reported to create more rigorously modified analogs8,9 that
might perhaps provide a higher degree of pharmacological
differentiation from the natural product leads. Our own
research in the area of natural-product-based microtubule
stabilizers has thus focused on the development of “hyper-
modified” epothilone analogs (i.e., molecules with very
limited, if any, structural similarity with the original epothilone
scaffold) that would eventually represent new chemotypes
for microtubule stabilization.9 In this context we have
previously reported the total synthesis of analog 3 (Figure
1), which exhibits potent tubulin-polymerizing and antipro-
liferative activity.9c
Compared to our synthesis of 3, which had relied on the
late stage stereoselective epoxidation of a C12-C13 E-
double bond after macrolactonization-based ring closure,9c
the presence of an additional double bond in 2 clearly
mandated the installment of the cyclopropane moiety to occur
at an earlier stage. This led to a completely different overall
strategy for the synthesis of 1 and 2 (compared to 3), which
is outlined in Scheme 1. Thus, while target structure 1 was
Scheme 1. Retrosynthetic Analysis for Target Structures 1
and 2
In a next step we are now exploring whether specific
structural changes in the Northern part of 3 will have similar
effects on biological activity as have been observed for
natural epothilones. Among the most relevant of these
modifications are the replacement of the epoxide moiety by
a cyclopropane ring (leading to target structure 1, Figure 1)
and the incorporation of an E-double bond between C9 and
C10 (target structure 2, Figure 1). Both types of modifications
are known to preserve or even increase the antiproliferative
activity of Epo B or D, while simultaneously providing
distinct advantages at the pharmacological level.10,11
(3) For reviews on the total synthesis of epothilones, see: (a) Watkins,
E. B.; Chittiboyina, A. G.; Avery, M. A. Eur. J. Org. Chem. 2006, 18,
4071-4084. (b) Altmann, K.-H. Org. Biomol. Chem. 2004, 2, 2137-2152.
(c) Nicolaou, K. C.; Ritze´n, A.; Namoto, K. Chem. Commun. 2001, 1523-
1535. (d) Harris, C. R.; Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434-
8456. (e) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem.,
Int. Ed. 1998, 37, 2015-2045.
(4) For recent reviews on the epothilone SAR, see: (a) Altmann, K.-H.;
Pfeiffer, B.; Arseniyadis, S.; Pratt, B. A.; Nicolaou, K. C. ChemMedChem
2007, 2, 396-423. (b) Ho¨fle, G.; Reichenbach, H. Anticancer Agents from
Natural Products; CRC Press: Boca Raton, 2005; pp 413-450.
(5) Larkin, J. M. G.; Kaye, S. B. Expert Opin. InVest. Drugs 2006, 15,
691-702.
(6) Altmann, K.-H. Curr. Pharm. Design 2005, 11, 1595-1613.
(8) For examples, see: (a) Alhamadsheh, M. M; Gupta, S.; Hudson, R.
A.; Perera, L.; Tillekeratne, L. M. V. Chem. Eur. J. 2008, 14, 570-581.
(b) Alhamadsheh, M. M.; Hudson, R. A.; Tillekeratne, L. M. V. Org. Lett.
2006, 8, 685-688. (c) Winkler, J. D.; Holland, J. M.; Kasparec, J.; Axelsen,
P. H. Tetrahedron 1999, 55, 8199-8214.
(9) (a) Feyen, F.; Cachoux, F.; Gertsch, J.; Wartmann, M.; Altmann,
K.-H. Acc. Chem. Res. 2008, 41, 21-31. (b) Feyen, F.; Gertsch, J.;
Wartmann, M.; Altmann, K.-H. Angew. Chem., Int. Ed. 2006, 45, 5880-
5885. (c) Cachoux, F.; Isarno, T.; Wartmann, M.; Altmann, K.-H. Angew.
Chem., Int. Ed. 2005, 44, 7469-7473. (d) Cachoux, F.; Schaal, F.; Teichert,
A.; Wagner, T.; Altmann, K.-H. Synlett 2004, 2709-2712.
