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

preprint
submitted on 17.01.2020 and posted on 21.01.2020 by Dongmin Xu, Nazaret Rivas-Bascón, Natalia M. Padial, Kyle W. Knouse, Bin Zheng, Julien C. Vantourout, Michael A. Schmidt, Martin Eastgate, Phil Baran

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.

Funding

Bristol Myers Squibb

NIGMS (GM106210)

Marie Skłodowska-Curie Global Fellowships (749359-EnanSET)

University of Granada for a mobility fellowship (PP2016- PYDI01)

History

Email Address of Submitting Author

pbaran@scripps.edu

Institution

Scripps Research

Country

United States of America

ORCID For Submitting Author

0000-0001-9193-9053

Declaration of Conflict of Interest

Non conflict of interest

Version Notes

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