Corey et al, have developed a
procedure for a one step conversion to the ketal. 30
Dithiane anions undergo conjugate additions to a,p-unsaturated
ketones at -78
'C
in the presence
of HMPA
or cuprous
iodide-
trimethylphosphite complex. 3 1 The conjugate addition to ua,1-unsaturated
30
Corey, E. J.; Andersen. N. H.; Carlson, R. M.; Paust, J.; Vedejs, E.; Vlattas, I.; Winter, R. E. K. J.
Am. Chem. Soc. 1968, 90, 3245.
31
(a) Ziegler, F. E.; Tam, C. C. Tetrahedron Lett. 1979, 49, 4717. (b) Lucchetti, J.; Dumont, W.; Krief,
A. Tetrahedron Lett. 1979, 29, 2695. (c) Brown, C. A.; Yamaichi, A. J. Chem. Soc., Chem. Commun.
1979, 100.
ChapterIV: Revised Strategy * 44
aldehydes is also observed in the presence of tetrahydorfuran-HMPA. 32 The
allyl dithiane was synthesized successfully and the ketene acetal of the
glutaconate was generated. The reaction was attempted using a combination
of the Overman approach and the conditions stated above. The glutaconateketene acetal 85 was added to two equivalents of lithiodithiane 91 at -78 'C
followed by the addition of HMPA and chlorotrimethylsilane (if the order of
the addition of chlorotrimethylsilane and the glutaconate-ketene acetal was
reversed, the dithiane anion was silylated). The double addition product 93
was isolated from this reaction in 23% yield. We suspect that the dithiane
anion adds to the ester first to form the intermediate 92 followed by the
conjugate addition of a second nucleophile to the ox,f-unsaturated ketone.
Several different variations of this reaction were performed, in each case
affording the same product 93.
Scheme 39: Favorable formation of bis-dithiane 93.
s
s
HMPA, THF, TMSCI, -78 C
91
OTMS
O
S
OCH3
S
[1,2] addition
92
H 3 CO
OCH 3
0
85
H 3 CO
TMSO
[1,4] addition
S
S
S
93
Perhaps treatment of ketone 81 with acid would allow isomerization to
32
E1-Bouz, M.; Wartski, L. Tetrahedron Lett. 1980, 21, 2897.
ChapterIV: Revised Strategy * 45
the more substituted olefin. With the endo double bond, it would be possible
to employ an allylic oxidation procedure.
Scheme 40: Functionalization of the bicyclic system.
O
O
O
.. m riato..
TMSO
.-.. . -.---............
TMSO
TMSO
95
94
81
\
Oxidation
Under mild acid conditions the trimethylsilyl ether is readily cleaved
affording the o-hydroxyl ketone 96 in 90% yield. Stronger acid conditions
may be necessary to isomerize the double bond.
Scheme 41: Acid treatment removes trimethylsilyl protecting group.
0
0
HCI, THF
90%
TMSO
81
HO
96
At this point, we believe it was worthwhile to replace the trimethylsilyl ether
with a tert-butyldimethylsilyl ether, as from prior experience, the tertbutyldimethyldilyl ether was stable to moderate acidic solution. With this
protected alcohol, the isomerization of the double bond may be achieved.
With the isomerization complete, the allylic oxidation could be attempted.
4.3 Future Prospects with The Barton Reaction
If the C-3 position can not be oxidized before the Wolff rearrangement,
there is still a possibility of oxidizing the carbocycle via a Barton oxidation
ChapterIV: Revised Strategy * 46
Starting with the butyldimethylsilyl
after the ring contraction is complete.
protected ether, the alkylated acid 97 could be obtained via the procedure
recently developed and discussed in Chapter III. Treating 97 with acid could
lead to the lactone which when treated with DIBAL would afford lactol 98.
The hydroxyl of the lactol is in close proximity to the C-3 position and
Forming
oxidation of this position via a radical procedure is promising.
nitrite ester 99 could be accomplished with the exposure of the lactol to
By employing the Barton reaction, it is
nitrosyl chloride and pyridine.
reasonable to expect the C-3 hydrogen to be abstracted by the oxygen radical
The cyclobutyl radical could then form the
generated when photolyzed.
oxime 100 by reacting either in a terminal fashion, or a radical chain process.
Hydrolysis of the oxime would afford the desired hydroxy ketone 101 and acid
induced closure would provide the cage-like structure of paeoniflorin.
Scheme 42: Proposed strategy to provide the desired oxidation at C-3
OH
0
0
BnO
BnO
OH
0
TBSO
TBSO
Lactone
TBSO
..
TBS
Prev ios
Lactol
CH 3
98
97
81
O
OH
O-N
BnO
BnO
nitrite ester
Hydrolyze
O
Barton Reaction
Formation of
Oxime
TBSO
TBSO
CH3
CH 3
100 N-OH
99
OH
BnO
BnO
0
CH3.
OH3
TBSO
101 0
Ring Closure
. .
-
O
TBSO
\
102
CH3
Introduction
Chapter V:
5.1 Biological Activity
Taxol® 33 (103) was originally isolated from bark extracts of the western
yew tree (Taxus brevifolia) by Barclay. 34
In 1964, Wani and co-workers
reported that Taxol@ exhibited cytotoxicity against 9KB and various leukemia
systems. 35
In a number of studies since its isolation, 36 Taxol@ has been
shown to exhibit antitumor activity against several different tumor models,
37
including ovarian tumors, MX-1 mammary tumors, and B16 melanoma.
Recently the FDA approved the use of Taxol@ for the treatment of metastatic
ovarian and breast tumors. 38
Scheme 43: The natural product, Taxol®.
AcO
Ph
0
OH
0
0"
BzHN
OH
HO
: H
OBz OAc
Taxol®, 103
Unfortunately, nature does not provide usable quantities of Taxol®.
One large scale harvest required ca. 12,000 trees, equaling 60,000 tons of bark,
33
Taxol is the registered trademark for the molecule with the generic name paclitaxel.
Junod, T. Life 1992, 15, 71.
35
Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggan, P.; McPhail, A. T. J. Am. Chem. Soc. 1971, 93,
2325.
36Reviews: (a) Rowinsky, E. K.; Onetto, N.; Canetta, R. M.; Arbuck, S. G. Semin. Oncol. 1992, 19,
646. (b) Holmes, F. A.; Walters, R. M.; Theriault, R. L.; Forman, A. D.; Newton, L. K.; Raber, M. N.;
Buzdar, A. U.; Frye, D. K.; Hortobagyi, G. N. J. Natl. Cancer Inst. 1991, 83, 1797. (c) Nicolaou, K. C.;
Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Eng. 1994, 33, 15.
37
(a) Wiernik, P. H.; Schwartz, E. L.; Strauman, J. J.; Dutcher, J. P.; Lipton, R. B.; Paietta, E. Cancer
Res. 1987, 47, 2486. (b) Mathew, A. E.; Mejillano, M. R.; Nath, J. P.; Himes, R. H.; Stella, V. J. J.
Med. Chem. 1992, 35, 145.
38
Slichenmeyer, W. J.; Von Hoff, D. D. Anti-Cancer Drugs 1991, 2, 519.
34
* 48
Chapter V: Introduction
and yielded 2.5 kg of Taxol®. Treatment of one patient typically requires two
grams of Taxol@.
The high demand for Taxol@ has depleted the
northwestern rain forests of this venerable species and upset the ecosystem.
To avoid this devastation, several research groups set forth to design a semisynthesis of Taxol@, with major contributions from Holton, Ojima and
Greene. 39
In 1988, Holton was successful in synthesizing Taxol@ from a
compound known as baccatin III (104) via reaction with p-lactam 106 (Scheme
44). First the C-7 alcohol of baccatin III was protected as the triethylsilyl ether,
then after treating 105 with DMAP and pyridine with p-lactam 106, product
107 was obtained. Deprotection afforded Taxol@ in good yield.
Scheme 44: Semi-synthesis of Taxol@ from baccatin III and p-lactam 106.
AcO
Ph
AcO
AcO O
O
O>106
HO'
HO
H
OBz OAc
0
OTES
OR
Ph
=
DMAP, pyr
Ph
O
Ph
N
H
O
O
HO
H
OBzOAc
O
107
R=H: Baccatin III, 104
R=TES, 105
Taxol, 103
The importance of this semi-synthesis is due to the fact that baccatin III is
isolated from the needles of the European yew (Taxus baccata). Harvesting
the needles does not threaten the survival of the tree, as unlike the bark, they
are easily regenerated. 40
39
(a) Holton, R. A. Eur. Pat. App. 400971, 1990. (b) Ojima, I.; Habus, I.; Zhao, M.; Georg, G.;
Jayasinghe, 1. R. J.Org. Chem. 1991, 56, 1681. (c) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y.
H.; Sun, C. m.; Brigaud, T. Tetrahedron 1992, 48, 6985.
40
(a) Denis, J.-N.; Greene, A. E.; Gudritte-Voegelein, F.; Mangatal, L.; Potier, P. J.Am. Chem. Soc.
1988, 110, 5917. (b) McCormick, D. Bio/Technology 1993, 11, 26.
Chapter V: Introduction
* 49
Taxol@ is a member of a class of antimitotic compounds including
Because these compounds
colchicine and podophyllotoxin (Scheme 45).
efficiently arrest cell division, they are a main focus of cancer research and
therapy. In 1979, Horwitz and coworkers found the mode of action exhibited
41
by Taxol@ to be unique for this class of antimitotic compounds.
Scheme 45: Other antimitotic compounds.
OH
0o
H 3 CO
I....
0 3.
NHCOCH 3
0
H3CO
CH30
/
H
OCH 3
OCH 3
H3CO
OCH 3
Podophyllotoxin
Colchicine
During the metaphase (M phase) of cell division, it is essential for the
mitotic spindle to form and move the chromosomes toward the poles of the
cell. After the migration is complete, the cell divides. Inability of the mitotic
spindle to perform its duties leads to cell arrest. The mitotic spindle consists
of a complex network of microtubules and associated proteins.
Each
microtubule contains 13 parallel columns of protofilaments which adopt a
cylindrical shape. The protofilaments are made up of two types of protein:
tubulin and P-tubulin, referred to in units as
ta-
p dimers, or tubulin. These xp
dimers are arranged 'head to tail' and assemble/disassemble sequentially in a
helical
fashion
in
the
longitudinal
direction.
Microtubules
assemble/disassemble on either end, but there is a preference for addition of
tubulin in one direction where the other prefers dissociation of tubulin
41
Schiff, P. B.: Fant, J.; Horwitz, S. B. Nature, 1979, 277, 665.
Chapter V: Introduction
* 50
subunits. The net growth of microtubules is dependent upon the hydrolysis
of bound GTP and the availability of GTP-tubulin subunits. Tubulin favors
dissociation at low temperatures or in the presence of Ca 2 +. Polymerization
and depolymerization of the dimers exists in a dynamic steady state; an
alteration of this state could lead to cell arrest.
Prior to 1979, antimitotic compounds were known to block cell
division by inhibiting the polymerization of tubulin.
Colchicine had the
most profound effect, but because of its toxicity it could not be used for anticancer treatment. There exists a high-affinity binding site for colchicine on
the tubulin subunits, and once colchicine binds to the unit it ceases growth
causing a net loss of microtubules and an accumulation of tubulin. In the
presence of colchicine, the mitotic spindle does not form and the
chromosomes are not moved to the poles of the cell, leading to cell arrest.
Taxol@, however, was the first compound discovered to promote the
formation of microtubules even in the absence of GTP and does not
disassemble in the presence of Ca 2 + or low temperatures.# 6 Once Taxol@bound microtubules form, they are resistant to depolymerization, and
without depolymerization the cell will not divide, promoting cell death.
Recently, three different compounds with structures unlike that of
Taxol@ were discovered and found to exhibit the characteristic microtubule
assembly/stabilization properties of Taxol@.
These compounds were (+)-
discodermolide, epothilones A and B, and eleutherobin (Scheme 46).
* 51
Chapter V: Introduction
Scheme 46: Compounds with the same mode of action as Taxol®.
OH
OH
N
N
CH3
R=H epothilone AOH
R=H epothilone A
R=CH
3
Eleutherobin
epothilone B
OH
OH
HO
O
HO
Discodermolide
Discodermolide was isolated from a Caribbean marine sponge, discoderma
dissoluta, and was found to possess immunosuppressive and cytotoxic
activities. 4 2 In more recent studies, discodermolide was shown to bind to
43
tubulin in mictotubules in a 1:1 ratio with a higher affinity than Taxol®.
The overall effect was the net polymerization of microtubules in the absence
of
microtubule associated proteins (MAPS) or GTP. Furthermore, the
disassembly was not induced at low temperatures or in high concentrations of
Ca 2 +.44 Epothilones A and B were isolated from myxobacteria of the genus
Sorangium and were found to have a broad activity against eukaryotic cells.
4 5 subsequent
They were first classified as antifungal cytotoxic compounds;
42
Gunasekera, S. P.; Gunasckera, M.; Longley, R. E.; Schulte, G. K. J. Org. Chem. 1990, 55, 4912.
43
Hung, D. T.; Chen. J.: Schreiber, S. L. Chem. Biol. 1996, 3, 287.
44
terHaar, E.; Kowalski, R. J.; Jamel, E.; Lin, C. M.; Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H.
S.; Day, B. W. Biochem. 1996, 35, 243.
45
(a) Gerth, K.; Bcdorf, N.; Hofle, G,; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 560. (b)
Hofle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed.
1996, 35, 1567.
Chapter V: Introduction
* 52
studies by a Merck based research group determined that they stabilize
microtubules by the same mechanism as Taxol@.
46
compete for the same binding site as Taxol@.
Epithilones A and B
Eleutherobin is the most
recently isolated compound to resemble the mode of action of Taxol@, and it
47 These compounds may
too competes for the same binding site as Taxol®.
eventually join Taxol@ as chemotherapeutic compounds.
Nearly every taxane isolated has been screened for bioactivity, but no
48 When
other natural taxane matches the potency or effectiveness of Taxol@.
Taxol@ was isolated and characterized, the tetraol (108) was one of the
degradation products which exhibited 0.001 times the activity of Taxol@
(Scheme 47).35
Scheme 47: A Taxol@ degradation product, and a synthetic analogue.
HO
O
HO
OH
HO
H
OBz OAc
108
OH
0
Ph
HO" "
O
0"
t-BuO 2 CHN
OH
HO
H
OBz OAc
109, Taxotere
The major drawback of Taxol@ is its low water solubility which leads to
complications in its formulation. Several research groups have focused their
efforts on synthesizing derivatives of Taxol@ from noncytotoxic natural
product extracts. 49 The emphasis of these studies is on the synthesis of new
Bollag, D. M.; McQuency, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides,
E.; Woods, C. M. Cancer Res. 1995, 55, 2325.
46
47
Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.; Carboni, J.; Fairchild, C. R. J.
Am. Chem. Soc. 1997, 119, 8744 and references cited within.
48
Taxane Anticancer 4gents: Basic Science and Current Status: Georg, G. I.; Chen, T. T.; Ojima, I.;
Vays, D. M., Eds.: ACS Symposium Series 583; American Chemical Society: Washington, 1995.
49
(a) Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J. Nat. Prod. 1990, 53, 1. (b) Gu6ritte-
Voefelein, F.; Gu6nard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, R. J. Med. Chem. 1991,
34, 992. (c) Swindell, C. S.; Krauss, N. E. J. Med. Chem. 1991, 34, 1176. (d) Mathew, A. E.;
Chapter V: Introduction
* 53
structures with increased water solubility without a decrease in the potency or
effectiveness of the drug. Many of the Taxol@ analogues synthesized to date
contain modifications of the side chain and/or altered functional groups at
various positions. Unfortunately, most of the compounds synthesized have
little effect on microtubule assembly, the exception being the synthetic
analogue, taxotere (109) (Scheme 47).5 0 Taxotere has shown greater levels of
cytotoxic activity than Taxol@, and its water solubility is much higher than
that of Taxol@. Taxotere can be obtained in large quantities form baccatin III
and the appropriate p-lactam. 5 1 Although this analogue has met and
surpassed the challenge of Taxol@, it has yet to be approved clinically in the
United States. 5 2
5.2 Structure
Taxanes are a class of diterpene natural products that are isolated from
various Yew (taxus) species. Over 100 isolated taxane derivatives have been
shown to contain the characteristic tricyclic core structure depicted below.
Scheme 48: Taxane framework and numbering system.
7
H3 C
8
133
4
1
This structurally
challenging aspects.
congested
2H
molecule
contains several
synthetically
The A-B unit is a bicyclo[3.5.1]undecane system that
Mejillano, M. R.; Nath, J. P.; Jimes, R. H.; Stella V. J. J. Med. Chem. 1992, 35, 145. (e) Georg, G. I.;
Cheruvallath, Z. S. J. Med. Chem. 1992, 35, 4230.
