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.

doi:10.1002/CHIN.200749189

Paper

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.

Published Jun 28, 2007 · Yonghong Yang, J. Coward

The Journal of organic chemistry

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27

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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.

Study Snapshot

This study demonstrates a method for synthesizing p-aminophenyl aryl H-phosphinic acids and esters, which can be used to create folic acid and related antifolates.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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.

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References

Citations

Asymmetric synthesis of the two enantiomers of β-phosphorus-containing α-amino acids via hydrophosphinylation and hydrophosphonylation of chiral Ni(ii)-complexes

This method allows for the asymmetric synthesis of -phosphorus-containing -amino acids with two enantiomers by using secondary phosphine oxides and dialkyl phosphites.

MW irradiation and ionic liquids as green tools in hydrolyses and alcoholyses

MW irradiation and ionic liquids can efficiently optimize hydrolysis and alcoholyses of alkyl diphenylphosphinates, with potential applications in phosphinate-phosphinic acid conversion.

Synopsis of recent synthetic methods and biological applications of phosphinic acid derivatives

Recent synthetic methods for phosphinic acid derivatives have shown promising progress in synthetic organic and biological fields, with potential applications in medicinal chemistry.

From Industrial Method to the Use of Silylated P(III) Reagents for the Synthesis of Relevant Phosphonylated Molecules

Bisphosphonates show potential as therapeutic agents for bone resorption inhibition and antitumor effects, with recent advances in phosphinate chemistry.

Phosphinic acids: current status and potential for drug discovery.

Phosphinic acid derivatives show diverse biological activities and structural diversity, making them a versatile tool for drug discovery against various diseases.

Phosphinate selective hosts and importance of CH hydrogen bonding for affinity modulation toward anion guests

The polarity of C H groups in phosphinate selective hosts can significantly modulate their affinity for anion guests, with host 3 showing the strongest affinity against all tested anion guests.