Stereocontrolled synthesis of antitumor alkaloids based on intramolecular hetero-Diels-Alder reaction of acylnitroso compounds

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The first total synthesis of tricyclic marine alkaloids (±)-fasicularin and (±)-lepadiformine 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 involving the simultaneous introduction of the nitrogenated quarternary center in a single step. On further elaboration of the six-membered or five membered ring, the trans-fused adduct provided either (±)-fasicularin or (±)-lepadiformine. The hydrochloride salt of synthetic (±)-lepadiformine was found to be identical with the isolated natural sample of lepadiformine, however, the tricyclic amino alcohol having proposed structure of lepadiformine, derived from the cis-fused adduct, was found to be different from lepadiformine by spectral comparison. These results unambiguously established the relative stereochemistry of lepadiformine, formerly assigned incorrectly, to be 3R^*,5S^*,7aR^*, 11aR^*.