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-cistrisubstituted 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 stereoselectively synthesized from ethyl L-lactate. © 2022 EDP Sciences. All rights reserved.