A unified approach to the synthesis of both enantiomers of anatoxin-a and homoanatoxin-a cyanotoxins

Abstract

Anatoxin-a and homoanatoxin-a are highly neurotoxic compounds produced by cyanobacteria, principally during surface water-blooms (SWBs). Owing to their powerful biological activity and unique structural characteristics, these natural alkaloids have been the subject of extensive research work in both pharmacological and synthetic studies. In this contribution we report a simple and efficient synthetic approach for the preparation of both the natural and unnatural enantiomers of these cyanotoxins, [(+)-1 and (+)-2] and [(−)-1 and (−)-2] respectively. Key features of this approach include: i) construction of the azabicyclic homotropane framework in both enantiomeric forms from cis-5,6-epoxycyclooctene, based on a microwave mediated epoxide ring opening reaction by a chiral benzyl amine followed by a transannular amine-alkene cyclization; ii) elaboration of the characteristic methyl or ethyl enone by means of a Sonogashira cross-coupling reaction of an enol-triflate with a C2 or C3 terminal alkyne, followed by a chemo- and regio-selective hydration of the resulting conjugated enyne group.