The pinene path to taxanes. 6. A concise stereocontrolled synthesis of taxol

Full text of DOI:10.1021/ja963539z

J. Am. Chem. Soc. 1997, 119, 2757-2758
2757
Scheme 1a
The Pinene Path to Taxanes. 6. A Concise
Stereocontrolled Synthesis of Taxol
Paul A. Wender,* Neil F. Badham, Simon P. Conway,
Paul E. Floreancig, Timothy E. Glass, Jonathan B. Houze,
Nancy E. Krauss, Daesung Lee, Daniel G. Marquess,
Paul L. McGrane, Wei Meng, Michael G. Natchus,
Anthony J. Shuker, James C. Sutton, and Richard E. Taylor
Department of Chemistry, Stanford UniVersity
Stanford, California 94305
ReceiVed October 9, 1996
In the preceding communication,1 we described the synthesis
of a potentially general precursor (2, Scheme 1) of the highly
promising chemotherapeutic agent Taxol2 (1, Scheme 2) and
its analogues. Our strategy for the elaboration of this AB-
bicyclic precursor into the ABC-tricyclic core of the taxanes
was predicated on the view1b that epimerization of the C7 center
of Taxol3 proceeds through the intermediacy of the AB-bicyclic
enolaldehyde or its ketone isomer, leading to the intriguing
possibility that the C-ring of Taxol could self-assemble under
exceptionally mild conditions from a considerably less complex
AB-bicyclic ketoaldehyde precursor (e.g., 9). In this com-
munication, the viability of this aldol cyclization strategy is
demonstrated in a synthesis of Taxol (1), representing the
shortest sequence yet reported for the preparation of this
important natural product.4,5
The elaboration of our general taxane precursor (2, Scheme
1) into Taxol started with its homologation with Ph3PC(H)-
OMe (91%)6 followed by a one-step hydrolysis of the enol ether
and acetonide groups (HCl, NaI) to provide aldehyde 3 (94%).7
Selective protection of the C9 hydroxyl was then accomplished
in 92% yield with TESCl and pyridine. Dess-Martin perio-
dinane oxidation8 of the C10 alcohol and introduction of C20
with [Me2NCH2]I (g0.1 M)9 and Et3N (excess) was conducted
in one operation to produce enal 4 in 97% yield. The remaining
carbons of the taxane skeleton were then introduced through
a (a) Ph3PCHOMe, THF, -78 °C, 91%. (b) 1 N HCl(aq), NaI, dioxane,
94% at 90% conversion. (c) TESCl, pyr, CH2Cl2, -30 °C, 92%. (d)
Dess-Martin periodinane, CH2Cl2; Et3N, Eschenmoser’s salt, 97%. (e)
allyl-MgBr, ZnCl2, THF, -78 °C, 89%. (f) BOMCl, (i-Pr)2NEt, 55
°C. (g) NH4F, MeOH, rt, 93% over two steps. (h) PhLi, THF, -78 °C;
Ac2O, DMAP, pyr, 79%. (i) 7, CH2Cl2, rt, 1 h, 80% at 63% conversion.
(j) O3, CH2Cl2, -78 °C; P(OEt)3, 86%.
the addition of 4 to a solution of allylmagnesium bromide and
ZnCl2 (89%)10 which after BOM (benzyloxymethyl) protection
(N,N-diisopropylethylamine solvent) provided the ether 5 as a
single diastereomer.10c The presence of ZnCl2 in the former
reaction completely suppressed addition of the Grignard reagent
to the cyclic carbonate.
(1) (a) Wender, P. A.; et al. J. Am. Chem. Soc. 1997, 119, 2755
(preceding paper). (b) For an overview of the pinene pathway, see ref 9 in
the preceding paper.
(2) Taxol is the registered trademark for the molecule with the generic
name paclitaxel. For reviews on Taxol, see refs 1a,b in the preceding paper.
(3) (a) Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J. Nat. Prod.
1990, 53, 1-12. (b) Miller, R. W.; Powell, R. G.; Smith, C. R., Jr.; Arnold,
E.; Clardy, J. J. Org. Chem. 1981, 46, 1469-1474.
(4) For recent reviews of synthetic studies from over 35 groups, see ref
7 in the preceding paper.
Removal of the C9 silyl group (NH4F, MeOH)11 provided
an unstable hydroxyketone (93% over two steps) which was
reacted immediately with PhLi12 to form the C2 benzoate
providing, after in situ acetylation, the acetate 6 in 79% yield.
