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Science. 2018 Sep 21;361(6408):1234-1238. doi: 10.1126/science.aau3369. Epub 2018 Aug 2.

Unlocking P(V): Reagents for chiral phosphorothioate synthesis.

Author information

1
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Chemical and Synthetic Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903, USA. michael.schmidt@bms.com martin.eastgate@bms.com pbaran@scripps.edu.
3
Chemical and Synthetic Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903, USA.
4
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
5
Department of Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, NJ 08543, USA.
6
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. michael.schmidt@bms.com martin.eastgate@bms.com pbaran@scripps.edu.

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.

PMID:
30072577
DOI:
10.1126/science.aau3369
[Indexed for MEDLINE]

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