Total Synthesis of the Marine Alkaloids (−)-Lepadins A, B, and C Based on Stereocontrolled Intramolecular Acylnitroso-Diels−Alder Reaction

The first syntheses of (−)-lepadins A and C, as well as a new synthesis of (−)-lepadin B, have been achieved from commercially available (S)-malic acid. The methodology is based on an intramolecular hetero-Diels−Alder reaction of the acylnitroso compound, affording the bicyclic oxazino lactam with trans selectivity, which was converted to the cis-decahydroquinoline via asymmetric enolate hydroxylation followed by intramolecular aldol cyclization. The total syntheses proceed by employing cis-decahydroquinoline bearing the (E)-iodoalkenyl group as the common key intermediate, which underwent a convergent coupling with the (E)-hexenyl unit via a palladium-catalyzed Suzuki cross-coupling reaction for the elaboration of the octadienyl side chain at the C5 position.