Total Synthesis of Cryptophycins. Revision of the Structures of Cryptophycins A and C

Abstract

The convergent total synthesis of cryptophycins C and D is described. It has been shown that in both natural products the absolute configuration of the a-amino acid corresponds to the D-series. The structural assignment for cryptophycin C has been corrected to reflect this fact. Since the structure of cryptophycin A has been correlated to cryptophycin C, the chloro-0-methyltyrosine unit in cryptophycin A has the D-configuration.Cryptophycins are potent tumor-selective cytotoxins associated with the terrestrial blue-green algae Nostoc sp. GSV 224' and Nostoc sp. ATCC 53789.2 The major cytotoxin in each alga, cryptophycin A, shows excellent activity against solid tumors implanted in mice, including a drug-resistant tumor. Over 20 related cytotoxins are present in the GSV 224 strain as minor constituent^,'^^ and some of these compounds, e.g., cryptophycins B and C, have been isolated in sufficient amounts for in vivo e~aluation.~ In order to acquire adequate quantities of selected naturally-occurring cryptophycins and synthetic analogs for structure-activity relationship (SAR) studies, preclinical evaluation, and human clinical trials, we have designed a general synthesis. Cryptophycins C and D, as described in the original paper, were chosen to be the initial targets as they represented examples from both of the alleged L-and D-tyrosine series. We report here the total syntheses of cryptophycins C and D which (1) revise the structures of cryptophycins A and C to reflect the D-configuration for the a-amino acid unit as depicted in the structural drawings in this paper and (2) confirm the structures of cryptophycins B and D.Retrosynthetic analysis of the cryptophycins was straightforward: the structure is composed of four units (A-D, Figure 1); consequently several convergent approaches could be envisioned. The combination of two pairs of units (e.g., A-B and C-D) appeared to be optimally convergent. Since the success of the synthesis depended on the formation of a 16-membered depsipeptide from an acyclic precursor, a macrolactamization involving the amino group of unit C and the carboxylate of unit B appeared to be the best choice. The acyclic precursor to cryptophycin D would therefore be 1. This, in turn, suggested a disconnection into two fragments, one represented by 2 and composed of (S)-( -)-2-hydroxy-4-methylvaleric (L-leucic) acid (D) and (R)-3-amino-2-methylpropanoic acid (C) units, and the other by 3 and composed of O-methyl-D-tyrosine (B) and (2E,7E,5S,6R)-5-hydroxy-6-methyl-8-phenyloctadienoic acid (A) units. In the direction of the synthesis, @ Abstract published in Advance ACS Absfracts, February 15, 1995. (1) 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, 4729-4731. (2) 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, 113-24. (3) Trimurtulu, G.; Ogino, J.; Heltzel, C. E.; Patterson, G...

Chiral amides via copper-catalysed enantioselective conjugate addition

“…21,22 The enantioselective CA to substrates 1 and 2 was performed, with EtMgBr (1.5 equiv. ), CuBr·SMe 2 (5 mol%) and L1 (7.5 mol%) in methyl tert-butyl ether (MTBE).…”

A novel consecutive three-component Heck-isomerization-Wittig sequence by way of in situ generated aldehydes

“…16 5-(Hetero)arylpent-2-enoates 4 are interesting intermediates in organic synthesis. They can be regarded as structural precursors for the preparation of numerous natural and pharmacological active compounds, such as kavalactones, 19 GnRh receptor antagonists, 20 chromanes, 21 dihydrochinoline 22 , cryptophycins, 23 eupolauramine, 24 and HIV-1 protease inhibitors. 25 As a consequence of the generation of an α,β-unsaturated ester, 5-(hetero)arylpent-2-enoates 4 are versatile reaction partners for Michael reactions, 26 dihydroxylations, 27 cycloadditions, 28 and for elaborations into allylic alcohols.…”

Total Synthesis of Cryptophycin A and Analogs

“…3 Cryptophycin A (1), is the most abundant cytotoxin of the cryptophycins. 4 Its structure was determined by Moore and coworkers in 1995 (Figure l).…”