Total Synthesis and Complete Stereostructure of Didemnaketal B

Abstract

Didemnaketals A, B, and C were isolated from the extract of the magenta ascidian Didemnum sp. collected at Auluptagel Island in Palau by Faulkner and co-workers. The gross structures of didemnaketals were determined by extensive 2D-NMR spectroscopic analyses. The absolute configuration of didemnaketal B was subsequently proposed on the basis of degradation/derivatization experiments, X-ray crystallographic analysis, and application of chiral anisotropic reagents. However, the total synthesis of a structural homologue didemnaketal A by Tu and co-workers questioned the stereochemical assignment made by Faulkner et al. Here we describe the first total synthesis of the proposed structure 2 of didemnaketal B, which featured (1) our spiroacetal synthesis strategy exploiting Suzuki−Miyaura coupling for the C7−C20 domain; (2) Evans syn-aldol and vinylogous Mukaiyama aldol reactions for the C1−C7 acyclic domain; and (3) a Nozaki−Hiyama−Kishi reaction for a late-stage introduction of the C21−C28 side chain. However, the NMR spectroscopic properties of synthetic 2 did not match those of authentic didemnaketal B. Careful comparison of the NMR spectroscopic data of synthetic 2 with those of the authentic sample as well as the application of the phenylglycine methyl ester (PGME) method to a C7−C20 spiroacetal model compound led us to postulate that the absolute configuration of the C10−C20 domain of 2 has been erroneously assigned. Accordingly, we revised the structure of didemnaketal B to be shown by 30, which was eventually verified by our total synthesis. Thus, we have established the complete stereostructure of didemnaketal B.