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

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.

Enantioseparation of P-Stereogenic 1-Adamantyl Arylthiophosphonates and Their Stereospecific Transformation to 1-Adamantyl Aryl-H-phosphinates

“…All of these applications show the importance of synthetic method development for P -stereogenic compounds. Asymmetric synthesis, separation of racemic compounds, and stereoselective transformations of intermediates bearing a stable P -stereogenic center are considered as the most popular methods for the preparation of the P -chiral compound of interest in enantiomerically pure form [ 11 , 12 , 13 , 14 ]. For the latter approach, secondary phosphine oxides and H -phosphinates [ 15 , 16 , 17 ], along with the corresponding borane derivatives, are usually the intermediates of choice [ 18 , 19 , 20 ] as they have good bench and configurational stability, as well as containing one or two functional group(s) that can be displaced in a stereospecific manner.…”