Stereodivergent Synthesis and Relative Stereostructure of the C1-C13 Fragment of Symbiodinolide

Abstract

Symbiodinolide (1), a 62-membered polyol macrolide marine natural product, was isolated from the cultured dinoflagellate Symbiodiniumsp. in 2007. This natural product exhibits voltage-dependent N-type Ca²⁺ channel-opening activity at 7 nM and COX-1 inhibition effect at 2 μM (65% inhibition). The planar structure of 1 was assigned by the detailed 2D NMR spectroscopic techniques. However, the stereostructure of 1 has not been elucidated yet because of its huge and complicated molecular structure characterized by molecular weight of 2,860 and 61 chiral centers. Previously, as a degradation of 1, we carried out the methanolysis and subsequent oxidative cleavage with Grubbs II catalyst/NaClO to yield the C1–C13 fragment 2. Herein, we report the stereostructural analysis, stereodivergent synthesis, and relative configuration of the C1–C13 fragment of 1.

First, we analyzed the stereostructure of the degraded product 2 by using the ¹H NMR data, which revealed that the relative stereochemical relationships at the C5 and C7 positions to the C6 position are same. Next, we synthesized all four possible diastereomers 2a–2d in a stereodivergent manner, wherein aldol reaction of methyl acetoacetate with the aldehyde, diastereoselective reduction of the resulting β-hydroxy ketone, and the stereoinversion at the C6 position were the key transformations. Detailed comparison of the ¹H NMR spectra of the synthetic 2a–2d with that of the degraded product 2 unambiguously elucidated the relative stereochemistry of the C1–C13 fragment to be that described in 2b.