Enantiodivergent Formation of C−P Bonds: Synthesis of P‑Chiral Phosphines and Methylphosphonate Oligonucleotides
Dongmin Xu, Nazaret Rivas-Bascón, Natalia M. Padial, Kyle W. Knouse, Bin Zheng, Julien C. Vantourout, Michael A. Schmidt, Martin D. Eastgate, Phil S. Baran
Abstract
Phosphorus Incorporation (PI, abbreviated Π) reagents for the modular, scalable, and stereospecific synthesis of chiral phosphines and methylphosphonate nucleotides are reported. Synthesized from translimonene oxide, this reagent class displays an unexpected reactivity profile and enables access to chemical space distinct from that of the Phosphorus−Sulfur Incorporation reagents previously disclosed. Here, the adaptable phosphorus(V) scaffold enables sequential addition of carbon nucleophiles to produce a variety of enantiopure C−P building blocks. Addition of three carbon nucleophiles to Π, followed by stereospecific reduction, affords useful P-chiral phosphines; introduction instead of a single methyl group reveals the first stereospecific synthesis of methylphosphonate oligonucleotide precursors. While both Π enantiomers are available, only one isomer is requiredthe order of nucleophile addition controls the absolute stereochemistry of the final product through a unique enantiodivergent design.