Organic Chemistry

Enantiodivergent Formation of C–P Bonds: Synthesis of P-Chiral Phosphines and Methyl-phosphonate Oligonucleotides


A simple limonene-derived P(V)-based reagent for the modular, scalable, and stereospecific synthesis of chiral phosphines and methyl-phosphonate oligonucleotide (MPO) building blocks is presented. Built on a translimonene oxide (TLO) core, this formally triply electrophilic reagent class displays starkly differing reactivity from the cis-limonene oxide derived reagents reported previously [dubbed phosphorus-sulfur incorporation reagents or Ψ (PSI) for short]. These new phosphorus-incorporation reagents (PI, abbreviated as Π) access distinctly different chemical space than Ψ. The P(V)-manifold disclosed herein permits the stereochemically controlled sequential addition of carbon-based nucleophiles (from one to three) to produce a variety of enantiopure C–P bearing building blocks. When three carbon nucleophiles are added, useful P-chiral phosphines can be accessed after stereospecific reduction. When a single methyl group is added, the remaining nucleophiles can be nucleosides thus opening the door to the first stereospecific access to MPO-based oligonucleotide building blocks. Although both enantiomers of Π are available, only one isomer is required as the order of nucleophile addition controls the absolute stereochemistry of the final product through a unique enantiodivergent design.

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Supplementary material

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Supporting Information