Natural Product Synthesis & Chemical Biology

6. Collective Synthesis of Lycopodium Alkaloids and Tautomer Locking Strategy for the Total...


The collective total synthesis of Lycopodium alkaloids (+)-fawcettimine (1), (+)-fawcettidine (2), (+)-alopecuridine (4), (−)-lycojapodine A (6), and (−)-8-deoxyserratinine (7) has been accomplished from a common precursor (15) based on a highly concise route inspired by the proposed biosynthesis of the fawcettimine- and serratinine-type alkaloids. An intramolecular C-alkylation enabled efficient installation of the challenging spiro quaternary carbon center and the aza-cyclononane ring. The preparation of the tricyclic skeleton as well as the establishment of the correct relative stereochemistry of the oxa-quaternary center were achieved by hydroxyl-directed SmI2-mediated pinacol couplings. An unprecedented tandem transannular N-alkylation and removal of a Boc group was discovered to realize a biosynthesis-inspired process to furnish the desired tetracyclic skeleton. Of particular note is the unique and crucial tautomer locking strategy employed to complete the enantioselective total synthesis of (−)-lycojapodine A (6). The central step in this synthesis is the late-stage hypervalent iodine oxidant (IBX or Dess–Martin periodinane)/TFA-mediated tandem process, which constructed the previously unknown carbinolamine lactone motif and enabled a biomimetic transformation to generate (−)-lycojapodine A (6) in a single operation.

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