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Synlett 2025; 36(12): 1623-1631
DOI: 10.1055/a-2572-0695
DOI: 10.1055/a-2572-0695
synpacts
Ligand-Enabled Cu-Catalyzed Stereoselective Synthesis of P-Stereogenic ProTides
Financial support for this work was provided by the National Natural Science Foundation of China (22101171), the Xiangfu Lab Research Project (XF012023B0100), the ‘Thousand Youth Talents Plan’, the Fundamental Research Funds for the Central Universities (23X010301599), and startup funding from Shanghai Jiao Tong University (SJTU). We also thank the Shanghai Institute of Rehabilitation with Integrated Western and Chinese Traditional Medicine (2023XKPT26-RC1) and the Shanghai Xuhui District Central Hospital Regional Cooperation Project (23XHYD-18) for financial support.
Abstract
We present a copper-catalyzed, stereoselective phosphorylation of nucleosides with phosphoryl(V) chlorides, providing an efficient and straightforward approach to the synthesis of a series of nucleoside analogues that demonstrate significant promise in the treatment of viral infections and cancers. The stereochemical configurations at the phosphorus center in ProTides are known to have a profound impact on their pharmacological properties. However, the asymmetric construction of P–O bonds remains a major challenge in the synthesis of nucleoside-based therapeutics. In this study, we introduce a base-promoted nucleophilic substitution pathway that facilitates the highly stereoselective synthesis of previously inaccessible (S,R P) and (R,S P)-ProTide derivatives, offering a powerful strategy for the diversification of nucleoside drug candidates.
Publication History
Received: 20 February 2025
Accepted after revision: 01 April 2025
Accepted Manuscript online:
01 April 2025
Article published online:
13 May 2025
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