The pinene path to taxanes. 4. Approaches to taxol and taxol analogs through elaboration of aromatic C-ring precursors

Full text of DOI:10.1021/jo961289z

7662
J . Org. Chem. 1996, 61, 7662-7663
Sch em e 1
Th e P in en e P a th to Ta xa n es. 4.
Ap p r oa ch es to Ta xol a n d Ta xol An a logs
th r ou gh Ela bor a tion of Ar om a tic C-Rin g
P r ecu r sor s
Paul A. Wender,* Timothy E. Glass,1a
Nancy E. Krauss,1b Michel Mu¨hlebach,1c
Bernd Peschke,1d and David B. Rawlins
Department of Chemistry, Stanford University,
Stanford, California 94305
for deprotonation. Removal of this conformational con-
straint through saturation of the C9 center was found to
resolve this problem, as demonstrated by the highly
efficient conversion of the hydroboration product 5 (with
t-BuOK/DMSO/O2 in THF at -25 °C) to the C1-oxidized
product 6 in 96% yield. The primary alcohol of 6 was
subsequently converted to the C9 ketone 7 (82%) by
oxidation with Dess-Martin’s periodinane6 to an alde-
hyde (84%) followed by oxidative decarbonylation using
t-BuOK/DMSO/O2.
Received J uly 10, 1996
The chemotherapeutic agent Taxol (3, Scheme 1),
originally obtained from Pacific yew tree bark, has shown
remarkable promise in the treatment of both breast and
ovarian cancer.2 As part of our ongoing research in this
area, we have developed a strategy for the synthesis of
taxanes based on pinene (1),3 which provides concise,
enantiomerically controlled access to the tricarbocyclic
taxane core (e.g., 2a in six steps), structural analogs, and
taxol itself.4 A recently introduced C9-C10 linker vari-
ant of this strategy has also provided tricycle 2b in only
seven steps from pinene (1).5 Herein we describe the next
phase of this program, the elaboration of 2b toward both
taxol and its analogs entailing concise solutions for the
functionalization of the B and C rings.
The elaboration of 2b began with protection of its C13
hydroxyl group as the TBS ether (4, Scheme 2). It is a
noteworthy consequence of the striking interconnected-
ness of functional group reactivities in this structural
series that 4 failed to undergo C1 deprotonation and
oxidation under conditions in which the closely related
silyl ether derivative of 2a reacted readily.3 At the core
of this reactivity difference is the C4 substituent (H vs
MeO), which restricts 4 to a conformation in which the
C1-CH bond is improperly aligned with the C2 carbonyl
Further elaboration of diketone 7 was initially ac-
complished by Birch reduction. However, complications
with over-reduction of the aromatic ring prompted our
selection of the C2 monoketone 8 in order to achieve
better control over this reduction. For this purpose,
ketone 8 (mp 149-150 °C) was prepared by double
reduction of 7 with sodium, followed by selective protec-
tion of the C9 alcohol and reoxidation of the C2 alcohol
(53% yield over three steps). When 8 was treated with
K/NH3/THF, the R- and â-C3-stereoisomers 9a and 9b/
9c were obtained in a ratio that was dependent on the
reaction conditions and workup. Although it was possible
to obtain either C3 epimer, compounds possessing the
â-CH configuration were selected for study since they
were expected to afford greater stereocontrol over the
introduction of groups at C8 and to be amenable to
epimerization at a later synthetic stage. Ketone 8 was
therefore selectively reduced to the â-CH derivatives 9b
and 9c (77% yield, along with a trace of 9a ). Silyl ether
9b was readily converted to 9c upon treatment with acid.
Access to our multipurpose analog precursor, enone 13,
entailed initial reduction of the C2 ketone of 9c with Na
in NH3/THF to the desired C2 alcohol stereoisomer 10
(85% yield). Subsequent treatment of 10 with triphos-
gene provided the carbonate 11 (99% yield), which when
exposed to phenyllithium yielded the C2 benzoate 12
(68% yield).7 Oxidation of the C9 alcohol using Dess-
Martin periodinane gave enone 13 (mp 175-176 °C) in
95% yield.
