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

• Published in: Journal of the American Chemical Society Vol. 122; no. 19; pp. 4583 - 4592
• Main Authors: Abe, Hideki, Aoyagi, Sakae, Kibayashi, Chihiro
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.05.2000; Amer Chemical Soc
• Subjects: ( plus or minus )-fasicularin; ( plus or minus )-lepadiformine; alkaloids; Chemistry; Chemistry, Multidisciplinary; Clavelina lepadiformis; Marine; natural products; Physical Sciences; Science & Technology; TRANSFORMATION; CYCLOADDITION; NATURAL-PRODUCTS; (+/-)-CYLINDRICINE-A; DERIVATIVES; ASCIDIAN CLAVELINA-CYLINDRICA; DL-CEPHALOTAXINE; LEPADIFORMINE
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9939284

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.