A Facile Total Synthesis of (-)-Frontalin, (-)-endo-Brevicomin and (-)-exo-Brevicomin through PtCl4Catalyzed Hydroalkoxylation Reaction

Abstract

Scheme 2 6,8-Dioxabicyclo[3.2.1]octane is a core structure of many natural products possessing various biological activities with wide structural diversity, and thus is considered one of privileged structures (Scheme 1). Among these natural products, relatively simple derivatives such as frontalin and brevicomins are not only major bioactive component of the aggregation pheromones of beetles but also long sought pheromones in mammalians as they are secreted by elephants. While these pheromones exhibit biological activity only as a single enantiomer in beetles, the same pheromones secreted by elephants with varying ratio of enantiomers depending on elephant’s age and musth show different sexual behavior and aggressions.5 While various synthetic route to the total synthesis of frontalin and brevicomins have been reported, we became interested in devising a versatile and efficient synthetic route to these pheromones and their analogs with varying enantiomeric ratio for future study on structure activity relationship and e.r. activity relationship. Recent progress in transition metal catalyzed hydroalkoxylation reaction of alkynes prompted us to envision a facile and versatile synthetic route to frontalin, brevicomins and their analogs in enantio-controlled manner. The synthetic plan is depicted in the Scheme 2. Starting from 5-hexynol, hex-1-en-5-yne system 1 with various substitution pattern can be readily prepared. Dihydroxylation of 1 would set up the required stereochemistry for enantiomerically differentiated diol 2 and PtCl4 catalyzed hydroalkoxylation reaction of 2