50
Bissery, M.-C.; Gu6nard, D.; Gu6ritte-Voegelein, F.; Lavelle, F. CancerRes. 1991, 51, 4845.
51
0jima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. Tetrahedron Lett. 1993, 34,
4149.
52
(a) Georg, G. I.; Chen, T. T.; Ojima, I.; Vyas, D. M. Taxane Anticancer Agents: American Cancer
Society: San Diego, 1995. (b) Kingston, D. G. I.; Molinero, A. A.; Rimoldo, J. M. Progress in the
Chemistry of OrganicNatural Products61; Springer-Verlag: New York, 1993.
Chapter V: Introduction
* 54
contains a bridgehead double bond, and attached to the eight membered ring
is a trans-fused cyclohexane. These features, combined with the high degree
of oxygenation and the number of stereocenters, make taxanes extremely
challenging synthetic targets.
In addition to the intricacies of the taxane ring system, Taxol@ contains
an additional oxetane ring as well as oxygenation at C-1, C-2, C-4, C-7, C-9, and
C-10. C-13 is not only oxygenated, it has a side chain with two stereocenters.
These features have challenged the synthetic community for decades. Several
different schemes have been devised to construct the congested framework,
but only few have been rewarded with the completed total synthesis.
Taxusin (110) was isolated from the heartwood of taxus cuspidata in
1968 by Shimizu and coworkers. 53 To date, taxusin has been synthesized by
two groups but neither group has made the product in its natural form.
55
Holton 54 and coworkers synthesized taxusin's enantiomer and Kuwajima
and coworkers synthesized taxusin as its racemate.
Scheme 49: (+)-Taxusin.
AcO
OAc
H
HO""
OAc
H
Taxusin, 110
Although taxusin is one the least functionalized in the taxane family, it
contains many of the challenges encountered with the other taxanes.
In
addition to the taxane ring structure, taxusin has an exo double bond on the
53 Miyazaki, M.: Shimizu, D.; Mishima, H.; Kurabayashi, M. Chem. Pharm. Bull. 1968, 16, 546.
54
Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J.
Am. Chem. Soc. 1988, 110, 6558.
55
Hara, R.; Furukawa, T.; Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186.
* 55
Chapter V: introduction
cyclohexane ring and oxygenation at C-5, C-9, C-10 and C-13.
Although
taxusin does not exhibit bioactivity, much can be learned about the taxane
system through its synthesis.
5.3 Synthetic Strategy
With its high bioactivity and interesting structure, Taxol@ has attracted
much interest in the field of total synthesis, with four syntheses published to
date: Holton 56 , Nicolaou
57 ,
Mukaiyama5 8 and Danishefsky 59 .
Scheme 50: Disconnections of the taxane system to afford actual
intermediates used to synthesize Taxol@.
CO 2 Me
BnO
0
OTES
0
0
C
H
H
A
OBn
T. Mukaiyama
111
:
C
A
TESO
I
AB -+ ABC
BC -- ABC
B1
O,. 0
A,C -- ABC
R. Holton
112
0
0
K.C. Nicolaou
113
56
Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shimdo, M.;
Smith, C. C.: Kim, S.; Nadizadch. H.; Yukio, S.; Tao, C.; Vu, P.; Tang, S.; Shang, P.; Murthi, K. K.;
Gentile, L. N.;Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1597.
57
Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.;
Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature 1994, 367, 630.
58
Shiina, I.; Saitoh, K.; Frechard-Ortuno, I.; Mukaiyama, T. Chem. Lett. 1998, 3.
59
Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D.
K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J. J. Am. Chem.
Soc. 118, 2843.
Chapter V: Introduction
* 56
The key feature and most challenging aspect of Taxol@ is its tricyclic core.
One can envision three different disconnections to construct this tricycle (A,
B, C below). Interestingly, each of these approaches has been explored in the
various syntheses of Taxol@.
Approach A involves closure of the A ring onto the BC ring.
The
disconnection at the ring juncture double bond has an advantage over other
disconnections within the A ring because of the lack of stereochemistry at that
position and the handful of ring closures that lead to double bonds.
However, this particular cyclization also has its disadvantages as the
conformation of the B ring required for the A ring cyclization may not be
easily attained due to steric constraints.
Disconnection B involves formation of the A and C rings separately
followed by a coupling of A and C, and then cyclization to form the complete
ABC system. This strategy is the most convergent but the formation of eight
membered rings is quite difficult, and usually low yielding, and it is
undesirable to have such a questionable reaction near the end of the
synthesis.
Finally, approach C involves the synthesis of the AB unit then
tethering on the C ring. The advantage of this approach is that there are a
number of reactions that could form the C-ring.
The disadvantage is the
potential isomerization of the stereocenters located at the ring juncture. A
review of the key steps of each of the previous syntheses will show how these
advantages were exploited and how the drawbacks were addressed.
In their recent synthesis of Taxol@,
Mukaiyama and coworkers
utilized approach A to design their synthetic route around three key
cyclizations.
A samarium(II) iodide mediated cyclization of 114 was
employed, followed by functional group protection and interconversion to
Chapter V: Introduction
intermediate
give the cyclooctenone
115.
* 57
This strategy allows for
60 Selective
modification or incorporation of functional groups on the B-unit.
changes in the system may permit the synthesis of novel candidates that
could have superior water solubility when compared to Taxol@.
The next
phase of their strategy involves an intramolecular aldol cyclization of a
Michael adduct which completes the C-ring. This cyclization provides the
trans-ring system in surprisingly high yields. A pinacol coupling between the
methyl ketone and the cyclooctanone yields the complete carbocyclic
framework.
Scheme 51: Approach A: B--BC-+ABC; Employed by Mukaiyama et al.
1. Sml 2, THF -78 'C
2. Ac 2 O, DMAP
OBn
Br BnO
H
O
,O
O,
O
PMB
TBS
3. DBU, benzene
54% overall yield
PMBO
OBn
115
114
NaOMe, MeOH,
THF 0 C, 98%
PMBO
OBn
PMBO
OBn
117
116
BnO
HO
HO
0
0
TiCI 2 , LiAIH 4,
O0
THF, 35
0C,
52%
TBSO
111
60
OBn
118
Yamada, K.; Tozawa, T.; Saitoh, K.; Mukaiyama, T. Chem. Pharm. Bull. 1997, 45, 2113.
Chapter V: Introduction
* 58
Approach B was first utilized by Nicolaou and, more recently, by
Danishefsky.
Nicolaou and coworkers began their synthesis with the
construction of A and C rings, incorporating the functionalization that could
6 1 The Shapiro
withstand the conditions necessary for the B ring cyclization.
reaction was employed to couple the bottom portion of the eight membered
ring affording compound 113. Later in the synthesis, cyclization of the B ring
62
was accomplished using a McMurry coupling reaction.
Scheme 52: Approach B: A,C--ABC; employed by Nicolaou, et al.
OBn
OTBS
TPSO'
+
I
1. 119, n-BuLi, THF
-* 25
0C
2. Cool to 0
oC,
-78
0C
TPSO
OTPS OBn
H
H
"'0O
NNHSO 2Ar
SH
HO
add 120, 82%
113
120
119
O
HO
OBn
OH OBn
(TiCI3)2-(DME) 3
_H
O
Zn-Cu, DME, 70
oC
H
O
O
OO 0
YK
0
O0
O
122
121
Approach C was employed by Holton and coworkers.
Starting with
camphor they were able to synthesize compound 123 which was designed to
undergo an alcohol fragmentation
to afford the AB ring system. 6 3
Epoxidation of 123 followed by the acid catalyzed rearrangement gave 124 in
excellent overall yield.
61
The next task was the incorporation of the C-1
Nicolaou, K. C.; Hwang, C.-K.; Sorensen, E. J.; Claiborne, C. F.; J. Chem. Soc., Chem. Commun.
1992, 1117.
62
Nicolaou, K. C.; Yang, Z.; Sorensen, E. J.; Nakada, M. J. Chem. Soc., Chem. Commun. 1993, 1024.
63
Holton, R. A. J. Am. Chem. Soc. 1984, 106, 5731.
* 59
Chapter V: Introduction
hydroxyl, accomplished by treating 125 with LTMP followed by addition of
(+)-camphorsulfonyl oxaziridine.
Scheme 53: Approach C; AB--ABC; employed by Holton, et al.
OTES
1. t-BuOOH, Ti(O'Pr) 4
CH 2 C12
'OTES
OH
123
OTES
TESO""0
2. BF3-OEt 2 , CF 3SO 3 H
CH 2 C12,
93% overall yield
LTMP, - 10
124
oC
then CSO, - 40
88%
0C
HO
0
125
EtO
OTES
OTES
OH
LDA, THF,
-78 "C
TS,/
then HOAc, 84%
TESO"
O
-HH
0
TESO_'
O
OEt
H
O O
OH
O
127
112
After reduction of the C-2 ketone and protection of the diol with phosgene,
the focus then shifted to the C-ring cyclization.
This was achieved by a
Dieckmann condensation of the ethyl ester and the lactone of 112 to afford
127.64
64
Gardner, P. D.; Jaynes, G. R.; Brandon, R. L. J. Org. Chem. 1957, 22, 1206.
Synthetic Modifications
Chapter VI:
6.1 Retrosynthetic Analysis
The complexity of the taxane system lies in the formation of the ABC
ring as a complete unit. It has been shown that the individual rings can be
synthesized quite readily on their own; it is the joining of the rings that is
Outlined in
most difficult. The system is sterically crowded and congested.
Scheme 54 is our synthetic plan to obtain taxusin in its natural from. A retro
aldol reaction would open ring A of 110 leading to diketone 128.
This
particular disconnection was chosen because of work by Swindell and
coworkers that will be discussed in Chapter VIII.
Scheme 54: Retrosynthetic analysis.
O
10
9 CH 3
O
OAc
HO'
O0-
8
8
0
H3C
O
1H
3
H
/
OCH 3
129
128
Br
O
OCH 3
H
O
132
131
0
OCH 3
SOH
CH 3
130
H
Br
NO2
O
133
134
Chapter VI: Synthetic Modifications * 61
Due to the difficulty of eight membered ring cyclizations, we were interested
in opening a fused bicyclic ring system at the central bond. Of the few options
available for forming eight membered rings, we chose to form a bicyclo[6.4.0]
ring system. By connecting C-3 to C-10 in 128, the next key intermediate was
cyclobutane, 129.
Cyclobutanes are easily accessible via photochemical
reactions, so it was then a matter of which olefin precursor would present the
most straightforward target to synthesize. Disconnecting C-3 and C-10 from C8 and C-9 would afford enone-olefin 130, which could be synthesized far more
readily than the compound formed from the disconnection of C-10 and C-9
from C-3 and C-8. Photo precursor 130 is disconnected at the aryl side chain
which allows for several types of coupling reactions for its formation.
The
chiral triflate slightly resembled a rearranged and ring expanded natural
product (1S-)-(+)-camphorsulfonic acid (133). Starting with the inexpensive
enantiomerically pure compound, the synthesis was centered around the
stereochemistry already fixed at the C-1 position. The synthesis of the aryl
side chain from commercially available 1-bromo-5-nitrotoluene (134) was
designed by Dr. Paige Mahaney; its significance will be discussed in Chapter
VII. 65
6.2 Modifications to the original synthetic route
The original synthetic strategy developed by Dr. Edward Licitra was
designed to provide flexibility in the type of side chain that would be joined to
the system prior to photocyclization. Formation of the enol triflate 131 would
accommodate the desire to synthesize a diverse selection of photo precursors
by employing cuprate coupling reactions with various side chains. The target
Mahaney, P. E. Efforts Toward The Synthesis of Taxane Natural Porducts. Ph.D. Thesis, Massachusetts
Institute of Technology, Cambridge, MA, June 1996.
65
ChapterVI: Synthetic Modifications * 62
resembles
enol-triflate
(135) in Liu's synthesis of
intermediate
an
khusimone 66 and was constructed in a similar fashion. Liu's intermediate
(135) is depicted below with enol triflate 131 and the preferred aryl side chain.
Scheme 55: Liu's intermediate with synthetic intermediates 131 and 132.
0
0
CH 3O
O
0
OCH 3
OTf
H
132
131
135
The synthesis of enol triflate 131 was accomplished in eight steps starting with
67
(1S-)-(+)-camphorsulfonic acid following the scheme outlined below.
Scheme 56: Synthesis of enol triflate 131.
H
KOH, 180
oC
then HCI(aq)
76%
HO3 S
i. NaH, Benzene/Hex
ii. DMF, (COCI) 2 0 0C
HO
O
O
iii. CH 2CI 2 /THF
EtMgBr, Cul -15
80%
H
H
0C
136
R-campholenic acid
1S-(+)-camphorsulfonic acid, 133
O
RuCI3 , NalO 4,
NaHCO 3
)CH 2)2, TsOH
Benzene
94%
H
--O
CC14:H20:CH 3 CN
75%
00
0
OR
O
H
137
CH R=H, 138
R=CH 3 , 139
0
O
i. NaH, THF
ii. PhN(Tf) 2
NaH, MeOH
DMSO/THF
56%
0
68%
H
140
66
67
0
O
H
131
Liu, H.- J.; Chan. W. H. Can. J. Chem. 1979, 57, 708.
Crist, B. V.; Rodgers, S. L.; Lightner, D. A. J. Am. Chem. Soc. 1982, 104, 6040.
OTf
ChapterVI: Synthetic Modifications * 63
We felt that the original route contained numerous steps and that the
reproducibility of the oxidative cleavage of the cyclopentene 137 on a large
scale was not optimal.
Several alterations were made to make this route a
more desirable one. The first modification was the one-pot conversion of the
R-campholenic acid to ethyl ketone 136. This decreased the sequence by one
step and increased the yield by 10%. The oxidative cleavage was problematic
due to the presence of the acid labile ketal. In the procedure developed by
Sharpless and coworkers,
sodium periodate is added to catalytic ruthenium
trichloride to generate the active ruthenium tetroxide oxidizing agent. This
mixture forms an acidic solution. Therefore, the addition of several portions
of sodium bicarbonate is necessary to adjust the pH of the system which in
turn effects the performance of the ruthenium oxidation.
Potassium
but
permanganate successfully oxidized the olefin to afford the keto acid 138
in only 38% yield. After several attempts to optimize the oxidative cleavage,
we decided that a more straightforward cleavage of the ring was essential to
the success of this scheme. Employing an ozonolysis reaction would provide
the keto aldehyde 141, not the desired keto acid 138. However, the ozonolysis
was not a dead end.
It was shown by Kuwajima and coworkers that the
addition of an aryl lithium to an aldehyde in the presence of an enone could
be accomplished in good yields with the presence of equimolar amounts of
cerium trichloride. 69 After Mahaney discovered the preferred side chain was
the aryl bromide 132, the ozone cleavage reaction became attractive.
The
ozonolysis seemed to be straightforward because the molecule did not contain
any sensitive groups.
68
Several attempts at the ozonolysis gave a maximum
Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.
Seto, M.; Morihira, K.; Katagiri, S.; Furukawa, T.; Horiguchi, Y.; Kuwajima, I. Chem. Lett. 1993,
133.
69
Chapter VI: Synthetic Modifications * 64
When performed in a mixture of methanol and
yield of only 59%.
dichloromethane, the reaction resulted in a mixture of the keto aldehyde and
the compound with the aldehyde in the hemiketal form.
The hemiketal
could be converted to the keto acid, but again, the yield was not greater than
59%. Unfortunately our new approach was more difficult than we originally
expected. Although the ozonolysis yield did not surpass that of the original
cleavage, this route offered fewer steps to the target molecule.
Scheme 57: Oxidative cleavage with ozone.
0
03, Sudan Red
CH 2 C12
0
H
then Me 2S
H
59%
0
H
141
137
With the desired keto aldehyde in hand, we turn our focus to the aryl
addition previously described by Kuwajima. 69 Kuwajima's system had an
unencumbered aldehyde and a cyclic enone that was blocked by geminal dimethyls. Our system resembled that of Kuwajima's in that the aldehyde was
easily accessible, and although our ketone was blocked by geminal dimethyls,
it was only a methyl ketone.
Scheme 58: Comparison of keto-aldehyde intermediates.
H
O Ac
0
142
141
Chapter VI: Synthetic Modifications * 65
The addition of the aryl bromide was accomplished in the presence of cerium
trichloride leading to a mixture of open and closed forms of the lactols 143
and 144.
Scheme 59: Cerium mediated aryl lithium addition to aldehyde 141.
t-Bu Li, Et20, -90
CeC13 , -90 oC-
Br
Br
OCH 3
oC,
HO CH 3
'
-50 C
Aldehyde 141,
CH 3
O
OCH 3
H
66%
132
143, 144
Due to the difficulty in separation, the oxidation to the diketone was
performed on the mixture of compounds.
During the oxidation with
PCC/alumina, we discovered that only one of the isomers formed a new
product.
After isolation and purification the new product was indeed the
desired diketone 145.
