Relative stereochemical determination of the C61-C83 fragment of symbiodinolide using a stereodivergent synthetic approach.

Structural determination is required in the use of marine natural products to create novel drugs and drug leads in medicinal chemistry. Symbiodinolide, which is a polyol marine natural product with a molecular weight of 2860, increases the intracellular Ca2+ concentration and exhibits inhibitory activity against cyclooxygenase-1. Seventy percent of the structure of symbiodinolide has been stereochemically clarified. Herein, we report the elucidation of the relative configuration of the C61-C83 fragment, which is among the remaining thirty percent, using a stereodivergent synthetic strategy. We first assigned the relative configuration of the C61-C74 fragment. Two candidate diastereomers of the C61-C74 fragment were synthesized, and their NMR data were compared with those of the natural product, revealing the relative stereochemistry of this component. We then narrowed down the candidate compounds for the C69-C83 fragment from 16 possible diastereomers by analyzing the NMR data of the natural product, and we thus selected eight candidate diastereomers. Stereodivergent synthesis of the candidates for this fragment and comparison of the NMR data of the natural product and the eight synthetic products resulted in the relative stereostructural clarification of the C69-C83 fragment. These individually determined relative stereochemistries of the C61-C74 and C69-C83 fragments were connected via the common C69-C73 tetrahydropyran moiety of the fragments. Finally, the relative configuration of the C61-C83 fragment of symbiodinolide was determined. The stereodivergent synthetic approach used in this study can be extended to the stereochemical determination of other fragments of symbiodinolide.

Unified Total Synthesis, Stereostructural Elucidation, and Biological Evaluation of Sarcophytonolides.

Sarcophytonolides are cembranolide diterpenes isolated from the soft corals of genus Sarcophyton. Unified total synthesis of sarcophytonolides C, E, F, G, H, and J and isosarcophytonolide D was achieved. The synthetic routes feature NaHMDS- or SmI2-mediated fragment coupling, alkoxycarbonylallylation, macrolactonization, and transannular ring-closing metathesis. These total syntheses led to the absolute configurational confirmation of sarcophytonolide H, elucidation of sarcophytonolides C, E, F, and G, and revision of sarcophytonolide J and isosarcophytonolide D. We also evaluated the antifouling activity and toxicity of the synthetic sarcophytonolides H and J and their analogues as well as the cytotoxicity of the synthetic sarcophytonolides and the key synthetic intermediates.