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Unlocking P(V): Reagents for chiral phosphorothioate synthesis

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Science  21 Sep 2018:
Vol. 361, Issue 6408, pp. 1234-1238
DOI: 10.1126/science.aau3369

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A swift citrusy path to chiral phosphorus

The phosphates in the backbones of DNA and RNA are often drawn like crosses but are in fact tetrahedral. Sulfur is sometimes substituted for one of the phosphate oxygens during development of nucleotide-based drugs. Because of the geometry, this swap can lead to two different isomers. Knouse et al. report a pair of phosphorus reagents that conveniently produce either isomer selectively. This ability depended on the configuration of appended limonene substituents that are subsequently jettisoned. In addition to simplifying the route to sulfur-substituted oligonucleotides, these reagents will enable more precise studies of each isomer's distinct bioactivity.

Science, this issue p. 1234

Abstract

Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]–based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

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