Fully substituted carbon centers by diastereoselective spirocyclization: stereoselective synthesis of (+)-lepadiformine C

J Am Chem Soc. 2010 Jul 21;132(28):9591-3. doi: 10.1021/ja104250b.

Abstract

Reductive lithiation of N-Boc alpha-amino nitriles generated alpha-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A(1,3)-strain effect that biases the conformation of the radical. In cyclohexane rings with alpha-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with alpha-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The alpha-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Carbon / chemistry*
  • Cyclization
  • Stereoisomerism

Substances

  • Alkaloids
  • lepadiformine
  • Carbon