(10) For cyclopropane-based epothilone analogs, see: (a) Nicolaou, K.
C.; Sasmal, P. K.; Rassias, G.; Reddy, M. V.; Altmann, K.-H.; Wartmann,
M.; O’Brate, A.; Giannakakou, P. Angew. Chem., Int. Ed. 2003, 42, 3515-
3520. (b) Nicolaou, K. C.; Namoto, K.; Ritze´n, A.; Ulven, T.; Shoji, M.;
Li, J.; D’Amico, G.; Liotta, D.; French, C. T.; Wartmann, M.; Altmann,
K.-H.; Giannakakou, P. J. Am. Chem. Soc. 2001, 123, 9313-9323. (c)
Nicolaou, K. C.; Namoto, K.; Li, J.; Ritzen, A.; Ulven, T.; Shoji, M.;
Zaharevitz, D.; Gussio, R.; Sackett, D. L.; Ward, R. D.; Hensler, A.; Fojo,
T.; Giannakakou, P. Chembiochem 2001, 2, 69-75. (d) Johnson, J.; Kim,
S. H.; Bifano, M.; DiMarco, J.; Fairchild, C.; Gougoutas, J.; Lee, F.; Long,
B.; Tokarski, J.; Vite, G. Org. Lett. 2000, 2, 1537-1540.
envisioned to be accessible from 2 through simple hydro-
genation, the latter was foreseen to be assembled via an
esterification-RCM sequence from building blocks 4 and
5. The synthesis of 4 would take advantage of the com-
mercially available (S)-Roche ester 9 as a precursor for
aldehyde 6,12 whose aldol reaction with γ-keto ester 79c
would set the stereocenters at C6, C7, and C8.
The Eastern part of the molecule would be derived from
dimethyl benzimidazole aldehyde 89b via enantioselective
allylation,13 homologation, and subsequent stereoselective
cyclopropanation of an allylic alcohol14 as the key step.
As illustrated in Scheme 2, the aldol reaction between
aldehyde 6 and γ-keto ester 7 produced two syn products in
a ratio of 1.4:1 in favor of 10. Separation of these dia-
stereomers by flash chromatography was straightforward, and
the stereochemistry of the major isomer 10 was established
by Mosher ester analysis.15 In light of the ease of isolation
of pure 10, no attempts were made at this point to improve
the selectivity of the reaction. TBS protection of the newly
formed secondary hydroxyl group followed by catalytic
hydrogenation of the double bond and oxidative cleavage
of the terminal PMB protecting group with DDQ then
furnished hydroxy ester 11. The latter was homologated by
TPAP/NMO oxidation16 and subsequent Wittig methyl-
enation to furnish olefin 12. Finally, ester hydrolysis gave
building block 4 in quantitative yield (from 12).
(11) For 9,10-dehydro-epothilones, see: (a) Chou, T. C.; Dong, H. J.;
Zhang, X. G.; Tong, W. P.; Danishefsky, S. J. Cancer Res. 2005, 65, 9445-
9454. (b) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Chou, T.
C.; Dong, H. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 10913-
10922. (c) Yoshimura, F.; Rivkin, A.; Gabarda, A. E.; Chou, T. C.; Dong,
H. J.; Sukenick, G.; Morel, F. F.; Taylor, R. E.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 2518-2521. (d) Rivkin, A.; Yoshimura, F.;
Gabarda, A. E.; Chou, T. C.; Dong, H. J.; Tong, W. P.; Danishefsky, S. J.
J. Am. Chem. Soc. 2003, 125, 2899-2901. (e) Chou, T. C.; Dong, H. J.;
Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Tong, W. P.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 4761-4767.
(12) Walkup, R. D.; Kahl, J. D.; Kane, R. R. J. Org. Chem. 1998, 63,
9113-9116.
(13) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995,
500, 1-19.
(14) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem.
Soc. 1998, 120, 11943-11952.
(15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(16) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625-1627.
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