Efficient synthesis of okadaic acid. 2. Synthesis of the C1-C14 domain and completion of the total synthesis

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-C13 intermediate was prepared in 11 steps and similar to 20% overall yield from a functionalized delta-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 alpha-hydroxyl, alpha-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 beta-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 similar to 2% overall yield in the longest linear sequence from the C22-C27 synthon methyl 3-O-benzyl-alpha-D-altropyranoside.