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제  목 : Chiral Phosphoric Acid-Catalyzed Asymmetric Control of P(III)-Stereogenic Center
연  사 : 권용석 교수(성균관대학교 약학과)
일  시 : 2021년 9월 30일(목) 오후 4시 30분

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Chiral Phosphoric Acid-Catalyzed Asymmetric Control of P(III)-Stereogenic Center 

Yongseok Kwon 

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea 

E-mail: y.kwon@skku.edu 

Synthetically modified oligonucleotides are of interest due to their various biological activities. Even though chemical modification of phosphodiester linkages often leads to increased metabolic stability and therapeutic potential, nucleotide synthesis in the stereocontrolled manner at the possible stereogenic phosphorus atom is still challenging. Since the Wada’s pioneering work, chiral auxiliaries have been widely used to control the P(III) stereogenic center which is sequentially oxidized with appropriate oxidizing agent. More recently, Baran has developed P(V)-based chiral phosphorothiolate, which also requires stoichiometric amount of chiral auxiliary. 

Herein, I would like to present catalytic and stereodivergent synthesis of dinucleotide by control of P(III) stereogenic center. Chiral phosphoric acid catalysts allow stereoselective and catalytic transfer of phosphoramidite through unprecedented mixed-valence P(III)-P(V) intermediates. We have observed that two disparate scaffolds of chiral phosphoric acid catalysts are required to achieve stereodivergence. That is, C2-symmetric class of chiral phosphoric acid is essential to produce one diastereomeric outcome. A complementary, and biologically inspired phosphothreonine-derived chiral phosphoric acid proves essential to achieve the opposite diastereomer. The application of our approach is demonstrated by the synthesis of a broad set of stereodefined dinucleotide product including venerable modulators of the STING pathway. 

References 

1. Featherston, A. L.†; Kwon, Y.†; Pompeo, M. M.†; Engl, O. D.; Leahy, D. K.*; Miller, S. J.* “Catalytic Asymmetric and Stereodivergent Oligonucleotide Synthesis” Science, 2021, 371, 702‒707. 

2. Knouse, K. W.; deGruyter, J. N.; Schmidt, M. A.; Zheng, B.; Vantourout, J. C.; Kingston, C.; Mercer, S. E.; Mcdonald, I. M.; Olson, R. E.; Zhu, Y.; Hang, C.; Zhu, J.; Yuan, C.; Wang, Q.; Park, P.; Eastgate, M. D.*; Baran, P. S.* “Unlocking P(V): Reagents for chiral phosphorothioate synthesis” Science 2018, 361, 1234–1238. 

3. Oka, N.; Wada, T.*; Saigo, K.* “Diastereocontrolled Synthesis of Dinucleoside Phosphorothioates Using a Novel Class of Activators, Dialkyl(cyanomethyl)ammonium Tetrafluoroborates” J. Am. Chem. Soc. 2002, 124, 4962–4963.