A Flexible Approach to the Synthesis of Type II and III Lepadin Alkaloids

A flexible approach to both type II and III lepadin alkaloids is developed for the first time. A key Diels-Alder reaction based on a novel chiral ketolactone dienophile is employed to obtain the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity. As the subsequent closure of the piperidine ring is devised at the N1 and C2 position via an intramolecular nucleophilic amination, the two stereochemical types of lepadin frameworks with the opposite configuration at C2 can be conveniently accessible from a common intermediate. By the approach, lepadins D, E (type II) and F (type III) are stereo-selectively synthesized from ethyl L-lactate.

Automated summary

A flexible approach to both type II and III lepadin alkaloids is developed for the first time. It involves employing a novel chiral ketolactone dienophile and an intramolecular nucleophilic amination to synthesize lepadin frameworks with different stereochemical types.