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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.

Apratoxin A (1), a potent cytotoxin with a novel skeleton, has been isolated from the marine cyanobacterium Lyngbya majuscula Harvey ex Gomont. This cyclodepsipeptide of mixed peptide-polyketide biogenesis bears a thiazoline ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. Its gross structure has been elucidated by spectral analysis, including various 2D NMR techniques. The absolute configurations of the amino acid-derived units were determined by chiral HPLC analysis of hydrolysis products. The relative stereochemistry of the new dihydroxylated fatty acid unit, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid, was elucidated by successful application of the J-based configuration analysis originally developed for acyclic organic compounds using carbon-proton spin-coupling constants ((2,3)J(C,H)) and proton-proton spin-coupling constants ((3)J(H,H)); its absolute stereochemistry was established by Mosher analysis. The conformation of 1 in solution was mimicked by molecular modeling, employing a combination of distance geometry and restrained molecular dynamics. Apratoxin A (1) possesses IC(50) values for in vitro cytotoxicity against human tumor cell lines ranging from 0.36 to 0.52 nM; however, it was only marginally active in vivo against a colon tumor and ineffective against a mammary tumor.