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Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf) 2 ‐Catalyzed Cycloisomerization Reaction and their Cytotoxic Activities
Author(s) -
Nishikawa Keisuke,
Yamauchi Kengo,
Kikuchi Seiho,
Ezaki Shinnosuke,
Koyama Tomoyuki,
Nokubo Haruka,
Matsumura Kunihiro,
Kodama Takeshi,
Kumagai Momochika,
Morimoto Yoshiki
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701475
Subject(s) - cycloisomerization , chemistry , ring (chemistry) , total synthesis , stereochemistry , decane , hydrochloride , tunicate , catalysis , enantioselective synthesis , trifluoromethanesulfonate , organic chemistry , biology , ecology
The enantioselective total syntheses of lepadiformine marine alkaloids, azatricyclic natural products isolated from marine tunicates, were completed. These alkaloids have a unique chemical structure characterized by the trans ‐1‐azadecalin (AB ring system) fused with the spirocyclic ring (AC ring system). Here we found that a cycloisomerization reaction from functionalized linear substrates to a 1‐azaspiro[4.5]decane framework corresponding to the AC ring in lepadiformines is promoted by a catalytic amount of mercury(II) triflate (Hg(OTf) 2 ). The total syntheses of (−)‐lepadiformines A and B were achieved in 28 % and 21 % overall yields, respectively, through the novel cycloisomerization reaction. The syntheses of (+)‐ and (−)‐lepadiformine C hydrochloride salts also enabled us to determine the absolute configuration of natural lepadiformine C. It has been found that a phenomenon of enantiodivergence occurs in lepadiformine alkaloids from a single species of marine tunicate, Clavelina moluccensis . The cytotoxic activities of synthesized lepadiformine hydrochloride salts and their synthetic intermediates were evaluated.