First Total Synthesis of the Marine Alkaloids (±)-Fasicularin and (±)-Lepadiformine Based on Stereocontrolled Intramolecular Acylnitroso-Diels−Alder Reaction

The first total synthesis of tricyclic marine alkaloids (±)-fasicularin ( 2 ) and (±)-lepadiformine ( 5 ) was accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels−Alder reaction of an N -acylnitroso moiety to an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively, leading to the trans- or cis-fused decahydroquinoline ring systems 21 or 39 involving the simultaneous introduction of the nitrogenated quaternary center in a single step. On further elaboration of the six-membered or five-membered ring A, the trans-fused adduct 21 provided either (±)-fasicularin ( 2 ) or (±)-lepadiformine ( 5 ). The hydrochloride salt of synthetic (±)- 5 was found to be identical with the isolated natural sample of lepadiformine; however, the tricyclic amino alcohol 4 having the proposed structure of lepadiformine in a nonzwitterionic form, derived from the cis-fused adduct 39, was found to be different from lepadiformine by spectral comparison. These results thus unambiguously established the relative stereochemistry of lepadiformine, formerly assigned incorrectly, to be 3 R *,5 S *,7a R *,11a R * shown by 5 .