Enantiodivergent Formation of C–P Bonds: Synthesis of P‑Chiral Phosphines and Methylphosphonate Oligonucleotides

• Published in: Journal of the American Chemical Society 2020-03, Vol.142 (12), p.5785-5792
• Main Authors: Xu, Dongmin, Rivas-Bascón, Nazaret, Padial, Natalia M, Knouse, Kyle W, Zheng, Bin, Vantourout, Julien C, Schmidt, Michael A, Eastgate, Martin D, Baran, Phil S
• Format: Article
• Language: English
• Subjects: Cyclohexane Monoterpenes - chemistry; Indicators and Reagents - chemistry; Oligonucleotides - chemical synthesis; Organophosphonates - chemical synthesis; Oxidation-Reduction; Phosphines - chemical synthesis; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b13898

Phosphorus Incorporation (PI, abbreviated Π) reagents for the modular, scalable, and stereo­specific synthesis of chiral phosphines and methyl­phosphonate nucleotides are reported. Synthesized from trans-limonene 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 requiredthe order of nucleo­phile addition controls the absolute stereo­chemistry of the final product through a unique enantio­divergent design.