Transposition of the acetoxyketone under kinetic5a or equilibrat-
ing conditions (Et2NH, KOAc, DMF)13 resulted in limited
success. However, when the guanidinium base 714 was em-
ployed for this transposition, the desired acetoxyketone 8 and
recyclable 6 were obtained in 80% as a 4:3 equilibrium mixture.
The monosubstituted alkene in 8 was then cleaved through
addition of an ozone solution to form aldehyde 9 in 86% yield.
The viability of the key aldol cyclization was addressed at
this point. Previous studies in our laboratory1b,15 showed that
ketoaldehydes similar to 9 but incorporating a C1-C2 cyclic
carbonate did not undergo aldol cyclization, preferring instead
(5) For total syntheses of Taxol, see: (a) Holton, R. A.; Somoza, C.;
Kim, H. B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith,
C. C.; Kim, S.; 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.
Holton, R. A.; Kim, H. B.; Somoza, C.; 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, 1599-1600. (b) Nicolaou, K. C.; Nantermet,
P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, E. J. J. Am.
Chem. Soc. 1995, 117, 624-633. Nicolaou, K. C.; Liu, J.-J.; Yang, Z.;
Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.;
Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117, 634-644.
Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claiborne, C. F.;
Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995, 117, 645-
652. Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, P. G.; Yang, Z.;
Renaud, J.; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995, 117, 653-
659 and references cited therein. (c) 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. 1996, 118, 2843-2859.
(6) Levine, S. G. J. Am. Chem. Soc. 1958, 80, 6150-6151.
(7) Williams, D. R.; Barner, B. A.; Nishitani, K.; Phillips, J. G. J. Am.
Chem. Soc. 1982, 104, 4708-4710.
(8) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(9) Takano, S.; Inomata, K.; Samizu, K.; Tomita, S.; Yanase, M.; Suzuki,
M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara, K. Chem. Lett. 1989, 1283-
1284.
(10) (a) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873-3888. (b)
Thiele, K.-H.; Zdunneck, P. J. Organomet. Chem. 1965, 4, 10-17. (c) The
stereochemistry at C5 was determined by NOE studies on the des-acetyl
derivative of the aldol product 10a.
(11) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177-1180.
(12) 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 and ref 5
cited above.
(13) To´th, I.; Szabo´, L.; Kajta´r-Peredi, M.; Baitz-Ga´cs, E.; Radics, L.;
Sza´ntay, C. Tetrahedron 1978, 34, 2113-2122.
(14) Johansen, J. E.; Piermattie, V.; Angst, C.; Diener, E.; Kratky, C.;
Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 261-263.
S0002-7863(96)03539-1 CCC: $14.00 © 1997 American Chemical Society

2758 J. Am. Chem. Soc., Vol. 119, No. 11, 1997
Communications to the Editor
Scheme 2a
induced A-ring rearrangement product.16 Difficulties encoun-
tered while attempting to form the oxetane through the displace-
ment of a leaving group on C20 by the â-oriented C5 hydroxyl17
prompted investigation of the complementary closure strategy
(nucleophilic C20 hydroxyl, C5 leaving group). Toward this
end, 12 was converted to the labile mesylate 13 (MsCl, DMAP,
pyridine) which was reacted with LiBr to give bromide 14.
Stereoselective introduction of oxygen at C4 and C20 was
5a
accomplished with OsO4. Direct closure of the resulting diol
to form the oxetane was preempted by transfer of the C2
benzoate group to the C20 hydroxyl. Consequently, after
osmylation, benzoyl migration was induced to proceed to
completion with imidazole and the resulting C1-C2 diol was
sequestered as a cyclic carbonate (triphosgene, pyridine) in 92%
yield. The C20 benzoate was then removed with KCN18 in
ethanol to form diol 15. Oxetane formation17,19 proceeded
smoothly with Hu¨nig’s base. Acetylation of the C4 hydroxyl
was accomplished in 89% yield with Ac2O and DMAP to give
16. Removal of the TIPS group from C13 with TASF5a
followed by addition of a solution of PhLi12 produced in one
operation baccatin III (17a, 33%) and 10-deacetylbaccatin III
(17b, 46%). Alternatively, when the C13 alcohol was isolated
(96% yield) and subsequently was reacted with PhLi, 17a and
17b (2:1, respectively) were obtained in a combined yield of
88%. Conversion of 17a and 17b to Taxol (1) has been
achieved by employing the known three- or four-step sequences,
respectively.20
In summary, this study introduces a new strategy for the
elaboration of taxanes, with pinene providing the complete A-
and key B-ring fragments and an aldol closure establishing the
C-ring. This strategy provides Taxol in the correct enantiomeric
form in 37 steps from verbenone, the air-oxidation product of
pinene. This represents the shortest reported synthesis of Taxol
and provides even more concise access to key analogues.
