A unified strategy for the synthesis of 7-membered-ring-containing Lycopodium alkaloids

J Am Chem Soc. 2014 Sep 24;136(38):13442-52. doi: 10.1021/ja507740u. Epub 2014 Sep 12.


A unique subset of the Lycopodium alkaloid natural products share a 7-membered-ring substructure and may potentially arise from a common biosynthetic precursor. To both explore and exploit these structural relationships, we sought to develop a unified biosynthetically inspired strategy to efficiently access these complex polycyclic alkaloids through the use of a cascade sequence. In pursuit of these goals, the first total synthesis of (+)-fastigiatine (2) was accomplished via a series of cascade reactions; we describe herein a full account of our efforts. Insight from these endeavors led to critical modifications of our synthetic strategy, which enabled the first total syntheses of (-)-himeradine A (1), (-)-lycopecurine (3), and (-)-dehydrolycopecurine (4), as well as the syntheses of (+)-lyconadin A (5) and (-)-lyconadin B (6). Our approach features a diastereoselective one-pot sequence for constructing the common 7-membered-ring core system, followed by either a biomimetic transannular Mannich reaction to access himeradine A (1), lycopecurine (3), and dehydrolycopecurine (4) or an imine reduction for lyconadins A (5) and B (6). This strategy may potentially enable access to all 7-membered-ring-containing Lycopodium alkaloids and provides additional insight into their biosynthetic origin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Lycopodium / chemistry*
  • Models, Molecular
  • Polycyclic Compounds / chemical synthesis
  • Polycyclic Compounds / chemistry
  • Quinolizines / chemical synthesis
  • Quinolizines / chemistry


  • Alkaloids
  • Heterocyclic Compounds, 4 or More Rings
  • Polycyclic Compounds
  • Quinolizines
  • himeradine A
  • lyconadin A
  • lyconadin B
  • lycopecurine