Efficient Synthesis of Okadaic Acid. 1. Convergent Assembly of the C15−C38 Domain

Abstract

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-α-d-altropyranoside. A C28−C38 intermediate with a primary alkyl bromide at C28 was prepared in 10 steps from methyl (S)-3-hydroxy-2-methylpropionate. These fragments were then joined in ∼55% yield by conversion of the bromide into an alkylcerium reagent then addition to a sensitive β,γ-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 β-keto phosphonate completed the synthesis of the fully functionalized C15−C38 portion of okadaic acid in 19 linear steps and ∼3% overall yield from methyl 3-O-benzyl-α-d-altropyranoside.

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