Abstract: 

Compounds containing stereogenic phosphorus atoms played a historically important role in the development of asymmetric catalysis, exemplified by early P-chiral phosphine ligands such as DIPAMP. More recently, P-stereogenic motifs have emerged in medicinal chemistry, as a growing number of drugs contain stereogenic P(V) centers bearing predominantly phosphorus–heteroatom bonds, which present distinct synthetic challenges.

The Dong group has a long-standing interest in transition metal–catalyzed hydrofunctionalization reactions. In my first project, hydrophosphination of cyclopropenes with secondary phosphines unexpectedly revealed modest configurational control at a stereogenic phosphorus center. This surprising result motivated me to spend the remainder of my PhD developing catalytic, asymmetric methods to access P-stereogenic compounds of medicinal relevance.

In pursuit of this goal, I explored multiple catalytic strategies, including phase-transfer, Lewis base, and Lewis acid catalysis. These efforts culminated in a general platform for the asymmetric synthesis of P(V) compounds bearing exclusively phosphorus–heteroatom bonds. This chemistry was applied to the stereoselective synthesis of P-chiral phosphoramidate and phosphate triester nucleotide prodrugs as well as P-stereogenic natural products.