* To whom correspondence should be addressed. Fax: (415) 725-
0259. E-mail: wenderp@leland.stanford.edu.
(1) (a) National Science Foundation Predoctoral Fellow. (b) National
Institutes of Health Postdoctoral Fellow. (c) Swiss National Science
Foundation Postdoctoral Fellow. (d) Recipient of a Forschungsstipen-
dium (USA) from the Deutsche Forschungsgemeinschaft.
(2) Taxol is the registered trademark for the molecule with generic
name paclitaxel. For a recent review of synthetic studies from over 35
groups, see: (a) Wender, P. A.; Natchus, M. G.; Shuker, A. J . In
TAXOL® Science and Applications; Suffness, M., Ed.; CRC Press: New
York, 1995; pp 123-187. For overviews of other aspects of taxol
research, see: (b) Taxane Anticancer Agents: Basic Science and
Current Status; Georg, G., Chen, T., Ojima, I., Vyas, D., Eds.; ACS
Symposium Series 583; American Chemical Society: Washington, DC,
1995. For total syntheses of Taxol, see: (c) Holton, R. A.; Somoza, C.;
Kim, H. B.; Liang, F.; Biediger, R. J .; Boatman, P. D.; Shindo, M.;
Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang,
S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J . H. J . Am. Chem.
Soc. 1994, 116, 1597-1598, 1599-1600. (d) Nicolaou, K. C.; Yang, Z.;
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. (e) Danishefsky, S. J .; Masters, J . J .; Young, W. B.; Link, J . T.;
Snyder, L. B.; Magee, T. V.; J ung, D. K.; Isaacs, R. C. A.; Bornmann,
W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, J . J . Am. Chem. Soc.
1996, 118, 2843-2859 and references cited therein.
Enone 13 serves as a potentially general precursor to
various classes of taxol analogs. For example, access to
7-deoxy analogs, many of which have similar biological
activity to taxol,8 requires introduction of a â-C8 methyl
group. This alkylation was achieved by reduction of 13
with Li/NH3 in THF followed by methyl iodide treatment,
affording the desired C8 methylated compound 16a (30%)
along with material arising from further reductive me-
thylation of the C2 benzoate, 16b (27%). Similarly, 7,8-
(3) Wender, P. A.; Mucciaro, T. P. J . Am. Chem. Soc. 1992, 114,
5878-5879. For
a recently reported attractive application of this
strategy, see: Winkler, J . D.; Bhattacharya, S. K.; Liotta, F.; Batey,
R. A.; Heffernan, G. D.; Cladingboel, D. E.; Kelly, R. C. Tetrahedron
Lett. 1995, 36, 2211-2214.
(6) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(7) This method of incorporating the C2-benzoate was used success-
fully in all of the reported syntheses of taxol.2c-e A similar reaction
was reported in an early phorbol synthesis from these laboratories:
Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J . D.; Wilhelm, R. S.;
Williams, P. D. J . Am. Chem. Soc. 1989, 111, 8957-8958.
(8) Chen, S.-H.; Huang, S.; Kant, J .; Fairchild, C.; Wei, J .; Farina,
V. J . Org. Chem. 1993, 58, 5028-5029.
(4) Presented in part at the ACS Western Regional Meeting, Oct
18-21, 1995, ORGN. 129. For an overview of our strategy see: Wender,
P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.;
Houze, J . B.; Krauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L.;
Meng, W.; Mucciaro, T. P.; Mu¨hlebach, M.; Natchus, M. G.; Ohkuma,
T.; Peschke, B.; Rawlins, D. B.; Shuker, A. J .; Sutton, J . C.; Taylor, R.
E.; Tomooka, K.; Wessjohann, L. A. In ref 2b, pp 326-339.
(5) Wender, P. A.; Glass, T. E. Synlett 1995, 516-518.
