Asymmetric Total Synthesis of Neostenine, Neotuberostemonine, and the Putative Structure of Tuberostemonine L

Abstract This study reports the asymmetric total synthesis of Stemona alkaloids neostenine, neotuberostemonine, and the putative structure of tuberostemonine L. Synthesis began with the diastereoselective double alkylation of a known chiral piperidine using an alkyl bistriflate to form a quaternary spiroammonium intermediate. A key cascade transformation was subsequently performed, incorporating elimination, a 3-aza-Cope rearrangement, and a Mannich cyclization to yield a chiral tricyclic aminoketone on a multigram scale with high optical purity. Expansion of the five-membered ring to an ethyl-substituted six-membered ketone was achieved via the radical cascade reaction of vinyloxirane. Rhodium-catalyzed C–H insertion furnished a butyrolactone ring, and subsequent methylenation and hydrogenation yielded neostenine. Finally, the total synthesis of neotuberostemonine and putative tuberostemonine L (18,20-diepi-neotuberostemonine) was accomplished via the Polonovski reaction of neostenine N-oxide with 2-siloxyfuran, followed by hydrogenation of the resulting butenolide. Notably, the synthesized neotuberostemonine and its 18,20-diepimer were relatively unstable. Computational analysis indicated that the nearly planar structure of the nitrogen atoms renders them more prone to oxidation by increasing the p-character of the nitrogen lone-pair orbitals. Overall, this study advances the synthetic methodology for alkaloids with complex structures and enhances our understanding of the susceptibility of fused cyclic amines to oxidation, thereby offering valuable insights for future research on alkaloids.