Phosphinic Acid Pseudopeptides Analogous to Glutamyl-γ-glutamate:  Synthesis and Coupling to Pteroyl Azides Leads to Potent Inhibitors of Folylpoly-γ-glutamate Synthetase

• Published in: Journal of organic chemistry Vol. 66; no. 15; pp. 5146 - 5154
• Main Authors: Valiaeva, Nadya, Bartley, David, Konno, Tsutomu, Coward, James K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.07.2001; Amer Chemical Soc
• Subjects: Azides - chemical synthesis; Chemistry; Chemistry, Organic; Chromatography, High Pressure Liquid; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Glutamates - chemistry; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Peptide Synthases - antagonists & inhibitors; Peptides - chemistry; Phosphinic Acids - chemistry; Physical Sciences; Science & Technology; MECHANISM-BASED INACTIVATION; DESIGN; METHOTREXATE ANALOGS; PHOSPHINOTHRICIN; PHOSPHAPEPTIDES; GLUTATHIONE; ESTERS; CHEMISTRY; TRANSITION-STATE; DISCOVERY
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo010283t

Several routes to a complex phosphinate phosphapeptide analogous to the γ-glutamyl peptide Glu-γ-Glu have been investigated. Formation of γ-phosphono glutamate derivatives via addition of a phosphorus-based radical to protected vinylglycine was found to be of limited value because of the elevated temperatures required. Alkylation and conjugate addition reactions of trivalent phosphorus (PIII) species were investigated. In situ generation of bis-trimethylsilyl esters of phosphinous acids proved to be an effective route to phosphinates of modest structural complexity. However, this chemistry could not be extended to the incorporation of an amino acid moiety at the N-terminal side of the desired phosphinate. A successful synthesis of the target phosphinate phosphapeptide was effected using PIII chemistry and dehydrohalogenation to yield an α,β-unsaturated phosphinic acid ester, following which conjugate addition of diethylacetamido malonate and acid-mediated hydrolysis afforded the desired phosphinate phosphapeptide. Coupling of the unprotected phosphinate phosphapeptide with two acyl azides derived from folic acid and methotrexate led to the corresponding pteroylphosphapeptides of interest as possible mimics of tetrahedral intermediates in the reaction catalyzed by folylpolyglutamate synthetase.