ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

Catalytic Asymmetric and Stereodivergent Oligonucleotide Synthesis

preprint
submitted on 26.10.2020, 20:13 and posted on 28.10.2020, 10:24 by Aaron L. Featherston, Yongseok Kwon, Matthew Pompeo, Oliver Engl, David K. Leahy, Scott Miller

We report the catalytic stereocontrolled synthesis of dinucleotides. Chiral phosphoric acid (CPA) catalysts are demonstrated to control the formation of stereogenic phosphorous centers during phosphoramidite transfer for the first time. Unprecedented levels of diastereodivergence are also demonstrated, enabling access to either phosphite diastereomer. Notably, two different CPA scaffolds prove essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides (CDNs) which are of broad interest in immono-oncology as agonists of the STING pathway.

Funding

Takeda Pharmaceuticals International Co.

National Institute of General Medical Sciences (NIH grant R35 GM132092 to SJM)

History

Email Address of Submitting Author

scott.miller@yale.edu

Institution

Yale University

Country

USA

ORCID For Submitting Author

0000-0001-7817-1318

Declaration of Conflict of Interest

The authors declare no conflict of interest.

Exports