Scheme 60: Lactol oxidation to diketone 145.
HO CH 3
0
PCC/Alumina
O
H
143,144
I
OCH 3
CH 2CI2, Pyridine, rt
47%
-
0
OCH3
H
145
The unreactive compound was identified as the lactol 143 and was assigned
the structure shown below. This structure is referred to as the S-isomer (the
stereochemistry at the newly formed stereocenter). Considering the anomeric
effect, the alcohol will occupy the axial position with the two bulky side
chains in the equatorial positions. NMR analysis of the CH 2 position of the
ChapterVI: Synthetic Modifications * 66
ring was consistent with two axial-axial coupling constants, and two
equatorial-axial coupling constants. The axial methyl has only one 1,3-diaxial
interaction due to the oxygen in the ring.
This lactol was unreactive to a
number of oxidation reactions, including PDC, Swern oxidation, S0 3 -pyridine
complex and silver carbonate on celite.
Scheme 61: Unreactive lactol in favorable conformation.
H
OH
CH 3
O1
O
CH 3
OMe
Stable lactol, 143
The R isomer forms a strained lactol with the aryl side chain occupying an
axial position in the chair conformation shown in Scheme 62. This instability
allows the ring to open, and in the presence of PCC/alumina the alcohol is
oxidized to the desired diketone product.
NMR analysis of the mixture
confirms a methyl ketone at 2.1 ppm.
Scheme 62: Unfavorable interaction provides equilibrium with open form.
Unfavorable 1,3diaxial interaction
MeO
O
OH
OH
H
O
CH 3
CH
CH
144
3
O
H
R
OH
3
ChapterVI: Synthetic Modifications * 67
Although the failure to oxidize the S isomer was a disappointment, we were
only one step away from the desired photo precursor.
Treatment of the
diketone with potassium hydroxide in methanol provided enone 130 in 98%
yield. With this new route, the key photo precursor was obtained in seven
steps in comparable yield to the previous nine step route.
Scheme 63: Formation of the key photo precursor 130.
0O
O
KOH/MeOH
0
OCH 3
0
980/o
0
H
145
i
H
130
OCH 3
Chapter VII:
B-Ring Formation
7.1 Previous Work
A [2+2] intramolecular photocyclization 70 between the enone and the
olefin of 146 afforded the desired tricyclic fused system 147 as well as 148
Licitra's system favored the formation of 148, the undesired
(Scheme 64).
addition product.
Scheme 64: Previous photocyclization gives a mixture of products.
S
hv,
O
H
H3C
0
147
Solvent
H3C
"
H
H
H
146
H
-
- 780C
0
o
O
Ratio of Products
148
CH2CI 2/Hex
1
7
Hexane
1
1.5
The conditions of the photocyclization reaction were optimized by Mahaney.
Mahaney's task was to design a side chain that could control olefin addition
to the top face of the enone. 6 5
methylene
to an aromatic
photocyclization.
Mahaney found that changing the exo
ring was crucial
to the success
Initial studies found the stabilization of the
of the
-radical with
an aromatic ring coupled with the more rigid conformation, favored the
addition of the olefin to the top face of the molecule. The methoxy moiety
was added to the phenyl ring in order to control the cleavage of the aryl
portion later in the synthesis. With this new side chain, exclusive formation
of cyclobutane 129 was obtained in excellent yield (Scheme 65).
70
de Mayo, P. Acc. Chem. Res. 1971, 4, 41.
Chapter VII: Oxidative Cleavage Attempts * 69
Scheme 65: Aryl system designed to give the correct addition product.
hv, Pyrex, 0
OCH 3
0C
0
Benzene/Hexane
89%
O
OCH 3
129
130
The reductive cleavage of the tricyclic fused system would lead to the
correct stereochemistry at C-8. However, the protonation at position C-3 was
unpredictable at this point, and it was believed that a mixture of cis and trans
fused products would be obtained.
After several experiments and
modifications, it was found the either the cis or the trans isomer could be
formed exclusively in excellent yields (Scheme 66).71
Scheme 66: Reductive cleavage affords cis or trans ring juncture exclusively.
Ca, NH3-THF
OCH 3
- 35 OC, quench
immediately
149
0
OCH 3
Li, NH3-THF
129
.OCH 3
- 35 'C, allow for
further reduction
150
Formation of the trans ring fused system with one equivalent of the
reducing agent was instantaneous at -30 OC in good yield.
Because small
amounts of the starting material were initially recovered, the reaction was
71
0ppolzer, W. Acc. Chem. Res. 1982, 15, 135.
Chapter VII: Oxidative Cleavage Attempts * 70
performed with excess metal. The hope was that higher yields of the trans
ring fusion product that was fully reduced to the alcohol would be isolated.
However, after oxidation of the alcohol with PCC/alumina a completely
The exclusive
different product was isolated; it was the cis fused ketone.
formation of the cis ring fusion was puzzling to us for quite some time.
However, there has been new insight which has led to a new proposed
mechanism.
7.2 New Proposed Mechanism
We have recently proposed a mechanism that accounts for the
formation of each of the ring opening products. During the metal reduction,
one electron adds to the ketone forming radical-anion 151. Cleavage of the
cyclobutane relieves the -26 kcal/mol strain of the ring, and forms an enolate
and a stabilized phenyl radical.
A second electron is added to the system
producing an anion which is protonated preferentially on the bottom face
affording the trans fused juncture, 149. With only one equivalent of reducing
agent present, the reaction stops at trans fused product 149 (Scheme 67).
Scheme 67: Reductive ring opening to exclusively afford trans ring juncture.
o
o
S
H
H
H3C
H3 C
Ca, NH 3 -THF
O
H-
35 C
H
CH 3
CH 3
Reduction then
OCH 3
O
Protonation
OCH3
"
H
152
149
Chapter VII: Oxidative Cleavage Attempts * 71
With an excess of dissolved metal, the cyclooctanone can be reduced to radical
anion 154. Once the cyclooctanone anion 154 adopts a conformation like that
shown in scheme 68, it can react intramolecularly and abstract the benzylic
hydrogen through a six-membered transition state.
This forms a stable
benzylic radical which, after further reduction, favors protonation of the top
face of the molecule, giving exclusively the cis ring fused alcohol 150.
Scheme 68: Further reduction to exclusively afford the cis ring juncture.
CH 3
CH3
H
H
OCH 3
O/O
H3 C
OCH 3
H 3C
Reduction then
*
H
H 3C
H
CH 3 0_
H3
154
H-abstraction
149
O_
OCH 3
0"
35 oC
H
CH 3 0
O
Li, NH3 -THF
Protonation
H 3C
H
OCH 3
H 3C
O_
K)
155
150
Although the epimerization of the cis system to the trans system has not been
studied, the fact that the taxane family contains the trans ring fusion makes it
likely that the stereocenter could be epimerized.
The ability to form either
ring fused product expands our reaction possiblities. The molecules have the
same functionality, but exist in different conformations.
The conformations
have an effect on the reactivity and in the following chapter, the reactions of
the trans and cis ring fused systems will be discussed.
Chapter VII: Oxidative Cleavage Attempts * 72
7.3 Oxidative Cleavage Attempts
The reductive cleavage of cyclobutane 129 proved to be a versatile
reaction, allowing the formation of either the desired trans ring fusion or the
We also considered performing an oxidative cleavage on
cis ring fusion.
cyclobutane
129 which could possibly allow for the introduction of
functionality at different areas of the B and C rings. The initial plan was to
use a Lewis acid to promote the ring opening to give a stable benzyl cation
that could lead to a styrene like compound (Scheme 69).72
Scheme 69: Proposed acid catalyzed ring opening reaction.
LA
LA
0
IH
CH3
"0
H3C
0
O
-----------------0
H
OM
e
H
OCH 3
129
156
However, the cyclobutane would not open after employing several
different Lewis acids, including boron trifluoride diethyl etherate, titanium
tetrachloride, titanium trichloride mono-isopropoxide, dimethylaluminum
chloride, as well as triflic acid and trifluoroacetic acid. Under all conditions,
starting material was either recovered or destroyed.
Using TMSC1 as the
Lewis acid, it seemed reasonable for the coordinated ketone to weaken the
ring fusion and in the presence of a strong base, facilitate abstraction of the y
hydrogen. This process would generate the desired styrene 156b.
72
Cargill, R. L.; Jackson, T. E.; Peet, N. P.; Pond, D. M. Acc. Chem. Res. 1974, 7, 106.
Chapter VII: Oxidative CleavageAttempts * 73
Scheme 70: Proposed y-hydrogen abstraction.
/MS
TMSCI
O
0 H
Proposed
y-hydrogen
abstraction
SH3C
0
O
CH3
O
HHH
H
HOCH
OCH 3
/
OCH 3
156b
129
Excess trimethylsilyl chloride was added to the ketone at -78 oC to coordinate
to the ketone before the LDA was added.
A new product began to form
within 30 minutes as the solution was warmed to 0 oC. NMR analysis of the
product did not show the presence of a styrene, nor the presence of hydrogen
adjacent to the carbonyl. Further analysis including 13C NMR revealed the
Although this
presence of a silyl enol ether exo to the cyclobutane ring.
enolization was not originally anticipated, it was intriguing that this highly
strained ring system was formed in high yield.
Scheme 71: Unexpected formation of trimethylsilyl enol ether.
0
-
OSiMe 3
H
TMSCI, THF
H3C
0
K--~
LDA, -78C
H
O
0
H3C
0
H
/
OCH 3
129
OCH 3
157
Oxidation of the benzylic position was unattainable via these oxidative
means.
It is likely that the incorporation of a functional group in the y
position could be attained earlier in the synthesis.
Chapter VIII:
A-Ring Cyclization Attempts:
8.1 Swindell's A-Ring Cyclization
In the original synthetic plan, the A ring cyclization was designed to
employ the work of Swindell and coworkers. 73 They demonstrated that the
bridged ring system could be synthesized from three different intermediates
that contained the BC-ring unit in its correct form (Scheme 72).
Scheme 72: Swindell's A-ring cyclizations.
CH 3
CH 3
1. Pd/H 2, 82%
_ H
2. KOtBu 85-90%
O
0
Et
i
H OH
159
OH
158
CH 3
tBuOOH
Triton B
80:20, 74%
KOtBu
85-90%
H
OH
160
O
AcO
OAc
OH3
C
DBU, LiCI,
H
-
Et
Ac 2 0, THF
70%
OH
H
OAc
162
161
First, they performed
an intramolecular
aldol cyclization
and
dehydration of the ethyl ketone with the cyclooctenone of 158 to afford 160.
Hydrogenation of the double bond gave the cyclooctanone and successful
aldol cyclization and dehydration gave 159. The most useful ring cyclization
73
Swindell, C. S.; Patel, B. P. J. Org. Chem. 1990, 55, 3.
Chapter VIII: A-Ring Cyclization Attempts * 75
designed was that for epoxide 161. Following the aldol cyclization, the alcohol
intermediate underwent a Payne rearrangement with the neighboring
epoxide. Subsequent elimination afforded cyclohexenone 162 with the correct
stereochemistry and functionality at C-9 and C-10.
8.2 A-Ring Cyclization Attempts with the trans-FusedRing System
Although Swindell reported three ways of obtaining the A-ring
cyclization, we were originally interested in obtaining the epoxide compound
as that would lead to the product with the correct functionalization in the Bring. The tert-butyl hydroperoxide nucleophilic epoxidation conditions
developed by Swindell were unreactive towards epoxidation of our enone
This failed reaction was troubling because our system was behaving
151.
differently than Swindell's enone 158 in this crucial first reaction. Because of
the inability to epoxidize enone 151 directly, a new method was developed to
synthesize epoxide 165 (Scheme 73).
Scheme 73: Synthesis of key epoxy-ketone 165.
CH3
CH3
LiAIH 4 , THF
.H
O
>-20 C
-78 oC --96%
H
HO
O
H
163
149
oq
o
VO(acac) 2,
t
BuOOH
CH 3
HO....
CH 20 2, 95%
H
O
1. PCC/Alumina
CH 2CI2, 94%
CH3
0
OCH
OCH 3 2. Acetone, HCI
0"
98%
H
H
H
164
165
Chapter VIII: A-Ring CyclizationAttempts * 76
Previous preparation included the reduction of enone 153 to allylic alcohol
163. Fortunately, the conformation of the cyclooctanone was such that the si
face of the carbonyl was more easily accessible to the hydride, thus, exclusively
A selective epoxidation of alcohol
forming the (-hydroxyl stereochemistry.
163 with VO(acac) 2 and tert-butyl hydroperoxide afforded epoxy alcohol 164 as
a single diastereomer.
In the previous epoxidation procedure, the mixture
was allowed to react for nine hours, and the epoxide was isolated via an
aqueous work-up. These combined factors led to a mixture of products, and
only produced the desired epoxide in 67% yield.
We found the reaction
proceeded to completion at room temperature in five minutes. The reaction
mixture
was
concentrated
and
purified
immediately
via
column
chromatography, affording the epoxide in 95% yield. None of the byproducts
formerly encountered were produced.
The previous strategy used for the
oxidation and ketal removal reactions were employed and the yields
increased from 87% and 88%/0 to 94% and 98%, respectively. The desired epoxy
diketone was synthesized in 84% overall yield form enone 153.
With epoxy diketone 165 in hand, we were prepared to attempt the
cyclization procedure developed by Swindell.
Using Swindell's conditions
(lithium chloride, acetic anhydride and DBU in THF), no reaction was
observed. Several variations in the reaction conditions were made. Changes
in concentration, temperature and varying of solvent gave no reaction.
Because Swindell and coworkers cyclized compound 158 and its saturated
version using potassium tert-butoxide as the base, we applied it to our
epoxide system.
The substrate did, in fact, react but no cyclization was
observed; NMR spectroscopy was used to identify the product, and it is
thought to be trans epoxide 166, resulting from epimerization of the
stereogenic
center
a to the ketone.
The eight membered ring can
Chapter VIII: A-Ring Cyclization Attempts * 77
accommodate the trans epoxide and after conformational analysis, it appears
to be less strained than the cis epoxide.
Scheme 74: Epimerization of the epoxide.
0
0
CH
-
3
CH
3
KtOBu, THF
H
OCH3
0"
SHOCH3
H
H
166
165
We were quite pleased with the formation of the trans epoxide as it could
possibly
accommodate
a
more
favorable
transition
state
for
the
intramolecular aldol cyclization. The conformation of the trans system could
facilitate the cyclization by allowing the side chain a less hindered approach to
the re face of the ketone (Scheme 75).
molecular modeling program.
This was displayed on Quanta, a
Several reactions were performed, but
unfortunately no cyclized products were isolated.
Scheme 75: Conformational analysis of the trans epoxide 166.
H3/
O
HI
CH3
OCH3
166
Because the B-ring of taxusin has oxygenation at C-9 and C-10, it was
proposed that dihydroxylation of enone 153 could provide a potential
candidate for the ring cyclization.
Perhaps the epoxide was not allowing
enough flexibility in the ring system, which could possibly be provided by the
Chapter VIII: A-Ring Cyclization Attempts * 78
less constrained diol. We observed the double bond was unreactive when
There was the
employing stoichiometric amounts of osmium tetroxide.
option to take the same detour used previously for the epoxidation, but in
order to differentiate the alcohols, the allylic alcohol would require protection
before the dihydroxylation.
It was worthwhile to examine the other types of systems that were
successful for Swindell (Scheme 72).
Previous attempts to cyclize
cyclooctanone 167 afforded tetracyclic fused system 168, formed from a retroMichael reaction followed by an aldol condensation.
The retro-Michael
reaction proceeds through the thermodynamic enolate of the acyclic ketone.
The energy required for the molecule to adopt the favorable conformation is
not present when the kinetic enolate is generated.
Scheme 76: Attempted cyclization leads to tetracyclic ring system 168.
H3C
CH3
,.
0
OH
KtOBu, HOtBu
OCH 3
0
""
OC H3
O.
H
H
168
167
Although the previous result was not promising, we felt it was necessary to
attempt the cyclization of the enone. Treating 149 with acid unveiled ethyl
ketone 169 in excellent yield. Treating this diketone with bases led to the
formation of several products. None of the products generated formed the
cyclized product.
If the cyclization was successful, a characteristic vinyl
methyl would be observed via spectral analysis.
Chapter VIII: A-Ring CyclizationAttempts * 79
Scheme 77: Formation of diketone 169.
_
CH 3
OCH 3
0
H
0
CH 3
0
0
HCI, Acetone
95%
OCH 3
H
0
H
H
169
149
The numerous attempts showed no signs of A-ring cyclization so our efforts
were directed toward cyclization of the system with the cis fused BC-ring
system.
8.3 A-Ring Cyclization Attempts with the cis-Fused Ring System
Failure to cyclize the A-ring was certainly disappointing, but we had
the opportunity to attempt the cyclization on the cis-fused ring system. Since
taxusin contains a trans ring fusion between rings B and C, this would require
an isomerization strategy at a later stage.
