Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 47, Pages 20814-20819Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202011527
Keywords
asymmetric catalysis; drug design; organocatalysis; phosphoramidates; synthetic methods
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Funding
- National Natural Science Foundation of China [91856106, 21991112]
- National Key R&D Program of China [2018YFE0126800]
- Medical-Engineering Cross Research Foundation of SJTU [YG2020YQ13]
- Shanghai Municipal Education Commission [201701070002E00030]
- Science and Technology Commission of Shanghai Municipality [19JC1430100]
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The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of theP-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1S(P):R-P). Mechanistic studies showed that this DyKAT is a first-order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10 gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.
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