Efficient Synthesis of Okadaic Acid. 2. Synthesis of the C1−C14 Domain and Completion of the Total Synthesis

Abstract

Described here are the full details of the preparation of a synthetic intermediate representing carbons 1−14 (C1−C14) of the marine natural product okadaic acid (1), the coupling of this fragment with the previously prepared C15−C38 domain, and the completion of an efficient total synthesis of 1. The C1−C14 intermediate was prepared in 11 steps and ∼20% overall yield from a functionalized δ-valerolactone derivative representing C3−C8 of 1. This featured a classic spiroketalization strategy to construct the highly substituted 1,7-dioxaspiro[5.5]undec-4-ene system, followed by incorporation of the intact C1−C2 α-hydroxyl, α-methyl carboxylate moiety using cis-(S)-lactate pivalidene enolate. The complete C1−C14 intermediate was converted into 1 in five additional steps. Coupling of the C1−C14 fragment with the C15−C38 domain of 1 via C14 aldehyde and C15 β-keto phosphonate moieties provided the complete carbon skeleton of 1 bearing a ketone at C16 and a mixed-methyl acetal at C19. Reduction of the C16 ketone using Corey's (S)-CBS/BH3 system and subsequent acid-triggered spiroketalization formed the central 1,6-dioxaspiro[4.5]decane ring system. Saponification of the C1−C2 pivalidene group and final reductive cleavage of the three benzyl ethers using lithium di-tert-butylbiphenylide in THF provided 1 in 48% yield from the C1−C14 aldehyde, and in 26 steps and ∼2% overall yield in the longest linear sequence from the C22−C27 synthon methyl 3-O-benzyl-α-d-altropyranoside.