2003 Volume 76 Issue 11 Pages 2059-2074
The first total synthesis of tricyclic marine alkaloids (±)-fasicularin (2) and (±)-lepadiformine (5) has been accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels–Alder reaction of an N-acylnitroso moiety with an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively. This reaction leads to the trans- or cis-fused decahydroquinoline ring systems 13 or 23 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 13 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 that has the proposed structure of lepadiformine in a non-zwitterionic form, derived from the cis-fused adduct 23, was found to be different from lepadiformine by spectral comparison. These results thus unambiguously established the relative stereochemistry of lepadiformine, formerly assigned incorrectly, as shown by 5. The synthesis of natural (−)-enantiomer of lepadiformine was then undertaken using a highly efficient protocol involving a new variant of the N-acyliminium ion-initiated intramolecular spirocyclization in which a conjugated diene was exploited as a π nucleophile. Thus, the synthesis is accomplished in nine steps with 31.4% overall yield, making this the most selective and shortest synthesis of lepadiformine to date. Direct comparison of chiral HPLC analysis of synthetic (−)-lepadiformine and the natural product allowed to assign the absolute configuration of natural lepadiformine to be 3R,5S,7aR,11aR.
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