Further development of this strategy and biological studies on
analogues will be reported in due course.
a (k) DMAP (xs), CH2Cl2; TrocCl, 62%. (l) NaI, HCl(aq), acetone,
97% at 67% conversion. (m) MsCl, pyr, DMAP, CH2Cl2, 83%. (n)
LiBr, acetone, 79% at 94% conversion. (o) OsO4, pyr, THF; NaHSO3;
imid, CHCl3, 76% at 94% conversion. (p) triphosgene, pyr, CH2Cl2,
92%. (q) KCN, EtOH, 0 °C, 76% at 89% conversion. (r) (i-Pr)2NEt,
toluene, 110 °C, 95% at 83% conversion. (s) Ac2O, DMAP, 89%. (t)
TASF, THF, 0 °C; PhLi, -78 °C, 46% 10-deacetylbaccatin III, 33%
baccatin III.
to undergo elimination of the C5 ether through deprotonation
of the aldehyde. However, a molecular modeling study (Macro-
model, MM2* force field, Monte Carlo search) indicated that,
by opening the C1-C2 cyclic carbonate to the hydroxybenzoate,
the B-ring conformation would change, placing the C8 hydrogen
in superior alignment with the C9 carbonyl for the desired
deprotonation. In accord with this analysis, exposure of 9
(Scheme 2) to 4-pyrrolidinopyridine provided 10a and its
recyclable epimer 10b (11:1, respectively) in a combined yield
of 72%. This product ratio reflects a kinetic selectivity since
neither 10a nor 10b epimerized when resubjected to the reaction
conditions. Their interconversion can, however, be accom-
plished with NaHCO3 in MeOH. Protection of the C7 hydroxyl
of 10a with TrocCl (2,2,2-trichloroethyl chloroformate) and
pyridine gave 11 in quantitative yield. Conversion of 9 directly
to 11 has also been accomplished in 62% yield by initiating
cyclization of 9 with DMAP and adding TrocCl after complete
conversion of starting material.
Acknowledgment. This communication is Dedicated to the late
Matthew Suffness, a pioneer in the development of Taxol. The support
of this work through a grant (CA 31845) provided by the National
Institutes of Health is gratefully acknowledged. Exact mass analyses
were performed by the University of California, San Francisco Regional
Mass Spectrometry Facility. Fellowship support from the following
institutions is also gratefully recognized: Eli Lilly and Roche (P.E.F.),
National Science Foundation (T.E.G.), ACS Division of Organic
Chemistry and Pfizer (J.B.H.), National Institutes of Health (N.E.K.),
Bristol-Myers Squibb (D.L., M.G.N.), Syntex (D.L.), SERC/NATO
(D.G.M., A.J.S.), and Merck (R.E.T.).
Supporting Information Available: Spectroscopic data and ex-
perimental procedures for the reported compounds (20 pages). See
any current masthead page for ordering and Internet access information.
JA963539Z
(16) Samaranayake, G.; Magri, N. F.; Jitrangsri, C.; Kingston, D. G. I.
J. Org. Chem. 1991, 56, 5114-5119.
(17) 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. In Taxane Anticancer Agents: Basic Science and Current Status;
Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium
Series 583; American Chemical Society: Washington, DC, 1995; pp 288-
301.
Introduction of the oxetane and final functionalization started
with cleavage of the C5 BOM ether in 11 with HCl and NaI7
to form alcohol 12 in 97% yield at 67% conversion. Higher
conversion resulted in the formation of an undesired acid
(15) (a) For other examples of aldol self-assembly reactions, see:
Williams, D. R.; Jass, P. A.; Tse, H.-L. A.; Gaston, R. D. J. Am. Chem.
Soc. 1990, 112, 4552-4554. Hirama, M.; Noda, T.; Ito, S. J. Org. Chem.
1988, 53, 708-710. (b) The use of DMAP alone in this reaction gives a
10a/10b ratio of 5:1. The presence of only one Troc derivative (11) in the
one-step DMAP/TrocCl reaction involving 9 suggests that only 10a is
converted to the Troc derivative 11.
(18) Mori, K.; Tominaga, M.; Takigawa, T; Matsui, M. Synthesis 1973,
790-791.
(19) Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991,
47, 9823-9838.
(20) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Son, C. M.;
Brigaud, T. Tetrahedron 1992, 48, 6985-7012 and refs 5a and 17 cited
above.