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 (5 S,6 R )-5-hydroxy-6-methyl-8-phenylocta-2( E),7( E) -dienoic acid (A) is coupled with an amino acid segment (B). Two stereoselective routes to A are described, the first employing allylation of an α-homochiral aldehyde and the second using asymmetric crotylation of an achiral aldehyde to establish the two stereogenic centers present in A. The styryl moiety of A was attached either via Stille coupling or through a Wadsworth−Emmons condensation with diethyl benzylphosphonate. The amino acid subunit B was prepared from benzyl (2 S )-2-hydroxyisocaproate by connection first to N -Boc-β-alanine or its (2 R )-methyl-substituted derivative and then to (2 R )- N -Boc- O -methyltyrosine or its m -chloro derivative. Fusion of the A and B subunits was accomplished by initial esterification of the former with the latter, followed by macrocyclization using diphenyl phosphorazidate. In this way, cryptophycin-3, -4, and -29 were obtained along with the nonnatural cyclic depsipeptide 52 . Epoxidation of cryptophycin-3 with dimethyldioxirane gave cryptophycin-1; analogous epoxidation of 52 afforded arenastatin A (cryptophycin-24).