Enone 170 is more conformationally mobile than the trans-fused
enone 153 and therefore we expected it to be less hindered towards attack by
osmium tetroxide.
Indeed, a stoichiometric osmium tetroxide addition to
enone 170 proceed in tetrahydrofuran at room temperature. After reductive
work-up, a single diol isomer 171 was obtained in 72% yield. Based on the
conformation of the eight-membered ring, attack of osmium tetroxide form
the top face of enone 170 was severely sterically hindered.
The diol 171 offered a convenient one-step protection/deprotection
opportunity to expedite our synthesis.
Treatment of diol 171 with 1%
hydrochloric acid and 2,2-dimethoxypropane in acetone at room temperature
effected rapid formation of the acetonide followed by the deprotection of the
ketal. nOe Experiments were performed to confirm the stereochemisty of the
Chapter VIII: A-Ring Cyclization Attempts * 80
acetonide. Upon irradiation of the benzylic ring fused proton we observed a
4.8% nOe on the proton P to the carbonyl. Upon irradiation of the proton oc to
the carbonyl, we observed a 8.0 % nOe on the same P proton. These results
confirm the addition of the osmium tertoxide occured from the bottom face
of the molecule. The crystalline acetonide 172 was obtained in 83% yield. The
molecule was ready for investigation under aldol condensation conditions.
Scheme 78: Fromation of the cis ring fused, cis diol 171.
OH
CH
C
HO
CH 3
0
Os0 4, THF
0
O H72%
OCH 3
0
OCH 3
0
then NaHSO 3 , EtOAc
H
H
O
OH
CH 3
-
HCI, Acetone
O
OCH 3
o
O
H
171
170
HO
3
O
CH
3
0
OCH 3
83%
H
H
171
172
The conformation of this system has many desirable aspects.
The
acetonide system is unique because it has the alcohols protected but not
conformationally locked like the epoxide systems 165 and 166. The added
flexibility of this systems possibly allows the additional mobility of the
cyclooctanone ring as well as the side chain. We began the A-ring cyclization
attempts with potassium tert-butoxide in benzene at room temperature.
What we observed was believed to be the isomerization to the trans
acetonide.
This was determined by spectral analysis, including dqcosy and
dqnoesy experiments. Other efforts to cyclize the cis or trans acetonide were
Chapter VIII: A-Ring CyclizationAttempts * 81
unsuccessful. There was yet another cis ring fused compund that could not be
ignored, enone 175.
Scheme 79: Formation of the trans acetonide 173.
H3
KtOBu, HOtBu
OH3
OCH3
OCH 3
S
H
0
H
H
H
173
172
We focused our attention on cyclizing compound 175. It was readily
prepared from the deketalization reaction of ketal 174 in 81% yield.
Treatment of the diketone with potassium tert-butoxide in benzene afforded a
new product.
Scheme 80: Dekalization of ketal 174 to afford enone 175.
CH3
CH 3
"'OCH
O
O
H H
174
3
OCH 3
HCI, Acetone
81%
H
0
H
175
This product was unlike any product we observed to date. By NMR analysis,
it was obvious that the ethyl ketone was still present, but it was not until we
performed dqcosy and dqnosey experiments that we were able to determine
the product to be the Michael addition of the thermodynamic enolate to the
enone. The formation of this compound was exciting because it indicates that
the side chain ethyl ketone can in fact approach from the bottom face of the B-
Chapter VIII: A-Ring CyclizationAttempts * 82
ring for an intramolecular cyclization. It is this type of conformation that the
system needs to adopt in order to have the A-ring cyclize.
Scheme 79: Michael addition reaction.
0H
CH 3
KtOBu, benzene
0
OCH 3
CH 3
'CH
0
3
CH 3
75%
H
OCH 3
176
175
In summary,
although
attempts
to cyclize
the
A-ring
were
unsuccessful, several new and interesting products were isolated. These new
products gave insight to the conformation of the diketone system and the
strain of the bridgehead double bond.
Closing the A-ring to give the
bridgehead double bond was far more difficult a task than envisioned.
Synthesis of the epoxide system used by Swindell and co-workers was
successful, but unfortunately our system did not cyclize the A-ring after
several attempts.
The interesting cyclizations that the various molecules
underwent were fascinating and the structures were challenging to solve.
Overall, our approach to obtaining the BC unit of the taxane ring system is
quite successful.
It would be worth while to try a pinacol type coupling
employed by Mukaiyama and co-workers to cyclize the A-ring. With that type
of coupling, attaining the complete ring system would be feasible.
Experimental Procedures
General Procedures
Reaction mixtures were stirred using a magnetic stirring apparatus
unless otherwise indicated.
All moisture or air sensitive reactions were
carried out under a positive pressure of argon, and were performed in
glassware that was oven and/or flame dried. Solvents and liquid reagents
were transferred via syringe or cannula. Reactions were monitored by thin
layer chromatography as described below. Organic solvents were removed
through concentration using a Bichi rotary evaporator at 20 - 40 mmHg.
Materials
Commercial solvents and reagents
were used without further
purification with the following exceptions:
Solvents
Acetonitrile was distilled under argon from calcium hydride.
Benzene was distilled under argon from calcium hydride.
Deuteriochloroform
was stored over granular
anhydrous potassium
carbonate.
Dichloromethane was distilled under nitrogen from phosphorus pentoxide.
N,N-Diisopropylamine was distilled under nitrogen from calcium hydride.
Diethyl ether was distilled under argon from sodium benzophenone ketyl.
Hexanes were distilled under nitrogen from calcium hydride.
Hexamethylphosphoramide was distilled at low pressure.
Pyridine was distilled under argon from calcium hydride.
ExperimentalProcedures * 84
Tetrahydrofuran was distilled under argon from sodium benzophenone
ketyl.
Toluene was distilled under nitrogen from sodium.
Triethylamine was distilled under nitrogen from calcium hydride.
Reagents
t-Butyldimethylsilyl chloride was distilled under argon.
n-Butyllithium in hexanes was titrated prior to use with s-butanol in
42
tetrahydrofuran at 0 OC using 1,10 - phenanthroline as an indicator.
t-Butyllithium in pentane was titrated prior to use with s-butanol in
diethyl ether at -78 'C using 1,10 - phenanthroline as an indicator.
Lithium diisopropylamide was prepared by the addition of 2.47 M nbutyllithium (4.05 mL) to a solution of N,N-diisopropylamine (1.54 mL) in
tetrahydrofuran (4.41 mL) at -78 OC followed by warming to 0 OC.
The
molarity was determined by titration with s-butanol in tetrahydrofuran at 00C
using 1,10-phenanthroline as an indicator.
Methanesulfonyl chloride was distilled at 20 mmHg.
Trimethylsilyl chloride was distilled under argon from calcium
hydride.
Ozone was generated from a Welsbach ozone generator using the
following settings: 1.5 S.L.P.M., 90 V and 5.5 kg/cm 2 .
Chromatography
Flash column chromatography was performed using Merck 230-400
mesh silica gel. HPLC grade solvents were used.
42 Watson, S.C.; Eastham. J.F. J. Organomet. Chem. 1967, 9, 165.
Experimental Procedures * 85
Thin layer chromatography (TLC) was performed as an analytical tool
using Baker high performance precoated glass silica gel (SiO 2 , approx. 5 mm
particle size) plates (200 mm thickness). The plates were assimilated with 254
nm fluorescent indicator. The procedure used was to elute using the solvent
mixture indicated in the text, followed by an observation by illumination
with a 254 nm ultraviolet light, and staining by dipping in an ethanolic
solution of 2.5% p - anisaldehyde (3.5 % sulfuric acid and 1.0 % acetic acid)
followed by heating on a hot plate.
Instrumentation
Melting points were determined on a Fisher - Johns hot stage apparatus
and are uncorrected.
FTIR spectra were recorded on a Perkin-Elmer spectrometer equipped
with an internal polystyrene sample as a reference.
1H
NMR were recorded on either a Varian Gemini 300 MHz
spectrometer, a Varian XL 300 MHz spectrometer, a Varian Unity 300 MHz
spectrometer or a Varian VXR 500 MHz spectrometer.
Chemical shifts are
reported as 8 in units of parts per million (ppm) downfield from
tetramethylsilane (8 0.0) using the residual chloroform signal (6 7.26) or
benzene signal (8 7.16) as a standard.
following abbreviations:
Multiplicities are reported in the
s (singlet), d (doublet), t (triplet), q (quartet), qnt
(quintet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of
doublets), etc.
13C NMR were recorded on a Varian 300 NMR at 75 MHz or a Varian
VXR 500 NMR at 125 MHz. The deuteriochloroform signal (8 77.0) was used
as a standard.
Experimental Procedures * 86
Optical rotations were determined using a Perkin-Elmer 241
polarimeter using a sodium lamp (D line) at 23 0C.
Mass spectra and high resolution mass spectra (HRMS) were recorded
on a Finnigan MAT System 8200, double focusing, magnetic sector, mass
spectrometer. The spectra were recorded using either electron impact (EI),
generating (M++1). Spectra were recorded in units of mass to charge (m/e).
Experimental Procedures * 87
0CH3
i. 10 equiv. Et3 N: THF-Hexane
H3 1.0 equiv. TBSCI, 0 °-- 23 0C
O
CH 3
TBSO
OTBS
ii. 1.0 equiv. TBSOTf,
-78 oC - 0 oC
87%
O
34
33
O
O
TBSO
OCH 3
OH
CH3
____
Toluene, rt
88%
OTBS
\
TBSO
&X
OTBS
enod:exo [3: 1]
33
32, 35
Methyl esters 32 and 35
A 200 mL round-bottomed flask containing 2-methyl-1,3-cyclopentanedione
(34) (2.59 g, 23.1 mmoles) under argon was charged with tetrahydrofuran (40
mL) and triethylamine (32 mL).
Once the starting material was completely
dissolved, hexane (100 mL) was added. t-Butyldimethylsilyl chloride (3.6 g, 1
equiv.) was added at rt and triethylamine-hydrochloride began to precipitate
immediately. After 20 min the reaction was filtered under argon and rinsed
with hexane (3 X 20 mL).
The solute was then cooled to -78 oC.
t-
Butyldimethylsilyl trifluoromethanesulfonate (5.16 mL, 1.05 equiv.) was
added to the solution and the reaction mixture was slowly warmed to 0 oC.
The reaction was left for ca. 1h. The triethylamine-trifluoromethanesulfonic
acid was not soluble in the reaction media and formed a separate, more dense
layer. The reaction was quenched by slowly pouring the mixture into a 1 L
separatory funnel containing ice cold water (500 mL) containing sodium
bicarbonate (3.0 g).
The product was extracted with a 10% ether/hexane
solution (3 X 125 mL) then dried over magnesium sulfate. Removal of the
solvent afforded bis-silyloxydiene, 33, as a white crystalline solid, (6.84 g) in
ExperimentalProcedures * 88
87% yield.
The crude diene was used without further purification.
The
spectroscopic properties were identical to that described previously. 15
A 200 mL round-bottomed flask containing bis-silyloxydiene 33 (6.84 g, 20.1
mmoles) under argon was charged with toluene (50 mL) and cooled to 0 'C.
Methyl acrylate (5.61 mL, 3.1 equiv.) was added and the solution was slowly
warmed to rt with stirring overnight.
The toluene was removed under
reduced pressure and the product was purified by column chromatography
(3% ethyl acetate/2% triethylamine/95% hexane).
The reaction afforded
Diels-Alder products 32 and 35 (7.50 g) as a mixture of diastereomers in a 3:1
(endo:exo) ratio in 88% overall yield.
carried on to the next step.
The mixture of diastereomers was
oo
00
0
\Al
U)
O
m
rn
E
ExperimentalProcedures * 89
-
F
r
F-
Ii
I-
K
t
n
ExperimentalProcedures * 90
0
CH 2 OH
OCH 3
TBSO
\
CH 3
OTBS
LiAIH 4, THF
-78 oC -, 0 C
TBSO
\
CH 3
OTBS
90%
36,37
(based on recovered
starting material)
endo:exo [3 : 1]
32, 35
Alcohol mixture 36 and 37:
A 500 mL round-bottomed flask containing a mixture of methyl esters 32 and
35 (7.41 g, 17.3 mmoles) under argon was charged with diethyl ether (200 mL).
The solution was cooled to -65 'C and a thermocouple thermometer was
inserted into the reaction media to monitor the temperature.
Lithium
aluminum hydride (0.58 equiv., 1 M solution) was added in 1 mL portions to
avoid large increases in temperature. Because a byproduct appeared on thin
layer chromatography, the reaction was quenched following the procedure in
Fieser and Fieser 74 : 1 mL water was added followed by 1 mL water with 0.05 g
Once the reaction mixture
sodium hydroxide followed by 3 mL water.
warmed to rt the solution was dried over magnesium sulfate, filtered and
concentrated. The product was purified by column chromatography (5% ethyl
acetate/1%
triethylamine/94%
hexane
-
10%
ethyl
acetate/1%
triethylamine/89% hexane) affording alcohols 36 and 37 (4.91 g) in 71% yield
(90% based on recovered starting material) and starting material ester 32 and
35 (1.39 g) in 19% yield. The spectroscopic properties were identical to that
described previously.15
74
Fieser, L. F., Feiser, M.; In Reagentsfor Organic Synthesis; John Wiley and sons, Inc.: New York,
1967, Vol. 1, 584.
Experimental Procedures * 91
H 2C
BSO
H 2C
CH 3
h
(CH 20H) 2, TsOH
Benzene,
77 %
(90% based on
45
recovered enone)
CH
TBSO
reflux
O
CH 2
CH 3
3
O
0
0
L/O
46
50
Ketal 46:
A 100 mL round-bottomed flask containing enone 45 (1.09 g, 3.9 mmoles) was
charged with benzene (50 mL). Ethylene glycol (10 mL, ca. 50 equiv.) and ptoluenesulfonic acid (10 mg, cat.) were added and the solution was heated to
reflux for 3 h. The reaction was cooled to rt and was quenched by the addition
of a saturated solution of sodium bicarbonate (10 mL).
The organics were
removed under reduced pressure and the aqueous phase was extracted with
diethyl ether (3 X 25 mL).
The combined organics were dried over
magnesium sulfate and concentrated.
The product was purified by column
chromatography (2'%, ethyl acetate/hexane-- 5% ethyl acetate/hexane),
affording ketal 46 (0.97 g) in 77% yield and starting material (159 mg) in 15%
yield. Rf 0.60 (30% ethyl acetate/hexane).
If the experiment was exposed to
acid for extended periods of time, rearranged product 50 would be generated.
15
The spectroscopic properties were identical to that described previously.
c
0
O
0j
ExperimentalProcedures * 92
r
----
1*
V
i-
7-
I-
C-)
Experimental Procedures * 93
I
S O
17
!
L
I
rHW
-
IL
IFtzt (I
19
ExperimentalProcedures * 95
O
0
N2
CH 3
3
TBSO
TrisN3 , Ben.
60 % KOH-H 20
CH
TBSO
3
phase tran. cat.
.
On
O
65%
O
30
31
o-Diazoketone 30:
A 10 mL round-bottomed flask containing ketone 31 (40 mg, 0.12 mmoles)
under argon was charged with benzene (2 mL).
Tetra-nbutylammonium
bromide (37 mg, 10 equiv.), 18-crown-6 (6 mg, 0.2 equiv.) and trisyl azide (71
mg, 2 equiv.) was added followed by the addition of saturated aqueous
potassium hydroxide (2 mL).
After 5 min, it was apparent by thin layer
chromatography that the addition of the azide was complete, as the starting
material was no longer visible and there was a new bright pink spot.
The
reaction was stirred vigorously for 8 h. After the bright pink spot changed to a
more orange color the reaction was quenched by the addition of a saturated
solution of sodium bicarbonate (10 mL).
The organics were removed under
reduced pressure and the aqueous phase was extracted with diethyl ether (3 X
5 mL).
The combined organics were dried over magnesium sulfate and
concentrated.
The product was purified by column chromatography (20%
ethyl acetate/hexane).
uo-Diazoketone 30 (29 mg) was obtained in 65% yield.
Rf0.19 (20% ethyl acetate/hexane).
1H
NMR (300 MHz, CDCl 3 ) 6 5.17 (qnt, 1H,
J=1.4 Hz), 4.13-3.94 (m, 4H), 3.29 (dd, 1H, J=2.5, 4.8 Hz), 2.37 (dd, 1H, J=0.98, 10.8
Hz), 1.77 (d, 1H, J=1.6 Hz), 0.90 (s, 9H), 0.18 (s, 3H), 0.05 (s, 3H). Analysis
calculated for C17H2 6 N 20 4 Si: C 58.26%; H 7.48%. Found: C 58.36%; H 7.81%.
0
r77-
Experimental Pr-ocedures
-
~i--r~r
-
96
E
cl
cl
e-.
