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

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 Land 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 16membered 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-methylD-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, 47294731. (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. M. L. ; Moore, R. E. Manuscript in preparation. An explanation of the structural misassignment for cryptophycins A and C is presented. (4) Heltzel, C. E. ; Ogino, J.; Trimurtulu, G. ; Mooberry, S. L. ; Patterson, G. M. L. ; Moore, R. E. ; Corbett, T. H. ; Valeriote, F. A,; Demchik, L. Manuscript in preparation. A Figure 1. Numbering system for each of the units of cryptophycins C and D. This numbering system is used for the NMR data.