Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition

Full text of DOI:10.1021/ja0155635

J. Am. Chem. Soc. 2001, 123, 3611-3612
3611
Stereoselective Syntheses of Epothilones A and B via
Directed Nitrile Oxide Cycloaddition1
Jeffrey W. Bode and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Zu¨rich
UniVersita¨tstrasse 16, CH-8092 Zu¨rich, Switzerland
ReceiVed January 19, 2001
The search for molecules which mimic the activity of the highly
successful anticancer drug Taxol has inspired impressive research
activity with particular emphasis by synthetic chemists on the
leading candidates, discodermolide and the epothilones.2 Herein
we describe concise, fully stereocontrolled syntheses of epothilones
A and B featuring diastereoselective, hydroxyl directed cycload-
ditions and convergent fragment couplings. This strategy provides
an expedient route to the constituent fragments that furthers the
ongoing, intense investigations aimed at developing a scalable
approach.
Figure 1.
Scheme 1a
The epothilones present two major stereochemical obstacles
to their effective syntheses. The first, construction of the C3-C8
region, has enjoyed intense scrutiny, particularly in the elegant
studies by Danishefsky.3 Additionally, notable approaches have
been documented by Nicolaou,4 Schinzer,5 Grieco,6 White,7
Panek,8 and Shibasaki.9 An important advance in this field was
recently reported by Mulzer,10 who described a highly stereose-
lective aldol addition involving a C7-C15 epoxy aldehyde
fragment.11 Approaches to the second obstacle, construction of
the C12-C15 cis-homoallylic epoxy alcohol, uniformly rely on
the stereoselective synthesis of the olefin and its oxidative
functionalization. While this approach has seen considerable use,
it encounters some difficulties associated with the stereocontrolled
synthesis of the cis-olefin as well as drawbacks of the ultimate
stereoselective epoxidation.
a Conditions: (a) tert-BuOCl, CH2Cl2; then 1.3 equiv of (R)-3-buten-
2-ol, 3.3 equiv of PrOH, 3.0 equiv of EtMgBr, room temperature; (b)
LiCl, DBU, 2-methylthiazole-4-carboxaldehyde, CH3CN, room temper-
ature; (c) TPAP, NMO, CH2Cl2, room temperature; (d) THF, -78 °C;
(e) TESOTf, Hu¨nig’s base, CH2Cl2, 0 °C.
i
cycloaddition was inspired by the work of Kanemasa,12 who has
reported the diastereoselective cycloaddition reaction of simple
aromatic nitrile oxides and allylic alcohols. Initial attempts to
utilize this method with nonaromatic nitrile oxides, in particular
those possessing the accompanying functionality required to effect
a convergent synthesis, were unsuccessful. In subsequent studies
we identified conditions which allowed for highly stereoselective
cycloaddition for a variety of reaction partners, including highly
functionalized ones. In this regard, the cycloadditions of the
versatile oxime 5 with chiral allylic alcohols is key to our strategy,
affording a highly convergent assembly of the epothilone subunits
4a,b. Combined with Mulzer’s diastereoselective aldol coupling,
this approach provides concise syntheses of the epothilones
(Figure 1).
The emerging limitations of contemporary, stereoselective
organic transformations (i.e., aldol, allylation, epoxidation) to a
practical epothilone synthesis prompted us to develop and explore
new reaction methodology for the facile introduction of stereo-
chemical complexity. The application of a directed nitrile oxide
Oxidation of 5 to the nitrile oxide was followed by highly
diastereoselective cycloaddition with commerically available (R)-
3-butene-2-ol to furnish 6 in 79% yield as a single isoxazoline
diastereomer (Scheme 1). Introduction of the thiazole side chain
utilizing Roush-Masamune conditions13 followed by Ley oxida-
tion14 of the secondary alcohol provided ketone 7 as a crystalline
solid. Chelation-controlled Grignard coupling with 815 proceeded
smoothly to afford the epothilone B C6-C15 fragment 4b in 81%
yield and >10:1 dr.16
The construction of the C6-C15 subunit for epothilone A
commmenced with the addition of 3-methylbutyn-3-ol17 to
aldehyde 11 (>20:1 dr) to furnish 12 following treatment of the
crude product with BzCl (Scheme 2). Acetylene deprotection of
12 (K2CO3, catalytic 18-crown-6) followed by LiAlH4 reduction
of the propargylic benzoate directly afforded allylic alcohol 13.
(1) Dedicated to Professor David A. Evans on the occasion of his 60th
birthday.
(2) For reviews, see: (a) Mulzer, J. Monatsh. Chem. 2000, 131, 205-238.
(b) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem., Int. Ed.
