Total synthesis of cryptophycins-1,-3,-4,-24 (arenastatin A), and-29, cytotoxic depsipeptides from cyanobacteria of the Nostocaceae

A convergent synthesis of cryptophycins has been developed in which (5S,GR) -5-hydroxy-6-methyl-8-phenylocta-2(E),7(E)-dienoic add (A) is coupled with an amino acid. segment (B). Two stereoselective routes to A are described, the first employing allylation of an alpha-homochiral aldehyde and the seco nd using asymmetric crotylation of an achiral aldehyde to establish the two stereogenic centers present in a. The styryl moiety of A was attached eith er via Stille coupling or through a Wadsworth-Emmons condensation with diet hyl benzylphosphonate. The amino acid subunit B was prepared from benzyl (2 S)-2-hydroxyisocaproate by connection first to N-Boc-beta-alanine or its (2 R)-methyl-substituted derivative and then to (2R)-N-Boc-O-methyltyrosine or its nt-chloro derivative. Fusion of the A and B subunits was accomplished by initial esterification of the former with the latter, followed by macroc yclization using diphenyl phosphorazidate. In this way, cryptophycin-3, -4, and -29 were obtained along with the nonnatural cyclic depsipeptide 52. Ep oxidation of cryptophycin-3 with dimethyldioxirane gave cryptophycin-1; ana logous epoxidation of 52 afforded arenastatin A (cryptophycin-24).