Efficient synthesis of okadaic acid. 1. Convergent assembly of the C15-C38 domain

A convergent synthesis of the C15-C38 domain of the marine natural product okadaic acid is reported. This involved the preparation of intermediates representing the C16-C27 and C28-C38 portions of okadaic acid, their direct coupling, and elaboration to the complete C15-C38 intermediate. A C16-C27 intermediate bearing an aldehyde at C27 was constructed in 14-steps from methyl 3-O-benzyl-alpha-D-altropyranoside. A C28-C38 intermediate with a primary alkyl bromide at C28 was prepared in IO steps from methyl (S)-3-hydroxy-2-methylpropionate. These fragments were then joined in similar to 55% yield by conversion of the bromide into an alkylcerium reagent then addition to a sensitive beta,gamma-unsaturated C27 aldehyde to give a mixture of C27 carbinols (27R:27S = 2.5:1). The configuration at C27 of the major coupling product was inverted by a simple oxidation-reduction sequence to establish the 27S-configuration of okadaic acid. Elaboration into a C15 beta-keto phosphonate completed the synthesis of the fully functionalized C15-C38 portion of okadaic acid in 19 linear steps and similar to 3% overall yield from methyl 3-O-benzyl-alpha-D-altropyranoside.