-2
z
I
~C
N
o
0
ExperimentalProcedures * 97
zI
"
oj 1
O=~i~=O
-
"
Si
I--,,-liE
Experimental Procedures * 98
C-D
-U-
ExperimentalProcedures * 99
0
C02CH 3
CH 3
TBSO
O
0
0 C hv
O
CH 2C1 2 , MeOH
O
95%
30
CH 3
TBS
57, 58
1.5:1 endo:exo
Methyl esters 57 and 58:
c-Diazoketone 30 (265 mg, 0.752 mmoles) was transferred into a 250 mL Pyrex
well with dichloromethane (ca. 5 mL). A 450 watt medium-pressure ConradHanovia immersion lamp was placed into the Pyrex immersion well with a
cooling system separating the reaction mixture from the light source.
container was evacuated and purged with argon, three times.
The
Anhydrous
methanol (100 mL) and dichloromethane (100 mL) were added.
The
apparatus was placed into an ice bath and cooled to 0 oC. The system was
attached to an oil bubbler to allow for the escape of argon and nitrogen
generated during the reaction. Argon was bubbled through the solution for
30 min prior to the start of the reaction to remove any dissolved oxygen in
the solvents. The reaction was irradiated for 1 h. The solution was added to a
500 mL round-bottomed flask and concentrated. The product was purified by
column chromatography (SiO 2 , 20% ethyl acetate/Hexane) to give a mixture
of isomers 57 and 58 (275 mg) in 95% yield.
exo Ester 58: Rf 0.59 (40% ethyl acetate/hexane).
FTIR (thin film, cm- 1 ) 2953,
2985, 2858, 1734, 1462, 1437, 1361, 1340, 1288, 1211, 1145, 1091, 1022, 970, 887, 837,
777, 676.
1H
NMR (300 MHz, CDC13 ) 8 5.14 (sept., 1H, J=1.2 Hz) 4.00-3.90 (m,
4H, ketal), 3.71 (s, 3H), 3.21 (d, 1H, J=5.5 Hz), 2.99 (t, 1H, J=8.0 Hz), 2.68 (dd, 1H,
J=2.4, 7.4 Hz), 2.21 (dd, 1H, J=5.8, 8.2 Hz), 1.82 (d, 1H, J=1.2 Hz), 0.88 (s, 9H), 0.08
ExperimentalProcedures * 100
(s, 3H), 0.04 (s, 3H).
13 C
NMR (75 MHz, CDC13 ) 8 171.0, 155.6, 117.5, 110.2, 64.8,
60.6, 51.6, 44.1, 36.7, 25.7, 18.2, 17.9, 2.7, -3.0.
endo Ester 57: Rf 0.52 (40% ethyl acetate/hexane).
1H
NMR (300 MHz, CDC13)
8 5.07 (td, 1H, J=1.5, 3.0 Hz) 4.07-3.95 (m, 4H, ketal), 3.64 (s, 3H), 3.21 (d, 1H,
J=7.3 Hz), 2.76 (dt, 1H, J=3.0, 6.9 Hz), 2.16 (dd, 1H, J=6.7, 8.2 Hz), 2.11 (d, 1H,
J=8.2 Hz), 1.86 (d, 1H, J=1.5 Hz), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
0
C1-
II
Ln"
LA,
II
Sr-
Ir
'
m
,F
Experimental Procedures • 101
o
O~
Sr
I-
I
i-
--,
OOL
0
-r
m
C
L
FoJ
K
1-.
Experimental Procedures * 102
-I
r
F
L
ExperimentalProcedures * 103
OH 3
TBSO
\
O
C0 2CH
BnO
CO2CH 3
H3
O
LDA, THF-HMPA
3
-20 oC
then BOMCI
O
-78 oC
endo: 70%, exo: 66%
59
57, 58
Cyclobutyl ester 59:
A 50 mL round-bottomed flask containing ester 57 (189 mg, 0.49 mmoles)
under argon was charged with tetrahydrofuran (4 mL) and the solution was
cooled to -78 'C.
Hexamethylphosphoramide (30 [tL, 4 equiv.) was added
followed by the addition of lithium diisopropylamide (90 tL, 2 equiv.). The
reaction was slowly warmed to -45 'C over 45 min The reaction was recooled
to -78 'C, benzyloxymethyl chloride (12 jiL, 2 equiv.) was added and the
mixture was slowly warmed to 0 oC. After no starting material was visible via
thin layer chromatography, the reaction was quenched by the addition of a
saturated solution of sodium bicarbonate (2 mL). The organics were removed
under reduced pressure and the aqueous phase was extracted with diethyl
ether (3 X 10 mL).
The combined organics were dried over magnesium
sulfate and concentrated.
The product
was purified
by column
chromatography (20% ethyl acetate/1% triethylamine/79% hexane).
The
alkylated product 59 (175 mg) was obtained in 70% yield. Rf 0.58 (45% ethyl
acetate/hexane). FTIR (thin film, cm-1) 2951, 2856, 1745, 1436, 1343, 1309, 1238,
1201, 1115, 1090, 1022, 898, 836, 773, 698.
1H
NMR (300 MHz, CDC13 ) 8 7.40-7.20
(m, 5H), 5.10 (s, 1H), 4.63 (d, 1H, J=12.4 Hz), 4.43 (d, 1H, J=12.4 Hz), 4.06-3.82 (m,
4H), 3.80 (s, 2H), 3.63 (s, 3H), 2.59 (dd, 1H, J=2.8, 7.4 Hz), 2.44 (dd, 1H, J=8.1, 8.2
Hz), 2.14 (d, 1H, J=2.1 Hz), 1.86 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H).
1 3C
NMR (125
ExperimentalProcedures * 104
MHz, CDC13 ) 8 171.9, 155.2, 138.0, 128.3, 127.8, 127.6, 116.8, 109.7, 73.4, 70.7, 66.4,
65.5, 63.9, 51.1, 42.8, 41.8, 25.9, 18.8, 18.3, -2.3, -3.0.
0
0
OO
c
OO
c
-
0
i
C71
cl
0
r
fn
L (D
-t
-j
•10
Experimental Procedures * 105
J
ExprienaIProedre
- -
~i~,
i
7_ N
Id
____
-
rE
106
!l
TuL
g
;iL
~c
---
-c
-- ~---------
--
j
i'
i
Experimental Procedures
_____ ____
----
-
Experimental Procedures * 107
BnO
CO2CH 3
TBSO
CH 3
DiBAI-H, -30 C
Hexane, 99%
BnO
OH
TBSO
CH 3
O
O
O
O
61
59
Alcohol 61:
A 25 mL round-bottomed flask containing alkylated ester 59 (175 mg, 0.347
mmoles) under argon was charged with hexane (10 mL). This solution was
cooled to -78 'C then diisobutylaluminum hydride (1.75 mL, 5 equiv., 1 M)
was added dropwise. The reaction was slowly warmed to -30 'C for 15 min
and was then quenched by the addition of ca. 0.5 mL glacial acetic acid and a
saturated solution of sodium bicarbonate (3 mL). A drop of triethylamine was
added to avoid removal of the ketal.
The layers were separated and the
aqueous phase was extracted with a 30% ethyl acetate/hexane solution
containing a small amount of triethylamine.
The combined organics were
dried over magnesium sulfate and concentrated. The product was purified by
column chromatography (20% ethyl acetate/ 1% triethylamine/79% hexane)
affording
alcohol
61 (163 mg) in 99% yield.
ether/dichloromethane).
1H
Rf 0.2
(4%
diethyl
NMR (300 MHz, CDC13 ) 8 7.32 (m, 5H), 5.27 (t,
1H, J=1.5 Hz), 4.65 (d, 1H, J=11.7 Hz), 4.52 (d, 1H, J=12.2 Hz), 3.80 (m, 8H), 2.65 (t,
1H, J=8.1 Hz), 2.37 (dt, 2H, J=4.2, 7.4 Hz), 2.09 (d, 1H, J=8.8 Hz), 1.78 (s, 3H), 0.84
(s, 9H), 0.05 (s, 3H), 0.02 (s, 3H).
0
0
O
CI
--
0
0
ExperimentalProcedures * 108
(D
ExperimentalProcedures * 109
H
AcO
OH
BnO
TBSO
I
OAc
OAc
O
BnO
facile
CH 3 rearrangement
0
CH 3
TBSO
O
O
O
(Dess-Martin
reagent)
O
0
,
CH 3
o-
O
61
O
BnO
OTBS
64
63
Claisen product 64:
A 25 mL round-bottomed flask containing alcohol 61 (56 mg, 0.12 mmoles)
under argon was charged with dichloromethane (6 mL). Pyridine (0.37 itL)
was added followed by the Dess-Martin reagent (102 mg, 2.1 equiv.).
The
solution was stirred for 1.5 h. after which time starting material was no longer
visible via thin layer chromatography.
The reaction was filtered through a
plug of silica gel and magnesium sulfate and thoroughly rinsed with ether.
After concentration, NMR analysis of the crude product showed a mixture of
two compounds: aldehyde 63 and retro-Claisen product 64. At rt the aldehyde
readily converted to the rearranged product (47 mg, 85% yield). Each of the
products are characterized below.
Aldehyde 63: Rf 0.34 (30% ethyl acetate/hexane).
1H
NMR (300 MHz, CDC13 )
8 9.88 (s, 1H), 7.32 (m, 5H), 5.13 (dd, 1H, J=1.5, 2.9 Hz), 4.57 (d, 1H, J=12.2 Hz),
4.42 (d, 1H, J=12.2 Hz), 4.06-3.82 (m, 4H), 2.81 (dd, 1H, J=2.9, 7.3 Hz), 2.52 (dd,
1H, J=7.8, 8.8 Hz), 2.14 (d, 1H, J=9.3 Hz), 1.77 (d, 3H, J=2.0 Hz), 0.85 (s, 9H), 0.018
(s, 3H), 0.014 (s, 3H).
Claisen rearrangement 64: Rf0.34 (30% ethyl acetate/hexane).
1H
NMR (300
MHz, CDC13 ) 6 7.32 (m, 5H), 6.26 (s, 1H), 4.50 (d, 1H, J=11.7 Hz), 4.34 (d, 1H,
J=11.2 Hz), 4.05 (m, 7H), 3.86 (d, 1H, J=12.2 Hz), 2.62 (ddd, 1H, J=2.2, 4.6, 16.4
Hz), 2.38 (td, 1H, J=2.3, 4.6 Hz), 2.25 (td, 1H, J=1.5, 16.6 Hz), 1.69 (t, 1H, J=2.0 Hz),
0.92 (s, 9H), 0.095 (s, 3H), 0.086 (s, 3H).
C.)
O'
Oc
mf
Experimental Procedures * 110
ExperimentalProcedures * 111
O
O
BnO
OCH 3
TBSO
CH 3
HCI, Acetone
BnO
OCH 3
TBSO
CH 3
98%
o
O
59
66
Keto ester 66:
A 10 mL round-bottomed flask containing alkylated ester 59 (25 mg, 0.049
mmoles) was charged with acetone (2 mL). Hydrochloric acid (1 drop, conc.)
was added at rt and after 2 min was quenched by the addition of a saturated
solution of sodium bicarbonate (2 mL).
The organics were removed under
reduced pressure and the aqueous phase was extracted with diethyl ether (3 X
4 mL).
The combined organics were dried over magnesium sulfate and
concentrated.
The product was purified by column chromatography (SiO 2 ,
30% ethyl acetate/hexane) affording alcohol 66 (23 mg) in 98% yield. Rf 0.52
(30% ether/hexane).
FTIR (thin film, cm- 1 ) 2953, 2930, 2858, 1738, 1696, 1454,
1434, 1361, 1257, 1234, 1206, 1131, 1008, 896, 836, 776, 699.
1H
NMR (300 MHz,
CDC13 ) 6 7.38-7.17 (m, 5H, phenyl), 5.55 (t, 1H, J=1.3 Hz) 4.58 (d, 1H, J=12.2 Hz),
4.49 (d, 1H, j=12.1 Hz), 3.90 (d, 1H, J=9.9 Hz), 3.84 (d, 1H, J=9.8 Hz), 3.61 (s, 3H),
3.18 (dd, 1H, J=2.3, 7.3 Hz), 2.73 (dd, 1H, J=8.0, 8.1 Hz), 2.42 (d, 1H, J=9.0 Hz), 1.97
(s, 3H), 0.92 (s, 9H), 0.086 (s, 3H), 0.072 (s, 3H). 13C NMR (125 MHz, CDC13 ) 5
199.9, 172.5, 172.2, 137.5, 128.4, 128.4, 127.8, 127.8, 119.7, 78.6, 73.5, 71.4, 69.4, 66.1,
51.7, 47.0, 46.4, 25.8, 25.8, 25.8, 19.3, 18.3, -2.4, -3.0.
o
I
O
O
I C3
O
0
11
Experimental Procedures * 112
ExpeimenaI Pocedres
5
r
c
r
tT
ExperimentalProcedures * 113
BnO
OCH 3
TBSO
CH 3
OCH 3
BnO
LDA, TBSOTf
TBSO
THF
O
OTBS
66
67
Silyl dienol ether 67:
A 25 mL round-bottomed flask containing enone-methyl ester 66 (27 mg,
0.063 mmoles) was charged with THF (5 mL) under argon. The solution was
cooled to -78 "C and TBSOTf (21 kL, 1.5 equiv.) was added followed by the
addition of LDA (94
tL, 1.5 equiv.).
After five minutes, only partial
conversion was detected by thin layer chromatography, so additional TBSOTf
(21 gL, 1.5 equiv.) and LDA (94 pL, 1.5 equiv.) were added. When the starting
material was no longer visible via thin layer chromatography the reaction
was quenched by the addition of a saturated solution of sodium bicarbonate.
The organics were removed under reduced pressure and the aqueous phase
was extracted with ether (3 X 20 mL portions). The combined organics were
dried over magnesium sulfate and concentrated, affording the mono-silyloxy
diene product 67.
The product was used in the next step without further
purification. Rf0.72 (30"%ethyl acetate/hexane).
FTIR (thin film, cm
- 1)
2954,
2930, 2857, 1740, 1633, 1608, 1472, 1351, 1314, 1254, 1198, 1121, 1006, 973, 892, 870,
838, 779, 745, 698.
1H
NMR (500 MHz, C6 D 6 ) 6 7.25-7.02 (m, 5H), 5.40 (d, 1H,
J=3.0 Hz), 5.17 (d, 1H, J=1.5 Hz), 4.80 (d, 1H, J=1.4 Hz), 4.40 (d, 1H, J=12.2 Hz),
4.32 (d, 1H, J=12.2 Hz), 4.10 (d, 1H, J=9.8 Hz), 3.90 (d, 1H, J=10.1 Hz), 3.39 (s, 3H),
2.93 (dd, 1H, J=2.8, 6.7 Hz), 2.41 (t, 1H, J=7.5 Hz), 2.01 (d, 1H, J=8.2 Hz), 1.01 (s,
9H), 0.99 (s, 9H), 0.30 (s, 3H), 0.24 (s, 3H), 0.07 (s, 3H), 0.00 (s, 3H).
1 3C
NMR (125
Experimental Procedures * 114
MHz, CDC13 ) 8 172.3, 164.8, 148.7, 139.0, 127.9, 127.8, 127.6, 103.0, 102.5, 80.5, 73.9,
71.4, 66.7, 51.5, 42.9, 39.8, 26.6, 26.2, 19.0, 18.6, -2.0, -2.3, -3.9, -4.0.
O
0
Experimental Procedures * 115
0
-.----
al
sa*1
6'S
Ar-t
L.8"
ExperimentalProcedures * 116
0
O
OCH 3 DiBAI-H, -78 C
BnO BnO
Toluene/Hexane
51% (based on
recovered 67)
TBSO
H
BnO
BnO
TBSO
OTBS
OTBS
68
67
Aldehyde 68:
A 10 mL round-bottomed flask containing crude methyl ester 67 (14 mg, 0.026
mmoles) was charged with hexane (1 mL) and THF (1 mL) under argon. The
solution was cooled to -78 'C and DIBAL (40 iL, 1.5 equiv.) was slowly added
dropwise along the side of the flask. After 30 min the reaction was quenched
by the addition of a solution of glacial acetic acid (0.1 mL) in hexane (1 mL).
After 5 min, a saturated solution of sodium bicarbonate (3 mL) was added.
The organics were removed under reduced pressure and the aqueous phase
was extracted with ether (3 X 5 mL portions). The combined organics were
dried over magnesium sulfate and concentrated.
The product was purified
via column chromatography (SiO 2 , 3% ethyl acetate/1% triethylamine/96%
hexane) affording aldehyde 68 (2 mg) in 18% yield (51% based on recovered
starting material) and starting material methyl ester 67 (9.3 mg) in 65% yield.
Rf 0.42 (5% ethyl acetate/hexane).