1998, 37, 2014-2045. (c) Altmann, K. H.; Bold, G.; Caravatti, G.; End, N.;
Florsheimer, A.; Guagnano, V.; O’Reilly, T.; Wartmann, M. Chimia 2000,
54, 612-621.
(3) (a) Balog, A.; Meng; Kamenecka, T.; Bertinato, P.; Su, D. S.; Sorensen,
E. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2801. (b) Harris, C. R.; Kuduk,
S. D.; Balog, A.; Savin, K.; Glunz, P. W.; Danishefsky, S. J. J. Am. Chem.
Soc. 1999, 121, 7050-7062. (c) Wu, Z.; Zhang, F.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2000, 24, 4505-4508.
(4) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 166. (b) Nicolaou, K. C.; Ninkovic,
S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang,
Z. J. Am. Chem. Soc. 1997, 119, 7974-7990.
(5) (a) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523. (b) Schinzer, D.; Bauer, A.; Bo¨hm,
O. M.; Limberg, A.; Cordes, M. Chem. Eur. J. 1999, 5, 2483. (c) Schinzer,
D.; Bauer, A.; Schieber, J. Chem. Eur. J. 1999, 5, 2492.
(6) May, S. A.; Grieco, P. A. Chem. Commun. 1998, 1597.
(7) White, J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999,
64, 684-685.
(12) Kanemasa, S.; Nishiuchi, M.; Kamimure, A.; Hori, K. J. Am. Chem.
Soc. 1994, 116, 2324-2339.
(13) Blanchette M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(14) Griffen, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. Chem.
Commun. 1987, 1625.
(15) Compounds 8 and 10 were prepared via pseudoephedrine enolates:
Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason,
J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(16) The addition of nucleophiles to similar systems has been reported:
Curran, D. P.; Zhang, J. J. Chem. Soc., Perkins Trans. 1 1991, 2613-2625.
(17) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org.
Lett. 2000, 2, 4233-4236.
(8) Zhu, B.; Panek, J. Org. Lett. 2000, 2, 2575-2578.
(9) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
10521-10532.
(10) (a) Martin, H. J.; Drescher, M.; Mulzer, J. Angew. Chem., Int. Ed.
2000, 39, 581-583. (b) For another approach, see: Mulzer, J.; Mantoulidis,
A.; O¨ hler, E. J. Org. Chem. 2000, 65, 7456-7467.
(11) Nicolaou has reported a similar observation by introduction of a remote
ether moiety: Nicolaou, K. C.; Hepworth, D.; King, N. P.; Finlay, M. R. V.;
Scarpelli, R.; Pereira, M. M. A.; Bollbuck, B.; Bigot, A.; Werschkun, B.;
Winssinger, N. Chem. Eur. J. 2000, 6, 2783-2800.
10.1021/ja0155635 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/23/2001

3612 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Communications to the Editor
Scheme 2a
Scheme 4a
a Conditions: (a) O3, CH2Cl2, PPh3; (b) 2.1 equiv of 3-methylbutyn-
3-ol, 2.1 equiv of (+)-N-methylephedrine, 2.0 equiv of Zn(OTf)2, NEt3,
room temperature; then BzCl, NEt3; (c) catalytic 18-crown-6, K2CO3,
PhCH3, reflux; (d) LiAlH4, Et2O; (e) 1.3 equiv of 5, 3.0 equiv of EtMgBr,
3.3 equiv of PrOH, CH2Cl2; (f) TBSOTf, Hu¨nig’s base, CH2Cl2, 0 °C;
(f) LiCl, DBU, 2-methylthiazole-4-carboxaldehyde, CH3CN, room tem-
perature.
t
a Conditions: (a) OsO4, NMO, BuOH-THF-H2O; then Pb(OAc)4,
EtOAc, 86%; (b) HF‚pyr, pyr, THF, 0 °C; then NaOCl2, 2-methyl-2-
butene-tBuOH, 76%; (c) 2,4,6-trichlorobenzoyl chloride, NEt3, DMAP,
room temperature, 74%; (d) Zn, NH4Cl, MeOH, room temperature, 84%;
(e) 3:1 (pyr[HF‚pyr]), 35-40 °C, 7 days, 38% at 40% conversion.
i
Scheme 3a
in anticipation of the key epoxide formation. We discovered a
convenient solution by 1,3-cyclic sulfite formation followed by
the action of Bu4NF‚3H2O in refluxingTHF to effect, in one pot,
desilylation, ring formation, and loss of SO2. This reaction resulted
in clean formation of â-hydroxy epoxide 16a,b in 77% overall
yield and provided considerable advantages over the correspond-
ing cyclic sulfate,22 as it avoids both the oxidation step and
sulfonic acid hydrolysis in the presence of the labile epoxide.
