A stereoselective synthesis of phosphinic acid phosphapeptides corresponding to glutamyl-gamma-glutamate and incorporation into potent inhibitors of folylpoly-gamma-glutamyl synthetase

J Org Chem. 2005 Aug 19;70(17):6757-74. doi: 10.1021/jo0507439.

Abstract

Radical addition of H3PO2 to N-/C-protected vinyl glycine led to the corresponding H-phosphinic acid in excellent yield. The non-nucleophilic H-phosphinic acid was converted to a nucleophilic P(III) species, RP(OTMS)2, which was used in two approaches to the target phosphinic acid containing pseudopeptide. New methodology was developed that led to excellent yields in the reaction of RP(OTMS)2 with unactivated electrophiles, including an acyclic homoallylic bromide. However, en route to the target pseudopeptide, Arbuzov reaction of RP(OTMS)2 with a cyclic homoallylic bromide, (R)-3-(bromomethyl)-cyclopent-1-ene, led to a rearranged allylic phosphinic acid rather than the desired homoallylic derivative, a putative glutarate surrogate. Conjugate addition of RP(OTMS)2 to alpha-methylene glutarate containing a chiral auxiliary resulted in only modest diastereoselectivity. Purification by flash chromatography provided protected derivatives of both diastereomers of the pseudopeptide. Following global deprotection, coupling of (S)-H-Glu-gamma-[Psi(P(O)(OH)(CH2))]-(S)-Glu-OH and (S)-H-Glu-gamma-[Psi(P(O)(OH)(CH2))]-(R)-Glu-OH to (4-amino-4-deoxy-10-methyl)pteroyl azide led to the target compounds for biochemical study as inhibitors of the ATP-dependent ligase, folylpoly-gamma-glutamate synthetase.

Publication types

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

MeSH terms

  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glutamates / chemical synthesis*
  • Glutamates / chemistry
  • Glutamates / pharmacology
  • Magnetic Resonance Spectroscopy
  • Peptide Synthases / antagonists & inhibitors*
  • Phosphinic Acids / chemistry*
  • Phosphopeptides / chemical synthesis*
  • Phosphopeptides / chemistry
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Enzyme Inhibitors
  • Glutamates
  • Phosphinic Acids
  • Phosphopeptides
  • glutamyl-gamma-glutamate
  • Peptide Synthases
  • folylpolyglutamate synthetase