S0022-3263(96)01289-3 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7663
Sch em e 2a
a
Reagents: (a) TBSCl, imidazole, DMF, 60 °C (91%); (b) (i) 9-BBN, THF, reflux, (ii) 6 N NaOH, 30% H2O2, reflux (66%); (c) t-BuOK,
O2, DMSO, THF, -25 °C (96%); (d) Dess-Martin periodinane, CH2Cl2 (84%); (e) t-BuOK, O2, DMSO, THF, -30 °C (84%); (f) Na, EtOH,
wet Et2O, 0 °C; (g) TMSCl, Et3N, CH2Cl2; (h) Dess-Martin periodinane, CH2Cl2 (53%, three steps); (i) (i) K, NH3, THF, -78 °C, (ii)
isoprene, (iii) NH4Cl (aq) (9a trace, 9b 58%, 9c 19%); (j) AcOH, MeOH (69%); (k) Na, NH3, THF, -78 °C (85%); (l) triphosgene, CH2Cl2,
pyridine (99%); (m) PhLi, THF, -78 °C (68%); (n) Dess-Martin periodinane, CH2Cl2 (95%); (o) (CH3)3S(O)I, NaH, THF, DMSO, 45 °C
(69%); (p) (i) KHMDS, THF, -78 °C, (ii) 2-(phenylsulfonyl)-3-phenyloxaziridine, -78 °C (52%); (q) (i) Li, NH3, THF, -78 °C, (ii) CH3I (16a
30%, 16b 27%); (r) acetone, Oxone, NaHCO3, CH2Cl2, 18-C-6, 0 °C (37).
cyclopropyltaxol analogs that exhibit comparable activity
to taxol9 are also potentially derivable from enone 13.
Key to accessing this class is the cyclopropanation of 13,
which was found to proceed with dimethylsulfoxonium
methylide in THF/DMSO10 to afford compound 14 (173-
176 °C)11 in 69% yield. Further modification of 14, as
required for structure-activity studies in this series, was
realized by selective oxidation of the C4-C5 enol ether
with dimethyldioxirane, giving ketone 17 and setting the
functionality required for oxetane formation.12 Alterna-
tively, selective introduction of C10 oxygenation was
accomplished by treatment of 14 with KHMDS at -78
°C followed by the addition of Davis’ oxaziridine,13
affording hydroxy ketone 15 in 52% yield.
in this latest advance in the pinene path strategy.
Elimination of the adverse conformational influence
imparted by the C4 methoxy group in 4 was achieved by
saturation of the C9 center, thereby allowing for efficient
access to C1 oxidized intermediates. The C2 carbonyl of
8 was shown to provide control over the reduction of the
aromatic ring while allowing retention of C9 oxidation.
The stereochemistry of this reduction was demonstrated
in turn to control reduction at C2 and stereoselective
introduction of groups at C8, a new development in the
elaboration of taxane tricycles. Finally, the strategy
preserves in differentiated form a ketone oxidation level
at C9 and C4 allowing for selective introduction of
substituents at C8 and oxidation at positions C10 and
C5 as required to access various taxol analogs as well as
taxol itself. Studies on these advanced intermediates will
be reported in due course.
In summary, the advanced taxoid precursor 13 has
been synthesized in 21 steps from commercially available
pinene (1). Several developments figured significantly
Ackn owledgm en t. The National Institutes of Health
(NIH CA31845) and Bristol-Myers Squibb are gratefully
acknowledged for financial support of this research.
Exact mass analyses were provided by the University
of California, San Francisco Regional Mass Spectrom-
etry Facility.
(9) Chen, S.-H.; Huang, S.; Wei, J .; Farina, V. J . Org. Chem. 1993,
58, 4520-4521.
(10) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1353-
1364.
(11) The stereochemistry of the cyclopropane was confirmed by NOE
experiments. Irradiating the C3 proton gave a 3% enhancement of one
of the cyclopropane hydrogens and a 7% enhancement of one of the
geminal methyls.
(12) Wender, P. A.; Rawlins, D. B. Tetrahedron 1992, 48, 7033-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 4-17 (9 pages).
7048.
(13) (a) Davis, F. A.; Vishwakarma, L. C.; Billmers, J . M.; Finn, J .
J . Org. Chem. 1984, 49, 3241-3243. (b) Davis, F. A.; Stringer, O. D.
J . Org. Chem. 1982, 47, 1774-1775.
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