Design and synthesis of a 3,4-dehydroproline amide discovery library

J Comb Chem. 2007 Jul-Aug;9(4):677-83. doi: 10.1021/cc070011p. Epub 2007 Jun 14.

Abstract

The synthesis of a discovery library of 80 3,4-dehydroproline amides was achieved in a four-step reaction sequence from easily accessible 3-aminoallene-3-carboxylate methyl esters. Diversification of these proline mimics was introduced at five different sites: the substituents at the 3-pyrroline unit (R1, R2, R3), at the nitrogen (R4), and the C-terminus (R5). The 3-pyrroline scaffold was synthesized in excellent yields by a silver-catalyzed intramolecular cyclization of aminoallenes, followed by N-functionalization reactions. Maximum diversity was introduced in the final step of the reaction sequence by taking advantage of the carboxylic acid handle of the 3-pyrroline subunit. Amide coupling reactions using polystyrene-carbodiimide (PS-carbodiimide) and 1-hydroxybenzotriazole (HOBt) under microwave irradiation led to 3,4-dehydroproline amides that were obtained in purities greater than 85% by LC/MS/ESLD after scavenging the excess HOBt on a silica-bound carbonate SPE cartridge.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / isolation & purification
  • Chemical Phenomena
  • Chemistry, Physical
  • Databases, Factual*
  • Molecular Structure
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / chemistry*

Substances

  • Amides
  • Proline