Asymmetric Synthesis of Stereogenic Phosphorus P(V) Centers Using Chiral Nucleophilic Catalysis.

Ahmed Numan,Matthew Brichacek

doi:10.3390/molecules26123661

Ahmed Numan, Matthew Brichacek

Open Access

https://doi.org/10.3390/molecules26123661

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Journal: Molecules (Basel, Switzerland)	Publication Date: Jun 15, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: University of Maine

Abstract

Organophosphates have been widely used in agrochemistry, as reagents for organic synthesis, and in biochemistry. Phosphate mimics possessing four unique substituents, and thereby a chirality center, are useful in transition metal catalysis and as nucleotide therapeutics. The catalytic, stereocontrolled synthesis of phosphorus-stereogenic centers is challenging and traditionally depends on a resolution or use of stochiometric auxiliaries. Herein, enantioenriched phosphorus centers have been synthesized using chiral nucleophilic catalysis. Racemic H-phosphinate species were coupled with nucleophilic alcohols under halogenating conditions. Chiral phosphonate products were synthesized in acceptable yields (33–95%) and modest enantioselectivity (up to 62% ee) was observed after identification of an appropriate chiral catalyst and optimization of the solvent, base, and temperature. Nucleophilic catalysis has a tremendous potential to produce enantioenriched phosphate mimics that could be used as prodrugs or chemical biology probes.

Highlights

Organophosphorus compounds are common motifs in nucleotides, [1,2,3] pesticides, [4,5]herbicides, [6,7] and flame retardants [8]
Chiral phosphate mimics have been extensively utilized in transition metal catalysts, [10]
Compounds with stereogenic phosphonate centers are of great interest in biological applications [16]

Summary

Introduction

Organophosphorus compounds are common motifs in nucleotides, [1,2,3] pesticides, [4,5]herbicides, [6,7] and flame retardants [8]. Organophosphorus compounds are common motifs in nucleotides, [1,2,3] pesticides, [4,5]. These compounds normally have stable configurations depending on the nature of the substitution around the phosphorus center [9]. Compounds with stereogenic phosphonate centers are of great interest in biological applications [16]. Previous studies have shown that nucleotide stereoisomers at phosphorus possess distinct therapeutic activities and physical properties [18,19,20,21]

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Results

Conclusion