Synthesis and stereochemistry of a helical 2,18-bridged biliverdin

Abstract

Biliverdin-IIIα dimethyl ester (1) when treated with acidic methanol undergoes ring closure of the exocyclic vinyl groups with consecutive addition of two methoxy groups and oxidation, predominantly affording (3). The four-membered bridge connecting the pyrrolinone rings possesses two chiral centres of equal configuration either (1′R,4′R) or (1′S,4′S). Due to the M/P helicity of the bilatriene backbone, (3) comprises two thermally interconvertible diastereoisomeric pairs of enantiomers, viz. (3a) of configuration [(P,1′R,4′R) and (M,1′S,4′S)] and (3b) of configuration [(M,1′R,4′R) and (P,1′S,4′S)]. Their stereochemistry was assigned by n.m.r. techniques. The flexibility of the bilatriene unit is restricted so the separation of (3a) and (3b) can be seen at moderately low temperatures. Despite geometric contraints the torsional angles of the bilatriene backbones are close to non-bridged helical shaped derivatives. A mechanism for the acid mediated cyclisation reaction is proposed and briefly discussed.