Synthesis of the core of welwistatin using a diazoketone rearrangement

Abstract

We have studied and developed the rearrangement of fused bicyclic α-diazo-β-hydroxyketones in the presence of rhodium catalysts, for the synthesis of a range of bicyclo[m.n.1]alkanediones, which constitute the frameworks of many polycyclic natural products. We have rationalized the migratory aptitudes of the substituents by stereoelectronic effects. We have proceeded to investigate the scope and limitations of this methodology by applying this reaction as a key step in a synthetic study of the bicyclo[4.3.1] core of welwistatin, a natural product isolated from the cyanobacteria Hapalosiphon welwitschii. Welwistatin is a potent antagonist of P-glycoprotein pump and could reverse multiple drug resistance of cancers. Our progress in this synthetic effort will be presented.