In Quest for Polyenic Macrolactam JBIR-150 Identity: Stereoselective Synthesis of DP4+-Based Purported Structure and Biogenetically Inspired Positional Stereoisomers

Abstract

Total synthesis of polyenic macrolactam JBIR-150 with all-trans geometries, hydroxyl substituents located at C8 and C10 and 8R,10R,19R absolute configuration, the most likely stereoisomer predicted by DP4+ calculations, was completed. The formal syn-1,3-diol was synthesized iteratively by enantio- and diastereoselective Krische’s allylation reactions. The construction of the conjugated triene units was based on a SuzukiMiyaura cross-coupling of the corresponding alkenylboronatesand alkenyliodides, and Horner-Wadsworth-Emmons (HWE) condensation reactions. Macrolactam formation promoted by HATU and DIPEA was best carried out by amine protecting groupexchange and release of both reactive functional groups under basic conditions. Given the lack of correspondence of the 1Hand 13C-NMR data for the synthetic and purported JBIR-150, thehydroxyl groups of JBIR-150 were alternatively proposed to be located at the odd-numbered positions (C9, C11) based on the general biogenesis of the family of polyenic macrolactams andthe collinearity principle of their modular sequence. The C11-diastereoisomers of the biogenetically inspired 9,11-dihydroxy positional isomers (termed iso-JBIR-150) with formal syn- andanti-diol configurations were completed. Much to our dismay, the NMR data of the synthetic diastereomeric polyenic macrolactams with 9S,11S,19R or 9S,11R,19R absolute configuration did not match those of the natural product, and the structural identity of JBIR-150 remains undetermined.