1H
NMR (300 MHz, CDC13 ) 8 9.52 (s. 1H),
7.31 (m,5H), 5.22 (d, 1H, J=2.8 Hz), 4.94 (d, 1H, J=1.3 Hz), 4.63 (s, 1H), 4.56 (d,
1H, J=11.9 Hz), 4.43 (d, 1H, J=11.9 Hz), 3.95 (d, 1H, J=10.1 Hz), 3.79 (s, 1H, J=10.1
Hz), 2.69 (dd, 1H, J=2.8, 6.7 Hz), 2.56 (t, 1H, J=7.5 Hz), 1.99 (d, 1H, J=8.2 Hz), 0.94
(s, 9H), 0.90 (s, 9H), 0.21 (s, 6H), 0.04 (s, 6H).
udci
I
I
I
I[t~~
I
I
I
I
i
I~i
t
I II
2/
I I
99
-osei
oug
Experimental Procedures * 118
OOH
BnO
H
HF aq., 0 0C
BnO
CH 3CN/H 20
TBSO
TBSO
H
34%
OTBS
69, 70
68
Aldol Products 69 and 70:
A 10 mL round-bottomed flask containing aldehyde 68 (4 mg, 0.007
mmoles) was charged with acetonitrile (1 mL) and distilled water (1 mL)
under argon. The solution was cooled to 0 'C and a 5% solution (1.5 mL)
containing hydrofluoric acid (aq.) in acetonitrile was added.
Additional
portions of the HF solution (2 mL) was added until the starting material was
no longer visible via thin layer chromatography. The reaction was quenched
by the addition of a saturated solution of sodium bicarbonate (1 mL). The
organics were removed under reduced pressure and the aqueous phase was
extracted with ether (3 X 5 mL portions). The combined organics were dried
over magnesium sulfate and concentrated.
The product was purified via
column chromatography (SiO 2 , 20% ethyl acetate/hexane) affording the
Mukaiyama aldol products 69 and 70 as a mixture of diastereomers (1 mg) in
34% yield.
Rf0.40 (30% ethyl acetate/hexane).
FTIR (mixture of
diastereomers) (thin film, cm -1) 3434, 2930, 2858, 1754, 1255, 1198, 1096, 1023,
896, 837, 774. Major isomer(70):
1H
NMR (300 MHz, CDC13 ) 8 7.38-7.27 (m,
5H), 5.23 (s, 1H), 4.59 (d, 1H, J=11.9 Hz), 4.54 (d, 1H, J=11.9 Hz), 4.15 (dd, 1H,
J=2.0, 9.0 Hz), 3.88 (d, 1H, J=10.4 Hz), 3.82 (d, 1H, J=10.4 Hz), 3.23 (t, 1H, J=2.0
Hz), 2.75 (t, 1H, J=9.5 Hz), 2.59 (dd, 1H, J=2.1, 9.4 Hz), 2.01 (d, 1H, J=8.9 Hz), 2.01
(d, 1H, J=9.8 Hz), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s. 3H).
Experimental Procedures * 119
Minor isomer(69):
1H
NMR (300 MHz, CDC13 ) 8 7.38-7.27 (m, 5H), 5.01 (s, 1H),
4.99 (s, 1H), 4.59 (d, 1H, J=11.9 Hz), 4.54 (d, 1H, 1=11.9 Hz), 3.99 (d, 1H, J=9.9 Hz),
3.91 (d, 1H, J=9.8 Hz), 3.21 (s, 1H), 2.70 (t, 1H, J=9.6 Hz), 2.60 (dd, 1H, J=1.8, 10.7
Hz), 2.03 (d, 1H, J=9.8 Hz), 2.01 (d, 1H, J=9.6 Hz), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 (s,
3H).
Experimental Procedures * 120
L '
899 L
cc-s
Experimental Procedures * 121
BnO
OCH 3
TBSO
CH 3
HMPA, EtSLi
rt, 3 d
O
'OH
BnO
O
CH 3
TBSO
O
0
75
59
Cyclobutyl carboxylic acid 75:
A 10 mL round-bottomed flask containing ester 59 (26 mg, 0.055 mmoles) was
charged with HMPA (2 mL).
A solution of ethyl mercapto lithium (0.5 M)
was prepared in HMPA and 1 mL was added to the mixture. The solution
was heated to 50 'C for 30 min
The solution was cooled to rt then was
quenched by the addition of a saturated solution of sodium bicarbonate (2
mL).
The organics were removed under reduced pressure and the aqueous
phase was extracted with 10 % diethyl ether/hexane (3 X 4 mL).
The
combined organics were dried over magnesium sulfate and concentrated
affording acid 75.
purification.
The product was used in the next step without further
ExperimentalProcedures * 122
CH 3
TBSO
OH
BnO
OH
BnO
CH 3 SO 3 H
CH 3
TBSO
BnO
TBSO
CH3
o5'
o7
CH 2012
76
71
75
Lactone 76:
A 10 mL round-bottomed flask containing crude acid 75 (17 mg, 0.037
mmoles) was charged with dichloromethane (5 mL). Methane sulfonic acid
(20 tL) was added at 0 oC and after 2 min was quenched by the addition of a
saturated solution of sodium bicarbonate (2 mL). The organics were removed
under reduced pressure and the aqueous phase was extracted with diethyl
ether (3 X 4 mL). The combined organics were dried over magnesium sulfate
and concentrated.
The product was purified by column chromatography
(SiO 2 , 20% ethyl acetate/hexane) affording lactone 76 (6 mg) in 22% yield (2
steps). Rf 0.47 (30%/ ethyl acetate/hexane).
1H
NMR (300 MHz, CDC13 ) 6 7.33
(m, 5H), 4.59 (d, 1H, J=11.5 Hz), 4.53 (d, 1H, J=11.5 Hz), 4.04-3.75 (m, 4H), 3.91 (d,
1H, J=9.9 Hz), 3.78 (d, 1H, J=9.9 Hz), 2.83 (d, 1H, J=7.0 Hz), 2.65 (dd, 1H, J=7.4,
10.2 Hz), 2.33 (d, 1H, J=14.7 Hz), 2.19 (d, 1H, J=14.4 Hz), 1.97 (d, 1H, J=10.3 Hz),
1.43 (s, 3H), 0.86 (s, 9H), 0.096 (s, 3H), 0.065 (s. 3H).
-
h
Experimental Procedures * 123
r
L
r
'-"
r
ivt
ExperimentalProcedures * 124
BnO'
TBSO
CH 3
DiBAI-H, CH 2CI 2 I
U
CH 3
-78 °C
O
O
79
78
Lactol 79:
A 5 mL round-bottomed flask containing lactone 78 (6 mg, 0.011 mmoles) was
charged with dichloromethane (2 mL) under argon. The solution was cooled
to -78 'C and DIBAL (24 jtL, 2 equiv.) was slowly added dropwise along the
side of the flask. After 5 min the reaction was quenched by the addition of a
solution of glacial acetic acid (0.1 mL) in diethyl ether (1 mL). After 5 min, a
saturated solution of sodium bicarbonate (3 mL) was added.
The organics
were removed under reduced pressure and the aqueous phase was extracted
with ether (3 X 5 mL portions).
The combined organics were dried over
magnesium sulfate and concentrated.
The product was purified via column
chromatography (SiO 2 , 50% ethyl acetate/hexane) affording lactol 79 (3 mg) in
50% yield (100% based on recovered starting material), and lactone 78 (3 mg)
in 50% yield.
1H
NMR (300 MHz, CDC13 ) 6 7.33 (m, 5H), 5.91 (d, 1H, J=12.8 Hz),
5.15 (d, 1H, J=12.8 Hz), 4.55 (s, 2H), 4.15-3.60 (m, 4H), 3.70 (d, 1H, J=9.8 Hz), 3.60
(d, 1H, J=10.1 Hz), 2.60 (d, 1H, J=7.6 Hz), 2.42 (dd, 1H, J=7.6, 9.8 Hz), 2.30 (d, 1H,
J=13.8 Hz), 2.26 (d, 1H, J=13.8 Hz), 1.821 (d, 1H, J=10.1 Hz), 0.86 (s, 9H), 0.061 (s,
3H), 0.033 (s, 3H).
--
I©
I
00
"1
Experimental Procedures
"--',,.
125
Cs*4
-S'2
"
er
Cs"
si
u6.C
93.
ExperimentalProcedures * 126
O
HO
0
OH
trans-glutaconic acid
12 h.
89%
0
O
H2 S0 4 , MeOH, A
H3 CO
OCH 3
84
Dimethyl Glutaconate (84):
Trans-glutaconic acid (25.0 g, 192 mmoles) was added to a 250 mL roundbottomed flask. Methanol (100 mL) and conc. sulfuric acid (5 mL) were then
added and the mixture was heated at reflux for 12 h. Once the acid was no
longer visible via thin layer chromatography the reaction was cooled to rt.
Water (75 mL) was added and then the solution was made basic by the
addition of solid sodium bicarbonate. The methanol was removed under
reduced pressure and the aqueous phase was extracted with ether (3 X 50 mL
portions).
The combined organics were dried over magnesium sulfate and
concentrated, affording dimethyl glutaconate 84 (27.2 g) in 89% yield. Rf0.60
(60% ethyl acetate/hexane). FTIR (thin film, cm - 1 ) 2955, 1738, 1725, 1662, 1437,
1277, 1204, 1162, 986. 'H NMR (300 MHz, CDC13 ) 6 7.00 (td, 1H, J=7.2, 15.6 Hz),
5.93 (td, 1H, J=1.6, 15.6 Hz), 3.73 (s, 3H), 3.70 (s, 3H), 3.24 (dd, 2H, J=1.5, 7.2 Hz).
13 C
NMR (75 MHz, CDC13 ) 6 170.1, 166.1, 139.7, 124.3, 52.1, 51.6, 37.2.
I
o
oL
00
0o
I
Ul
Experimental Procedures * 127
O
00"
ExperimentalProcedures * 128
OCH
H3 CO
3
THF/Hexane
OTMS
0
NEt 3 , TMSOTf, O "C
0
0
H3CO
OCH 3
85
84
i. THF, Mg, 40
ii. Cul, -35
0
0C
0C
iii. 85, 79%
H3CO
H3 CO
O
83
Butenyl glutarate 83:
A 250 mL round-bottomed flask containing magnesium turnings (1.03 g, 78.3
mmoles) was charged with THF (100 mL) under argon. To this solution, 4bromo-l-butene (10 g, 2 equiv.) was added dropwise to retain a constant
reflux.
The reaction was olive green in color and small shaving of
magnesium were still visible after 1 h.
prepared.
Meanwhile, the TMS ether was
A 200 mL round-bottomed flask containing dimethyl glutaconate
(84) (5.87 g, 37.1 mmoles) was charged with hexane (55 mL) and THF (50 mL)
under argon. The solution was cooled to 0 C then triethylamine (27 mL, ca. 5
equiv.) and TMSOTf (7.5 mL, 1.1 equiv.) were added. The solution was stirred
at 0 C for 20 min then it was warmed to rt for 40 min The Et 3 N* HOTf
formed an insoluble more dense layer that was removed via syringe.
The
solvents were removed en vacuo, and the TMS enol ether product (85) was
used without further purification. THF (100 mL) was added to the crude silyl
enol ether then was cooled to -60 C. TMSC1 (15 mL, 3 equiv.) and cuprous
iodide (1.43 g, 0.2 equiv.) were added followed by the dropwise addition of the
Grignard solution.
The reaction was not warmed above -30 C.
Once the
starting material was no longer visible via thin layer chromatography, the
reaction was quenched by the addition of a saturated solution of ammonium
ExperimentalProcedures * 129
chloride (150 mL). The organics were removed under reduced pressure and
the aqueous phase was extracted with ether (3 X 50 mL portions).
The
combined organics were dried over magnesium sulfate and concentrated.
The product was purified via column chromatography (SiO 2 , 10% ethyl
acetate/hexane) affording dimethyl ester 83 (6.27 g) in 79% yield. Rf0.35 (10%
ethyl acetate/hexane). FTIR (thin film, cm - 1 ) 2951, 1737, 1641, 1437, 1373, 1255,
1208, 1166, 997, 913.
1H
NMR (300 MHz, CDC13 ) 5 5.77 (tdd, 1H, J=6.6, 10.1, 17.1
Hz), 5.02 (ddd, 1H, J=1.6, 3.4, 17.1 Hz), 4.96 (tdd, 1H, J=1.3, 2.0, 10.1 Hz), 3.66 (s,
6H), 2.38 (d, 5H, J=1.5 Hz), 2.09 (ddd, 1H, J=1.3, 6.5, 15.5 Hz), 1.45 (m, 2H).
NMR (75 MHz, CDC13 ) 6 172.8, 137.9, 114.9, 51.5, 38.1, 33.1, 31.5, 30.8.
13 C
I
Cm
0 0
0
cll
j j
C
i
q
L
n
Experimental Procedures * 130
Ii
L n
!
,L
L
r=
i
X-
r
,
SU,
i Sm
LA
rI,n
r
i
ExperimentalProcedures * 131
0
H3 CO
i. Na, Tol, A
H3 CO
ii. TMSCI, #
1 h, A 97%
TMSO
TMSO
0
83
82
Bis-silyl enol ether 82:
A 500 mL 3-necked round-bottomed flask equipped with a condenser, an
addition funnel and a glass coated stir bar was charged with toluene (200 mL)
under argon. Sodium (2.58 g, 4.5 equiv.) was added in one piece and the
solution was heated to reflux, at which time the sodium melted and the high
speed stirring caused a fine dispersion. The addition funnel was charged with
diester 83 (5.35 g, 25.0 mmoles), freshly distilled chloro-trimethylsilane (14.3
mL, 4.5 equiv.) and toluene (15 mL). This mixture was slowly added to the
refluxing reaction mixture over 1 h. The reaction was initially cloudy with a
yellow tint, and after ca. 45 min the precipitate turned to a light purple color.
After the addition was complete, the addition funnel was rinsed with 2 X 10
mL portions of toluene. The reaction was left at reflux for lh and was then
cooled to rt. The mixture was filtered under argon, as the precipitate formed
during the reaction was pyrophoric. The precipitate was rinsed with toluene
and the filtrate was concentrated. The crude product was filtered through a
mixture of silica gel (treated with triethylamine) and magnesium sulfate and
the solids were rinsed. The solution was concentrated affording bis-silyl enol
ether 82 (7.20 g) in 97% yield. Rf 0.63 (10% ethyl acetate/hexane).
FTIR (thin
film, cm- 1) 2959, 2924, 2846, 1707, 1642, 1340, 1310, 1251, 1097, 913, 870, 843, 754.
1H
NMR (300 MHz, CDC13 ) 8 5.81 (tdd, 1H, J=6.6, 10.1, 17.2 Hz), 5.00 (qd, 1H,
J=1.7, 17.1 Hz), 4.94 (tdd, 1H, J=1.1, 2.3, 10.1 Hz), 2.37 (m, 2H), 2.20-1.87 (m, 5H),
Experimental Procedures * 132
1.47 (q, 2H, J=7.6 Hz), 0.18 (s, 18H). 13C NMR (75 MHz, CDC13 )
114.4, 36.9, 36.3, 31.7, 30.6, 0.76.
138.8, 129.5,
0
CI
Experimental Procedures * 133
0
oc0
Experimental Procedures * 134
O
TMSO
Pd(OAc) 2
NaOAc
TMSO
CH 3CN, rt
44%
TMSO
81
82
[3.2.1]Bicycloketone 81:
A 200 mL round-bottomed flask containing bis-silyl enol ether 82 (7.20 g, 24.1
mmoles) was charged with acetonitrile (100 mL) under argon. The solution
was cooled to -10 'C then sodium acetate (3.96 g, 2 equiv.) and palladium II
acetate (6.5 g, 1.2 equiv.) were added. The reaction was keep between -20 oC
and -10 'C for 36 h. The mixture was filtered though a glass fritted funnel
with a silica gel plug.
The reaction was quenched by the addition of a
saturated solution of sodium chloride (150 mL) and water (100 mL).
The
aqueous phase was extracted with pentane (3 X 50 mL portions).
The
combined organics were dried over magnesium sulfate and concentrated.
The product was purified via column chromatography (SiO 2 , 10% ether
/pentane) affording the bicyclic ketone 81 (2.39 mg) in 44% yield. We believe
the low yield is due to the volatile product formed. It may be worthwhile to
distill the product in the future. Rf0.46 (10% ethyl acetate/hexane).
(thin film, cm
1H
- 1)
FTIR
2951, 1756, 1454, 1403, 1249, 1211, 1171, 1113, 1025, 902, 841.
