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 3R*,5S*,7aR*,11aR* shown by 5.