title: Synthesis of p-aminophenyl aryl H-phosphinic acids and esters via cross-coupling reactions: elaboration to phosphinic acid pseudopeptide analogues of pteroyl glutamic acid and related antifolates.
abstract: The synthesis of suitably protected p-aminophenyl H-phosphinic acids and esters from the corresponding para-substituted aryl halides has been accomplished via the Pd-catalyzed cross-coupling reaction of anilinium hypophosphite, either in the absence or presence of a tetraalkyl orthosilicate, to provide the free H-phosphinic acid or the corresponding ester, respectively. Subsequent conjugate addition of either a PIII species or phosphorus anion, generated in situ from either the free H-phosphinic acid or ester, to a 2-methylene glutaric acid ester provided the aryl phosphinic acid analogue of p-aminobenzoyl glutamic acid. Alkylation of these suitably protected p-aminophenyl phosphinic acid esters with a 6-(bromomethyl)pteridine or the corresponding (bromomethyl)pyridopyrmidine, followed by hydrolytic removal of protecting groups, provided the target aryl phosphinic acid analogues of folic acid and related antifolates. Alternatively, for the synthesis of the folate or 5-deazafolate analogues on a slightly larger scale, reductive amination with either N2-acetyl or N2-pivaloyl-6-formylpterin or the corresponding formylpyridopyrmidine and the same suitably protected p-aminophenyl phosphinic acid esters, followed by removal of protecting groups, is preferred. In the course of this research, it was observed that the nucleophilicity of both the aniline nitrogen and various PIII species derived from p-aminophenyl phosphinic acid derivatives is significantly reduced compared to that of the unsubstituted counterpart.
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Yang
authors.forename: James K
authors.initials: JK
authors.lastname: Coward
mesh_terms: D004952:Esters; D005492:Folic Acid / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides / Q000737:chemistry*; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004952:Esters; D005493:Folic Acid Antagonists; D010455:Peptides; D010721:Phosphinic Acids; D005492:Folic Acid