ORGANIC
LETTERS
2002
Vol. 4, No. 10
1637-1640
Stereospecific Synthesis of
Cryptophycin 1
Lian-Hai Li and Marcus A. Tius*
Department of Chemistry, 2545 The Mall, UniVersity of Hawaii,
Honolulu, Hawaii 96822
Received January 2, 2002
ABSTRACT
A brief stereospecific synthesis of cryptophycin 1 is described in which (R)-mandelic acid serves as the sole source of asymmetry for unit
A. The key step is a hetero-Diels−Alder cycloaddition.
A systematic effort to collect, culture, and screen extracts
from cyanophytes (blue-green algae) was initiated in the
1980s by Richard E. Moore and Gregory M. L. Patterson in
the University of Hawaii Chemistry Department.1 During the
time that this program was active, a large number of potent
cytotoxins, many of which possessed unique, unprecedented
structures, were discovered. The most potent selectively
cytotoxic compound to emerge from this program, crypto-
phycin 1, was isolated from a crude lipophilic extract of
Nostoc sp. GSV 224.2 Some years earlier, researchers at
Merck had isolated the same compound from Nostoc sp.
ATCC 53789.3,4 Although the Merck group elucidated the
gross structure, no details of the relative or absolute
stereochemistry were disclosed. Our group published the first
total synthesis of the cryptophycins in 1995.5 The total
synthesis also served to correct the structure of cryptophycin
1. Since then, the realization that the cryptophycins represent
a new class of extraordinarily potent, solid tumor-selective
cytotoxins6 led to the development of a number of total
syntheses, as well as syntheses of cryptophycin analogues
and fragments.7
The cryptophycins can be logically divided into four units.
Unit A is polyketide-derived, whereas units B-D are derived
from amino acids. The first obvious retrosynthetic step is
removal of the epoxide function. This leads to cryptophycin
3, a naturally occurring congener. This approach is appealing,
(6) Shih, C.; Teicher, B. A. Curr. Pharm. Des. 2001, 7, 1259.
(7) (a) Salamonczyk, G. M.; Han, K.; Guo, Z.-W.; Sih, C. J. J. Org.
Chem. 1996, 61, 6893. (b) Rej, R.; Nguyen, D.; Go, B.; Fortin, S.; Lavalle´e,
J.-F. J. Org. Chem. 1996, 61, 6289. (c) Gardinier, K. M.; Leahy, J. W. J.
Org. Chem. 1997, 62, 7098. (d) Ali, S. M.; Georg, G. I. Tetrahedron Lett.
1997, 38, 1703. (e) Varie, D. L.; Brennan, J.; Briggs, B.; Cronin, J. S.;
Hay, D. A.; Rieck, J. A., III; Zmijewski, M. J. Tetrahedron Lett. 1998, 39,
8405. (f) Furuyama, M.; Shimizu, I. Tetrahedron: Asymmetry 1998, 9, 1351.
(g) Dhokte, U. P.; Khau, V. V.; Hutchison, D. R.; Martinelli, M. J.
Tetrahedron Lett. 1998, 39, 8771. (h) Liang, J.; Hoard, D. W.; Khau, V.
V.; Martinelli, M. J.; Moher, E. D.; Moore, R. E.; Tius, M. A. J. Org.
Chem. 1999, 64, 1459. (i) White, J. D.; Hong, J.; Robarge, L. A. J. Org.
Chem. 1999, 64, 6206. (j) Christopher, J. A.; Kocienski, P. J.; Kuhl, A.;
Bell, R. Synlett 2000, 463. (k) Eggen, M.; Mossman, C. J.; Buck, S. B.;
Nair, S. K.; Bhat, L.; Ali, S. M.; Reiff, E. A.; Boge, T. C.; Georg, G. I. J.
Org. Chem. 2000, 65, 7792. (l) Barrow, R. A.; Moore, R. E.; Li, L.-H.;
Tius, M. A. Tetrahedron 2000, 56, 3339. (m) Pousst, C.; Haddad, M.;
Larcheveque, M. Tetrahedron 2001, 57, 7163. (n) Eggen, M.; Nair, S. K.;
Georg, G. I. Org. Lett. 2001, 3, 1813. See also: Kobayashi, M.; Kurosu,
M.; Wang, W.; Kitagawa, I. Chem. Pharm. Bull. 1994, 42, 2394. Kobayashi,
M.; Wang, W.; Ohyabu, N.; Kurosu, M.; Kitagawa, I. Chem. Pharm. Bull.
1995, 43, 1598.
(1) Moore, R. E.; Corbett, T. H.; Patterson, G. M. L.; Valeriote, F. A.
Curr. Pharm. Des. 1996, 2, 317.
(2) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.; Corbett,
T. H.; Valeriote, F. A.; Demchik, L. J. Am. Chem. Soc. 1994, 116, 4729.
(3) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.; Chartrain,
M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J.; Liesch, J. M.; Yudin,
K. J. Ind. Microbiol. 1990, 5, 113.
(4) Hirsch, C. F.; Liesch, J. M.; Salvatore, M. J.; Schwartz, R. E.; Sesin,
D. F. U.S. Patent 4,946,835, August 7, 1990.
(5) Barrow, R.; Hemscheidt, T.; Paik, S.; Liang, J.; Moore, R. E.; Tius,
M. A. J. Am. Chem. Soc. 1995, 117, 2479.
10.1021/ol020001r CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/18/2002