Catalytic enantioselective total synthesis of picrotoxane alkaloids and guaiane sesquiterpene englerins A and B

Abstract

Alkaloids from the picrotoxane family are biologically potent natural products that show hypertensive, antipyretic, analgesic and anti-influenza A virus activities. Herein a concise catalytic, enantioselective total synthesis of (-)-dendrobine, (-)-mubironine B and (-)-dendroxine is described with an overall yield of 6.7%, 7.8% and 7.4%, respectively. This represents a significantly improved yield as compared to synthetic approaches reported in the past, and it is the first report on the total synthesis of (-)-dendroxine. Importantly, the asymmetric Yb-catalyzed Diels-Alder reaction between Danishefsky’s diene and an oxazolidinone moiety allowed for an enantioselective synthesis of the natural products in the enantioselective way, while the Fe-catalyzed aerobic oxidation, Cu- or Au-catalyzed cycloisomerization and hydroazidation underlined the strength of modern synthetic sequences in total synthesis. Englerin A is a guaiane sesquiterpene natural product that shows antitumor activity when binding to the TRPC4/5 target (a new target for antitumor compounds) in vitro. In this part a bio-inspired, catalytic enantioselective strategy towards the total synthesis of (-)-englerins A and B in 12 or 13 steps with 6.7% or 4.8% yield, respectively, is described. The success was initialized by a biomimetic catalytic enantioselective decarboxylative aldol reaction for chirality introduction. A [4+3] cycloaddition with neighboring group participation was used for the construction of the central core structure, which was inspired by the biogenesis of tropinone. A late stage one-pot Heck coupling-regioselective hydrosilylation-Fleming oxidation cascade sequence afforded the cyclopentane core while a kinetic CBS reduction enriched enantiopurity and eventually delivered the natural products.