ABSTRACT
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 (-)-lepadiforminesâ A and B were achieved in 28 % and 21 % overall yields, respectively, through the novel cycloisomerization reaction. The syntheses of (+)- and (-)-lepadiformineâ C hydrochloride salts also enabled us to determine the absolute configuration of natural lepadiformineâ 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.
Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Urochordata/chemistry , Alkaloids/pharmacology , Animals , Antineoplastic Agents/pharmacology , Aquatic Organisms , Catalysis , Cell Proliferation , Cell Survival , HT29 Cells , HeLa Cells , Humans , Leukemia P388 , Magnetic Resonance Spectroscopy , Mass Spectrometry/methods , Molecular Structure , StereoisomerismABSTRACT
A cytotoxic marine alkaloid (-)-lepadiformine A (1) possesses a unique structure characterized by the trans-1-azadecalin AB ring system fused with the AC spiro-cyclic ring. In this research, we found that a cycloisomerization reaction from amino ynone 2 to a 1-azaspiro[4.5]decane skeleton 3, corresponding to the AC ring system of 1, is promoted by Hg(OTf)(2). Thus, we have accomplished the efficient total synthesis of (-)-lepadiformine A in 28% overall yield by featuring the novel Hg(OTf)(2)-catalyzed cycloisomerization.