NMR (300 MHz, CDC13 ) 8 5.10 (t, 1H, J=2.1 Hz), 4.78 (t, 1H, J=2.1 Hz), 2.65
(m, 1H), 2.46 (dd, 1H, J=4.9, 14.6 Hz), 2.44 (dd, 1H, J=7.6, 18.9 Hz), 2.24 (dd, 1H,
J=3.7, 18.9 Hz), 2.20 (dd, 1H, J=5.8, 11.6 Hz), 2.18 (d, 1H, J=3.7 Hz), 1.92 (dd, 1H,
1=3.4, 11.1 Hz), 1.74 (m, 1H), 1.64 (s, 3H). 13C NMR (75 MHz, CDC13 ) 8 217.6,
147.3, 105.9, 84.7, 45.0, 41.1, 31.0, 29.1, 28.5, 2.0.
00
Experimental Procedures * 135
~~S
~-Th
Experimental Procedures * 136
0
0
HCI, THF
90%
TMSO
HO
96
81
xo-Hydroxy ketone 96:
A 25 mL round-bottomed flask containing TMS ether 81 (245 mg, 1.1 mmoles)
was charged with THF (10 mL). Hydrochloric acid (conc. 1 drop) was added to
the solution. The reaction was stirred for 15 min at rt. The reaction was
quenched by the addition of a saturated solution of sodium bicarbonate (10
mL).
The aqueous phase was extracted with pentane (3 X 15 mL portions).
The combined organics were dried over magnesium sulfate and concentrated.
The crystalline solid was rerystallized from pentane affording alcohol 96 (148
mg) in 90% yield. m.p. 56.0-57.5 'C. Rf0.53 (80% ethyl acetate/hexane).
FTIR
(thin film, cm - 1 ) 3456(b), 2940, 2860, 1748, 1645, 1450, 1403, 1320, 1202, 1167,
1150, 1100, 1068, 1010, 897, 636, 536.
1H
NMR (300 MHz, CDC13 ) 8 5.12 (d, 1H,
J=1.5 Hz), 4.78 (s, 1H), 2.91 (s, 1H), 2.69 (d, 1H, J=3.0 Hz), 2.47 (dd, 1H, J=7.6, 19.4
Hz), 2.47 (dd, 1H, J=5.2, 9.8 Hz), 2.28 (dd, 1H, J=3.4, 19.2 Hz), 2.21 (m, 1H), 2.09
(dd, 1H, J=5.2, 11.3 Hz), 1.94 (dd, 1H, J=3.0, 11.3 Hz), 1.75 (m, 2H). 13C NMR (75
MHz, CDC13 ) 8 217.6, 147.3, 105.5, 82.5, 43.3, 40.2, 30.9, 29.1, 28.5.
Experimental Procedures * 137
ExperimentalProcedures * 138
HO
O
-
i. NaH, Ben/Hex
ii. DMF, (COCI)2 0 C
H
iii. CH 2 C12/THF
EtMgBr, Cul -15
R-campholenic acid
80%
0C
-
H
136
Ethylketone 136:
A 500 mL round-bottomed flask containing R-campholenic acid (10.0 g, 59.4
mmoles) under argon was charged with benzene (50 mL) and hexane (20 mL).
The solution was cooled to 0 OC then sodium hydride (1.57 g, 1.1 equiv.) was
added in three equal portions. The reaction was stirred at 0 'C for 20 min
Dimethyl formamide (3 drops) was added along with oxalyl chloride (6.23 mL,
1.2 equiv.). The reaction was stirred at 0 oC for 3 h. The solvent was removed
under reduced pressure then THF (120 mL) and dichloromethane (60 mL)
were added. The solution was cooled to -15 oC then to it was added cuprous
(I) iodide (0.566 g, 0.05%) followed by the dropwise addition of ethyl Grignard
until the acid chloride was no longer visible via thin layer chromatography.
The reaction was quenched by the addition of a saturated solution of sodium
bicarbonate (100 mL).
The organic solvents were removed under reduced
pressure and the aqueous phase was extracted with diethyl ether (4X100 mL).
The product was purified by distillation, (67 'C/2 mm Hg) affording ethyl
ketone 136 (8.6 g) in 80% yield. Rf 0.65 (50% diethyl ether/hexane). FTIR (thin
film, cm - 1 ) 3036, 2954, 1713, 1459, 1412, 1374, 1360, 1285, 1211, 1112, 1015, 854,
797.
1H
NMR (300 MHz, CDC13 ) 8 5.22 (s, 1H), 2.51-2.31 (m, 5H), 2.23 (ddd, 1H,
J=3.9, 7.8, 11.7 Hz), 1.79 (ddd, 1H, J=2.4, 9.3, 15.6 Hz), 1.60 (s, 3H), 1.05 (t, 3H,
J=7.3 Hz), 0.98 (s, 3H), 0.77 (s, 3H).
(M+):180.15142. Found: 180.15167.
HRMS calculated for C 12 H 2 0 0
7b
f--
i
r
i
--
-~
1
Experimental Procedures * 139
.
ExperimentalProcedures * 140
03, Sudan Red
CH 2C12
0
then Me 2S
59/o
H
"-
H
0
H
141
137
Keto aldehyde 141:
A 200 mL round-bottomed flask containing cyclopentene 137 (9.50 g, 42.4
mmoles) was charged with dichloromethane (100 mL). Sudan III (5 mg) was
used as an indicator.
The solution was cooled to - 78 'C and ozone was
bubbled through the solution until the pink color faded to clear then was
removed. At - 78 'C dimethyl sulfide (15.6 mL, 5 equiv.) was added and the
reaction was warmed to rt. The reaction was allowed to stir for 12 h. The
reaction was quenched by the addition of a saturated solution of sodium
bicarbonate (10 mL). The aqueous phase was extracted with ether (3X70 mL).
The combined
concentrated.
organics
were
dried over magnesium
sulfate,
and
The product was purified by column chromatography (15%
ethyl acetate/hexane), affording keto-aldehyde 141 (6.40 g) in 59% yield. Rf
0.29 (50% ether/hexane). [ca]
-6.66 (c=4.25, CHC13 ). FTIR (thin film, cm-1)
2973, 2883, 2720, 1722, 1702, 1466, 1355, 1202, 1112, 1054, 950, 904.
1H
NMR (500
MHz, CDCl 3 ) 6 9.71 (t, 1H,J=1.0 Hz) 4.00 (m,4H), 2.71 (dtd, 1H, J=2.0, 5.0, 9.6
Hz), 2.61 (ddd, 1H, J=1.7, 5.1, 17.8 Hz), 2.39 (ddd, 1H, J=6.0, 5.1, 17.8 Hz), 2.18 (s,
3H), 1.62-1.49 (m,4H), 1.03 (s, 3H), 1.01 (s, 3H), 0.85 (t, 3H, J=7.5 Hz).
13 C
NMR
(75 MHz, CDC13 ) 6 213.4, 201.5, 111.6, 64.5, 64.2, 51.2, 46.8, 37.3, 32.3, 30.0, 35.1,
31.6, 20.3, 8.0.
O
I
-t
i[
'-
C-
K
ee-_- i -
C2.C
Experimental Procedures * 141
-
j
0
I
Experimental Procedures * 142
t-Bu Li, Et20, -90 oC,
CeC13 , -90 C-> -50C0
HO CH 3
'
0
Br
0
Aldehyde 141,
66%
3
OCH3
143, 144
132
Lactols 143 and 144:
A 100 mL round-bottomed flask containing aryl bromide 132 (1.40 g, 1.15
equiv.), was charged with diethyl ether (20 mL) under argon. This solution
was cooled to -78 'C then to it was added t- butyllithium (7.59 mL, 1.45 M, 2.3
equiv.) The reaction was stirred at - 78 'C for 45 min, then to it was added
anhydrous cerium trichloride (1.18 g, 1.0 equiv.) in THF (15 mL) via
canulation. The reaction was stirred at -78 'C for 1 h. Keto-aldehyde 141 (1.23
g, 4.78 mmoles) was dissolved in THF (5 mL) then added via canulation, and
washed with three additional portions of THF (2 mL ea.). The reaction was
warmed to - 20 ' C over 1 h. When the starting material was no longer visible
via thin layer chromatography, the reaction was quenched.
A saturated
solution of sodium bicarbonate (30 mL) was added followed by the removal of
the organic solvent under reduced pressure. The aqueous phase was extracted
with ether (3 X 30 mL portions).
The combined organics were dried over
magnesium sulfate and concentrated.
The product was purified by column
chromatography (25% ether/hexane), affording a mixture of lactols 143 and
144 (1.36 g mixture) in 66% yield. Rf(R-isomer)0.29, Rf(S-isomer)0.31 (50%
ether/hexane).
The following information is based on R-isomer. FTIR (thin
film, cm -1) 3424, 2964, 2933, 1649, 1584, 1464, 1374, 1259, 1165, 1092, 1070, 926,
799.
1H
NMR (300 MHz, CDC13 ) 6 7.18 (dd, 1H, J=7.8, 7.8 Hz) 7.13 (dd, 1H, 1=1.4,
8.0 Hz), 6.77 (dd, 1H, 1=1.5, 7.7 Hz), 5.26 (dd, 1H, J=2.6, 11.9 Hz), 4.77 (m, 2H,
ExperimentalProcedures * 143
vinyl CH 2 ), 3.95-3.85 (m, 4H, ketal), 3.80 (s, 3H), 2.90-2.72 (m, 2H), 2.20 (t, 2H,
1=8.2 Hz), 2.04 (td, 1H, J=3.2, 13.6 Hz), 1.85 (s, 3H), 1.81 (s, 3H), 1.77 (dd, 1H,
J=1.5, 14.3 Hz), 1.67 (q, 2H, J=7.5 Hz), 1.39 (s, 3H), 1.29 (dd, 1H, J=9.1, 14.4 Hz),
1.04 (s, 3H), 0.97 (s, 3H), 0.90 (t, 3H, J=7.4 Hz).
1 3C
NMR (125 MHz, CDC13 ) 6
157.4, 146.8, 141.8, 128.3, 126.8, 118.5, 112.5, 109.2, 109.1, 101.4, 68.4, 65, 34.6, 55.5,
38.8, 37.8, 37.0, 36.6, 35.0, 30.1, 25.5, 24.2, 22.8, 22.6, 17.6, 8.0.
0.../
I"
F2
IO
I 00
/
-**
T
0
t
r--
I
un
Experimental Procedures * 144
~--~-c
--~~
7----
I ,
i
-7
SB "
LS2a
e9"2
6W 2
18Ct
61'2
16"
26"1
8 'C
66"
E6 I
LS2O
E6LA
ExperimentalProcedures * 145
-
O
PCC/Alumina
0
OCH 3
0
47/
H
OCO
O CH
CH 2 CI2 , Pyridine, rt
3
0
H
145
143 ,144
Aryl diketone 145:
A 250 mL round-bottomed flask containing lactols 143 and 144 (1.91 g, 4.41
mmoles), was charged with dichloromethane (100 mL) and pyridine (3 drops)
under argon.
PCC on alumina (8g, 1 g=1 mmole) was added at room
temperature.
The solution was left for 3 d.
When the R-isomer was no
longer visible via thin layer chromatography, the reaction terminated.
The
reaction was filtered through a glass fritted funnel with a celite and silica gel
plug.
The product was purified by column chromatography
(20%
ether/hexane), affording diketone 145 (0.89 g) in 47% yield. Rf0.50 (20%
diethyl ether/hexane). FTIR (thin film, cm- 1 ) 2962, 1701, 1456, 1355, 1262, 1108,
1055, 784, 737.
1H
NMR (500 MHz, CDC13 ) 8 7.22 (t, 1H, J=7.9 Hz) 7.09 (dd, 1H,
J=1.1, 7.8 Hz), 6.92 (dd, IH, J=0.9, 8.2 Hz), 4.71(s, 2H), 4.02-3.84 (m, 4H, ketal),
3.84 (s, 3H), 3.81 (d, 1H, J=8.2 Hz), 3.11 (dd, 1H, J=3.5, 19.4 Hz), 3.01 (m, 1H), 2.83
(dd, 1H, J=5.2, 12.2 Hz), 2.80 (dd, 1H, J=5.5, 19.5 Hz), 2.72 (ddd, 1H, J=5.1, 11.4,
12.2 Hz), 2.25 (s, 3H), 1.78 (s, 3H), 1.61 (dq, 2H, J=2.4, 7.6 Hz), 1.56 (m, 3H), 1.05
(s, 3H), 1.02 (s, 3H), 0.88 (t, 3H, J=7.5 Hz). 13C NMR (125 MHz, CDC13 ) 8 214.4,
204.4, 157.9, 146.4, 141.7, 129.1, 126.5, 119.1, 112.1, 112.0, 109.2, 65.0, 64.7, 55.6,
51.7, 46.5, 38.2, 37.9, 32.4, 30.5, 25.4, 25.3, 22.6, 21.8, 20.3, 8.3.
-r
Ii
a
em..---
-77 t
J'C
Experimental Procedures * 146
0,
N
Nr-
311-
Experimental Procedures * 147
0
KOH/MeOH
OCH 3
960/o
OCH 3
'O
130
145
Aryl enone 130:
A 25 mL round-bottomed flask containing diketone 145 (116 mg, 0.269
mmoles), was charged with THF (5 mL) under argon. To this mixture was
added a solution of potassium hydroxide (36 mg) in methanol (7 mL). The
reaction was stirred at room temperature for 2 d. The reaction was quenched
by the addition of a saturated solution of sodium bicarbonate (15 mL)
followed by the removal of the organic solvent under reduced pressure. The
aqueous phase was extracted with ether (3 X 15 mL portions). The combined
organics were dried over magnesium sulfate and concentrated.
Enone 130
(104 mg) was obtained in 98% yield. Rf 0.45 (50% diethyl ether/hexane).
(thin film, cm
-1 )
FTIR
3854, 3750, 3676, 3649, 3069, 2967, 2935, 2880, 2363, 1668, 1576,
1456, 1437, 1381, 1261, 1198, 1150, 1098, 1069, 947.
1H
NMR (500 MHz, CDC13 ) 8
7.17 (t, 1H, J=8.3 Hz) 6.81 (d, 1H, J=8.3 Hz), 6.67 (d, 1H, J=8.3 Hz), 5.89 (d, 1H,
J=1.5 Hz), 4.68 (s, 1H), 4.65 (s, 1H), 3.95-3.83 (m, 4H, ketal), 3.82 (s, 3H), 2.89 (dd,
1H, J=4.9, 19.5 Hz), 2.73 (ddd, 1H, J=5.9, 11.2, 12.7 Hz), 2.64 (ddd, 1H, J=5.9, 10.8,
12.7 Hz), 2.50 (ddd, 1H, J=2.0, 9.3, 19.5 Hz), 2.19 (ddd, 1H, J=5.4, 14.7, 14.7 Hz),
2.14 (ddd, 2H, J=1.5, 4.9, 9.3 Hz), 1.90 (dd, 1H, 1=2.0, 14.7 Hz), 1.73 (s, 3H), 1.63 (q,
2H, J=7.3 Hz), 1.56 (dd, 1H, J=9.8, 14.7 Hz), 1.21 (s, 3H), 1.02 (s, 3H), 0.90 (t, 3H,
J=7.3 Hz).
13 C
NMR (125 MHz, CDC13 ) 8 204.3, 160.8, 157.6, 146.0, 142.0, 127.0,
126.8, 126.7, 119.2, 112.0, 109.8, 109.7, 65.0, 64.5, 55.5, 44.3, 39.6, 38.2, 36.6, 36.0,
29.9, 26.5, 22.5, 19.0, 8.1.
7-
0
0
-
-
cc,R)
(u
a
Experimental Procedures * 148
---_%
Lr~
ExperimentalProcedures * 149
OSiMe 3
0H
0
H3C
0
TMSCI, THF
0
0
LDA, -78 oC
81%
H
H3
H
/ OCH 3
/
OCH 3
157
129
TMS silyl enol ether 157:
A 5 mL round-bottomed flask containing cyclobutane 129 (23 mg, 0.055
mmoles), was charged with THF (1 mL) under argon.
This solution was
cooled to -78 'C then TMSC1 (63 IL., ca. 10 equiv.) and LDA (500 pL., 1 M, ca. 10
equiv.) were added. The solution was warmed to 0 'C over 30 min When the
starting material was no longer visible via thin layer chromatography, the
reaction was quenched.
A saturated solution of sodium bicarbonate (1 mL)
was added followed by the removal of the organic solvent under reduced
pressure. The aqueous phase was extracted with ether (3 X 5 mL portions).
The combined organics were dried over magnesium sulfate and concentrated.
The product was purified by column chromatography (20% ether/hexane),
affording TMS enol ether 157 (22 mg) in 81% yield.
Rf 0.26 (10% ethyl
acetate/hexane). FTIR (thin film, cm - 1 ) 2955, 1736, 1697, 1582, 1469, 1362, 1336,
1252, 1221, 1159, 1117, 1071, 948, 890, 842, 760, 738.
