An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels–Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by SN2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (−)-lepadin F is synthesized from ethyl l-lactate for the first time. © 2020 Wiley-VCH GmbH