Evolution of the Short Enantioselective Total Synthesis of the Unique Marine Myxobacteria Polyketide Salimabromide

Abstract

Salimabromide, a unique and scarce marine tetracyclic polyketide, was synthesized in both racemic and optically active forms. A novel carboxylic acid-directed method for tandem oxidative difunctionalization of olefins was developed, whereby the formation of bridged butyrolactone and enone moieties occurs concurrently. Density functional theory (DFT) calculations indicate that this reaction follows a [3+2] process rather than the [2+2] process. In the meantime, the distinctive benzo-fused [4.3.1] carbon skeleton and highly hindered vicinal quaternary stereocenters were simultaneously constructed through a challenging intramolecular Giese-Baran radical cyclization. Furthermore, deuterium kinetic isotopic effects were utilized to enhance the efficacy of this pivotal step. This represents a new illustration of the application of kinetic isotope effects in natural product synthesis. Then, the short asymmetric synthesis of (+)-salimabromide (13 or 15 steps) was accomplished by combing this method with rhodium-catalyzed enantioselective hydrogenation of a cycloheptenone derivative (97% ee) or conjugate addition of an aryl boronic acid with 2-cyclohepten-1-one (> 99% ee).