Collective synthesis of Lycopodium alkaloids and tautomer locking strategy for the total synthesis of (-)-lycojapodine A

J Org Chem. 2013 Feb 1;78(3):800-21. doi: 10.1021/jo3017555. Epub 2012 Sep 20.

Abstract

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 SmI(2)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Aza Compounds / chemistry
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Lactones / chemistry
  • Lycopodium / chemistry*
  • Molecular Structure
  • Stereoisomerism

Substances

  • Alkaloids
  • Aza Compounds
  • Heterocyclic Compounds, 4 or More Rings
  • Lactones
  • alopecuridine
  • fawcettimine
  • lycojapodine A