Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as beta-turn mimics

J Org Chem. 2005 Jul 22;70(15):5954-63. doi: 10.1021/jo050529k.

Abstract

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn, while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-d-proline II helix.

Publication types

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

MeSH terms

  • Aldehydes / chemistry
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Carboxylic Acids / chemistry
  • Cysteine / chemistry
  • Lactams / chemical synthesis*
  • Molecular Mimicry
  • Peptides / chemistry
  • Pipecolic Acids / chemistry*
  • Protein Structure, Secondary
  • Pyrrolidinones / chemistry
  • Spiro Compounds / chemical synthesis*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiazines / chemistry

Substances

  • Aldehydes
  • Bridged Bicyclo Compounds
  • Carboxylic Acids
  • Lactams
  • Peptides
  • Pipecolic Acids
  • Pyrrolidinones
  • Spiro Compounds
  • Thiazines
  • polyproline
  • pipecolic acid
  • Cysteine