1H
NMR (500 MHz, CDC13) 6
7.15 (t, 1H, J=7.8 Hz) 7.02 (d, 1H, J=7.8 Hz), 6.72 (d, 1H, J=7.8 Hz), 3.92-3.80 (m,
4H, ketal), 3.83 (s, 3H), 2.96 (ddd, 1H, J=3.9, 3.9, 14.7 Hz), 2.32 (d, 1H, J=11.7 Hz),
2.31 (dd, 1H, J=5.9, 15.1 Hz), 2.25 (d, 1H, J=11.7 Hz), 2.21 (ddd, 1H, J=3.9, 12.2,
15.1 Hz), 1.82-1.75 (m, 2H), 1.29 (s, 3H), 1.20 (dd, 1H, J=8.5, 14.9 Hz), 1.12 (s, 3H),
1.04 (s, 3H), 0.97 (dd, 1H, J=12.4, 15.9 Hz), 0.86 (t, 3H, J=7.3 Hz), 0.16 (s, 3H).
13 C
NMR (125 MHz, CDC13 ) 6 155.4, 150.6, 148.4, 128.9, 126.2, 118.9, 116.0, 112.4,
ExperimentalProcedures * 150
107.5, 64.9, 64.5, 55.6, 53.0, 46.7, 44.3, 42.7, 38.5, 38.4, 37.9, 37.0, 30.0, 24.2, 22.2,
21.6, 19.8, 8.1, 0.56.
I
I
0
O
SO
ExperimentalProcedures * 151
C2
ExperimentalProcedures * 152
OCH 3
OCH 3
HCI, Acetone
H
95%
0
H
H
169
149
trans Diketone 169:
A 25 mL pear-shaped flask containing ketal 149 (34 mg, 0.083 mmoles) was
charged with acetone (4 mL). To this mixture, 10 % aq. HC1 (3 drops) was
added at rt.
After 12 h. the reaction was quenched by the addition of a
saturated solution of sodium bicarbonate (3 mL).
extracted with ether (3 x 15 mL).
The aqueous phase was
The combined organics were dried over
magnesium sulfate and concentrated, affording ketone 169 (29 mg) in 95%
yield. Rf 0.43 (50% ether/hexane).
FTIR (thin film, cm- 1 ) 2969, 2936, 1714,
1682, 1582, 1460, 1438, 1375, 1258, 1174, 1080, 1061, 908, 778, 740.
1H
NMR (500
MHz, CDC13 ) 8 7.10 (t, 1H, J=8.1 Hz), 6.89 (d, 1H, J=8.3 Hz), 6.64 (d, 1H, J=8.3 Hz),
5.84 (d, 1H, J=13.2 Hz), 5.71 (d, 1H, J=13.2 Hz), 3.79 (s, 3H), 3.18 (tdd, 1H, J=2.0,
9.8, 12.2 Hz), 2.92 (dd, 1H, J=2.9, 12.7 Hz), 2.73 (ddd, 1H, J=2.2, 5.1, 17.8 Hz), 2.57
(dd, 1H, J=2.0, 17.1 Hz), 2.52 (m, 1H), 2.48 (dq, 1H, J=7.3, 17.6 Hz), 2.36 (dq, 1H,
J=7.3, 17.6 Hz), 2.25 (dd, 1H, J=9.8, 17.1 Hz), 1.98 (ddd, 1H, J=3.5, 12.6, 14.5 Hz),
1.64 (dd, 1H, J=2.4, 5.4, 13.2 Hz), 1.45 (ddd, 1H, J=3.4, 12.7, 14.2 Hz), 1.42 (dt, 1H,
J=4.9, 13.2 Hz), 1.17 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H), 1.07 (t, 3H, J=7.3 Hz). A
DQCOSY experiment (CDC13 , 500 MHz) was performed to determine coupling
partners.
A NOESY experiment (CDC13, 500 MHz) was performed to
determine relative stereochemistry. 13C NMR (75 MHz, CDC13 ) 8 214.0, 210.1,
157.0, 146.4, 139.9, 137.9, 126.1, 125.8, 120.8, 119.4, 107.0, 55.4, 50.0, 44.4, 36.2, 38.8,
37.1, 36.9, 36.4, 26.8, 19.7, 17.6, 15.6, 7.8.
- -
_
..------
_I_, . .
.
--
Al_
L. L
tl
__I._L _,_-_ --- J _-
-
691.
H
H
O
CHOO
O
0
ExperimentalProcedures * 154
0
OCH3
OCH3
H UCH
H
2 GI 2 , 95%
164
163
Epoxy alcohol 164:
A 10 mL round-bottom flask containing allylic alcohol 163 (41 mg, 0.10
mmoles) was charged with dichloromethane (2 mL).
tButylhydroperoxide
(0.5 mL) was added followed by the addition of VO(acac) 2 (1 mg). After 5 min
at rt, the reaction was complete.
pressure.
The solvent was removed under reduced
The product was purified via column chromatography (25%
ether/hexane)
affording 164 (41 mg) in 95% yield.
65
properties were identical to that described previously.
The spectroscopic
Experimental Procedures * 155
r
L.
Hto
L
Experimental Procedures * 156
0
OCH 3
H
",
5
O
, EtOAc
then NaHSO
72%3
OCH 3
0
0
H
171
170
Diol 171:
A 25 mL round-bottomed flask containing enone 170 (13 mg, 0.031 mmoles)
was charged with THF (2 mL). The solution was cooled to 0 oC then pyridine
(22 tL) and Os04 (12 mg, 1.5 equiv.) were added. The reaction was stirred for
1.5 h. at 0 'C then warmed to rt for 24 h. after which time the starting material
had completely converted to the osmate ester (baseline spot via thin layer
chromatography).
The osmate ester was reductive cleaved by the addition of
ethyl acetate (5 mL) and 5% aq. sodium bisulfite solution (5 mL) with
vigorous stirring for 20 h. A saturated solution of sodium bicarbonate (1 mL)
was added followed by the removal of the organic solvent under reduced
pressure.
The aqueous phase was extracted with ethyl acetate (3 X 10 mL
portions).
The combined organics were dried over magnesium sulfate and
concentrated.
ether/hexane),
ether/hexane).
The product was purified by column chromatography (70%
affording diol 171 (10 mg) in 72% yield.
Rf 0.10 (50%
FTIR (thin film, cm -1) 3445, 2971, 2882, 2836, 2246, 1694, 1586,
1464, 1437, 1382, 1372, 1312, 1257, 1206, 1154, 1135, 1078, 1039, 988, 911, 781, 733.
1H
NMR (500 MHz, CDC13) 6 7.07 (t, 1H, J=7.8 Hz), 6.97 (d, 1H, J=7.3 Hz), 6.58
(d, 1H, J=7.8 Hz), 4.88 (t, 1H, 1=5.1 Hz), 4.38 (dd, 1H, J=4.6, 11.0 Hz), 4.18-4.01 (m,
4H, ketal), 4.10 (d, 1H, J=6.4 Hz), 3.78 (s, 3H), 3.44 (d, 1H, 1=10.7 Hz), 2.73 (dd,
1H, J=6.4, 18.1 Hz), 2.69 (d, 1H, J=11.2 Hz), 2.30 (ddd, 1H, J=6.8, 11.7, 18.1 Hz),
2.16 (ddd, 1H, J=3.7, 3.7, 9.3 Hz), 1.83 (d, 1H, J=14.7 Hz), 1.80 (m,1H), 1.76 (q, 1H,
J=7.3 Hz), 1.73 (q, 1H, J=7.3 Hz), 1.69 (ddd, 1H, J=2.9, 2.9, 16.1 Hz), 1.51 (dd, 1H,
Experimental Procedures * 157
J=9.3, 14.6 Hz), 1.38 (ddd, 1H, J=3.9, 11.7, 16.1 Hz), 1.33 (ddd, 1H, J=6.8, 12.7, 12.7
Hz), 1.22 (s, 3H), 1.03 (s, 3H), 0.98 (t, 3H, J=7.3 Hz), 0.96 (s, 3H).
1 3C
NMR (75
MHz, CDC13 ) 8 215.0, 207.4, 156.5, 144.1, 126.1, 123.8, 122.1, 112.1, 106.3, 76.0, 64.8,
64.5, 55.1, 51.0, 48.8, 42.5, 42.3, 39.3, 37.6, 30.1, 25.8, 24.0, 22.0, 19.9, 17.9, 15.3, 8.5.
_
~_
iL
O
I \I_,_1
C, 4,
-
_
~--._ ---~1 .
.
~...
, [
,
,
_I _
-
__
09
L _I _
_,
_ ._I__
l L--J__
,Y
n-n ' --'
0
HOO
ExperimentalProcedures * 159
-
CH 3
.00CH
0
-
OC
0
O
0
OH
HO
H
CI, Acetone
CH 3
O
83%
3
OCH 3
0_.-OH
H
172
171
Diketo acetonide 172:
A 25 mL round-bottomed flask containing diol 171 (70 mg, 0.157 mmoles) was
charged with acetone (10 mL). To this solution, conc. HC1 (1 drop) and 2,2dimethoxy propane (1 mL) were added. The mixture was stirred for 30 min
The reaction was neutralized by the addition of a saturated solution of
sodium bicarbonate (1 mL) followed by the removal of the organic solvent
under reduced pressure. The aqueous phase was extracted with ether (3 X 5
mL portions).
The combined organics were dried over magnesium sulfate
and concentrated. The product was purified by column chromatography (50%
ether/hexane), affording diketone/acetonide 172 (58 mg) in 83% yield. Rf0.22
(50% ether/hexane).
FTIR (thin film, cm- 1 ) 2976, 2939, 1715, 1586, 1467, 1380,
1258, 1210, 1171, 1078, 1034, 731.
1H
NMR (500 MHz, CDC13 ) 6 7.02 (t, 1H, J=7.8
Hz), 6.58 (d, 1H, J=7.8 Hz), 6.47 (d, 1H, J=7.8 Hz), 5.15 (d, 1H, J=7.8 Hz), 4.72 (d,
1H, J=7.3 Hz), 3.76 (s, 3H), 2.89 (d, 1H, J=11.7 Hz), 2.70 (dd, 1H, J=6.8, 18.6 Hz),
2.59 (m, 1H), 2.57 (dd, 1H, J=2.4, 16.6 Hz), 2.50 (m, 1H), 2.47 (m, 1H), 2.39 (dd,
1H, J=10.3, 16.6 Hz), 2.34 (ddd, 1H, J=8.3, 11.7, 18.1 Hz), 1.72 (dd, 1H, J=7.8, 13.7
Hz), 1.64 (s, 3H), 1.56 (ddd, 1H, J=7.3, 11.7, 14.1 Hz), 1.45 (ddd, 1H, J=3.2, 12.2,
16.1 Hz), 1.39 (s, 3H), 1.19 (s, 3H), 1.18 (t, 3H, J=7.3 Hz), 1.12 (ddd, 1H, J=3.0, 3.0,
16.1 Hz), 0.99 (s, 3H), 0.97 (s, 3H).
13 C
NMR (75 MHz, CDC13 ) 8 210.7, 209.0,
156.8, 143.9, 126.2, 123.9, 121.4, 106.5, 106.2, 86.0, 77.8, 55.1, 50.2, 48.4, 45.0, 41.8,
41.0, 37.2, 36.9, 26.4, 24.2, 24.0, 20.1, 19.9, 17.5, 15.3, 7.9.
0
0''
C)L
/
0
°/
ExperimentalProcedures
I
160
L
[_
n- LA C_r?
tIN
S J"
C--
i
K
i"
K
4!
ExperimentalProcedures * 161
0
0
SOCH
H
O
3
HCI, Acetone
8 1%
_
H
0
H
OCH 3
H
174
175
A 25 mL pear-shaped flask containing ketal 174 (22 mg, 0.053 mmoles) was
charged with acetone (4 mL). To this mixture, 10 % aq. HC1 (3 drops) was
added at rt.
After 12 h. the reaction was quenched by the addition of a
saturated solution of sodium bicarbonate (3 mL).
extracted with ether (3 x 15 mL).
The aqueous phase was
The combined organics were dried over
magnesium sulfate and concentrated.
The product was purified via column
chromatography (silica gel, 20% ether/hexane) affording 16 mg 175 (81%
yield).
Rf0.35 (500/, ether/hexane).
FTIR (thin film, cm - 1 ) 2966, 2932, 1712,
1686, 1586, 1467, 1367, 1258, 1074, 782, 753.
1H
NMR (500 MHz, CDCl 3 ) 6 7.11 (t,
1H, J=7.8 Hz), 6.77 (d, 1H, J=7.8 Hz), 6.62 (d, 1H, J=7.8 Hz), 5.92 (d, 1H, J=13.2
Hz), 5.52 (d, 1H, J= 13.2 Hz), 3.78 (s, 3H), 2.73 (dd, 1H, J=6.6, 18.3 Hz), 2.63 (s, 1H),
2.48 (ddd, 1H, J=7.3, 12.2, 19.0 Hz), 2.46 (s, 1H), 2.46 (qd, 1H, J=7.3, 18.0 Hz), 2.37
(dd, 1H, J=1.5, 16.1 Hz), 2.26 (qd, 1H, J=7.5, 17.6 Hz), 2.15 (dd, 1H, J=10.1, 15.9
Hz), 1.92 (ddd, 1H, J=3.9, 10.2, 15.1 Hz), 1.80 (dt, 1H, J=7.1, 12.6 Hz), 1.50 (dd, 1H,
J=7.32, 13.2 Hz), 1.19 (s, 3H), 1.10 (s, 3H), 0.96 (t, 3H, J=7.3 Hz), 0.95 (s, 3H). 13C
NMR (75 MHz, CDC13) 6 215.7, 209.8, 156.8, 143.4, 128.1, 126.5, 121.5, 121.4, 106.8,
55.1, 48.8, 47.0, 45.3, 44.4, 39.1, 38.8, 36.4, 29.1, 25.0, 24.1, 19.9, 18.6, 7.7.
_;_ 1
~.~ _i~__~______~________~_~~ ~_
__~___
:I)
0
~C-~--~--c~---nl=-----s~---~-~~
Experimental Procedures * 162
L
-to
_
;Z113IT
tu
c
i
r
H
8..
_=
I;
ExperimentalProcedures * 163
0
KtOBu, benzene
OCH
3
O
O
75%
H
OCH3
176
175
A 25 mL pear-shaped flask containing enone 175 (8 mg, 0.022 mmoles) was
charged with benzene (3 mL).
Solid potassium tert-butoxide (24 mg, 10
equiv.) was added to the solution. The heterogeneous, yellow mixture was
stirred at rt for 90 min
The reaction was quenched by the addition of a
saturated solution of sodium bicarbonate (1 mL).
extracted with ether (3 x 15 mL).
The aqueous phase was
The combined organics were dried over
magnesium sulfate and concentrated. The product was purified via column
chromatography (silica gel, 20% ether/hexane) affording 6 mg 176 (75% yield).
Rf0.34 (40% ether/hexane). FTIR (thin film, cm- 1 ) 2934, 1701, 1586, 1466, 1259,
1080, 779, 668. 1H NMR (500 MHz, CDC13 ) 8 7.08 (t, 1H, J=7.8 Hz), 6.64 (d, 1H,
J=8.3 Hz), 6.58 (d, 1H, J=8.3 Hz), 3.8 (s, 3H), 3.17 (dd, 1H, J=5.6, 16.8 Hz), 2.92 (s,
1H), 2.83 (dd, 1H, J=7.3, 18.1 Hz), 2.82 (qd, 1H, J=7.3, 17.6 Hz), 2.66 (td, 1H, J=2.0,
16.6 Hz), 2.58 (s, 1H), 2.53 (m, 1H), 2.51 (qd, 1H, J =7.3, 17.6 Hz), 2.33 (dd, 1H,
J=2.0, 5.0 Hz), 2.25 (dd, 1H, J=4.6, 12.9 Hz), 2.13 (td, 1H, J=3.9, 14.7 Hz), 2.07 (dt,
1H, J=7.1, 12.6 Hz), 1.66 (dt, 1H, J=3.7, 13.8 Hz), 1.28 (s, 3H), 1.25 (m, 1H), 1.13 (t,
3H, J=7.3 Hz), 1.02 (s, 3H), 0.92 (s, 3H).
A DQCOSY experiment (500 MHz,
CDC13 ) was performed to determine coupling partners. A NOESY experiment
(500 MHz, CDC13 ) was performed to determine relative stereochemistry.
13 C
NMR (75 MHz, CDC13 ) 6 216.8, 213.6, 172.9, 157.1, 140.8, 126.3, 121.9, 107.0, 55.2,
50.4, 48.0, 46.6, 43.4, 40.0, 38.1, 37.7, 35.4, 33.1, 28.3, 27.5, 23.5, 21.9, 20.6, 8.2.
Experimental Procedures * 164
OCH 3
176
II
I
I
3.5
3.0
2.5
I
1.
2.0
1.5
I
1.0
I
1 .0
f
p
I
I
ppm
F2
(PP
1.0
3.0'
3.5
3.5
3.0
2.5
Fl
2.0
(ppm)
1.5
1.0
0.5