Following transformation of 16a,b, aldehydes 3a,b were poised
for stereoselective aldol couplings. Although the aldol addition
of 17 to 3b has precedence in the work of Mulzer, the success of
the corresponding reaction in the epothilone A series was far from
clear given the abundance of remote effects in related systems.3,10
However, both 3a and 3b underwent smooth aldol coupling with
174b to provide 2a,b in 86% yield and >10:1 dr (1H, 13C NMR
analysis).
With a formal synthesis of epothilone B in hand, epothilone A
was completed, confirming the stereochemistry of the aldol
reaction and the viability of our approach. Following transforma-
tion of 18a to seco-acid 19a, macrolactonization was effected in
74% yield. Although C7-OTroc deprotection proceeded without
incident, the C3-OTBS proved remarkably recalcitrant. Careful
optimization of HF‚pyr conditions (3:1 pyr:[HF‚pyr], 40 °C)
afforded synthetic epothilone A (1a) identical with the reported
data (1H, 13C, IR, HRMS, [R]D).
In summary, we have reported the expedient, completely
stereocontrolled total synthesis of epothilone A (21 steps) and
the concise construction of the fully assembled epothilone B
backbone 2a (11 steps), constituting its formal synthesis (18 steps
in total). As well, we have introduced and established a powerful,
directed nitrile oxide cycloaddition which utilizes readily available,
stable starting materials to achieve a convergent and highly
diastereoselective coupling under operationally simple reaction
conditions. These studies provide a timely contribution to the
development of a practical synthetic approach to the epothilones
and analogues.
a Conditions: (a) SmI2, THF, 0 °C, 75-76%; (b) Et3B, NaBH4, THF-
MeOH, -78 °C, 88-90%; (c) SOCl2, NEt3; then Bu4NF‚3H2O, THF,
reflux, 77%; (d) TESCl, NEt3, CH2Cl2, 75-79%; (e) 3:3:1 AcOH:THF:
H2O, room temperature; then TPAP, NMO, CH2Cl2 64-81%; (f) 1.5
equiv of 17, 1.5 equiv of LDA, then 3, -78 °C, 86%; (g) TrocCl, pyr,
CH2Cl2, 0 °C, 91%.
We were pleased to observe that this allylic alcohol underwent
clean, diastereoselective cycloaddition, which after protection and
olefination afforded 9a.
The completion of the syntheses of both epothilones subse-
quently followed a parallel course (Scheme 3). Although reduction
of isoxazolines to â-hydroxy-ketones18 is well-precedented, this
transformation is virtually unknown for conjugated isoxazolines.19
All attempts to effect this transformation on 9a,b with conven-
tional reagents (Raney-Ni, Mo(CO)6, O3) were unsuccessful due
to competing reaction of the conjugated olefin. We were pleased
to discover that treatment of 9a,b with SmI2 (THF, 0 °C) resulted
in clean reduction of the N-O bond without injury to the olefin.20
Reduction of the resulting ketone21 (Et3B, NaBH4) provided
syn-diol 15a,b and left us to differentiate the two hydroxyl groups
(18) Alternatively, we have observed that the isoxazoline may be reduced
to an amino alcohol providing a potential entry to aza-epothilones related to
those described in elegant semisynthetic studies: Borzilleri, R. M.; Zheng,
X.; Schmidt, R. J.; Johnson, J. A.; Kim, S. H.; DiMarco, J. D.; Fairchild, C.
R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem.
Soc. 2000, 122, 8890-8897.
(19) Torsell has reported a two-step procedure via alkylation of the
isoxazoline nitrogen followed by electrochemical reduction: Isager, P.;
Thomsen, I.; Torsell, K. G. B. Acta Chem. Scand. 1990, 44, 806. This method
is not compatible with our highly functionalized substrate.
(20) The use of SmI2 to cleave N-O bonds of alkoxylamines and
hydroxamic esters has been described: (a) Keck G. E.; McHardy, S. F.; Wager,
T. T. Tetrahedron Lett. 1995, 41, 7419. (b) Chiara, J.; Destabel, C.; Gallego,
P.; Marco-Contelles, J. J. Org. Chem. 1996, 61, 359.
(21) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.; Repic,
O.; Shapiro, M. J. Chem. Lett. 1987, 1923-1926.
Acknowledgment. We are grateful to Prof. Mulzer for copies of
spectra for 2b and 3b and to Boehringer-Ingelheim for a generous gift
of (R)-3-buten-2-ol. Support has been provided by generous funds from
the ETH, Kontaktgruppe fu¨r Forschungsfragen (KGF), Merck, and
Hoffmann-La Roche. J.W.B. thanks the National Science Foundation
(USA) for a predoctoral fellowship.
Supporting Information Available: Experimental procedures, spec-
tral data, and structure correlation for all relevant compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA0155635
(22) Lohray, B. B. Synthesis 1992, 1035-1052.