Gibbosolide A, a highly functionalized 20-membered macrolide with a terminal cis-fused 2-methylhexahydro-2H-furo[3,2-b]pyran motif: insights into late-stage cyclization of marine macrolides

Abstract

A sailboat-shaped 20-membered macrolide, named gibbosolide A, featuring a rare cis-fused 2-methylhexahydro-2H-furo[3,2-b]pyran motif, was obtained from the South China Sea dinoflagellate, Amphidinium gibbosum. Its planar structure and absolute configuration, containing twelve carbon stereocenters, were unambiguously established by extensive NMR investigations, J-based configuration analysis, NOE interactions, ozonolysis of the carbon–carbon double bonds, and the modified Mosher's α-methoxy-α-(trifluoromethyl)phenylacetyl (MTPA) ester method. It displays activation effects on human farnesoid–X–receptor within the concentration range of 200.0 nM to 2.0 μM. Its late-stage cyclization mechanisms are proposed. Most notably, ozonolysis of the carbon–carbon double bonds combined with the modified Mosher's ester method is a useful approach for the unambiguous determination of absolute configurations of hydroxy-bearing carbon stereocenters within the complex macrolide core.