Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (10): 3237-3248.DOI: 10.6023/cjoc202005030 Previous Articles     Next Articles

Special Issue: 黄乃正院士七十华诞专辑


刘祎辰a,c, 程杰飞b, 洪然a   

  1. a 中国科学院上海有机化学研究所分子合成卓越中心 天然产物有机合成化学重点实验室 上海 200032;
    b 上海中医药大学 创新中药研究院 上海 201203;
    c 中国科学院大学 北京 100049
  • 收稿日期:2020-05-13 修回日期:2020-06-11 发布日期:2020-06-20
  • 通讯作者: 刘祎辰, 程杰飞, 洪然;;
  • 基金资助:

Asymmetric Synthesis of Prodrug Nucleotides (ProTides): Construction of the P-Stereogenic Centers

Liu Yichena,c, Cheng Jiefeib, Hong Rana   

  1. a CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032;
    b Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203;
    c University of Chinese Academy of Sciences, Beijing 100049
  • Received:2020-05-13 Revised:2020-06-11 Published:2020-06-20
  • Supported by:
    Project supported by the Key Research Program of Frontier Sciences (No. QYZDY-SSW-SLH026); the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB20000000).

As an antivirus drug, remdesivir is currently in clinical studies for the treatment of COVID-19. Remdesivir is a prodrug originally developed by Gilead for the treatment of Ebola. The prodrug nucleotide (ProTide) technology is a prodrug-designing strategy developed by McGuigan and co-workers, in which a phosphoramidate side-chain is covalently attached to the hydroxy group of a drug molecule in order to enhance the cell permeability and metabolic activation efficiency. This approach has proved to be very successful in the identification of nucleoside analogues with antiviral or antitumor activities. It is also adapted in the application of non-nucleoside agents, such as neurodegeneration therapeutics, further demonstrating its usefulness in drug discovery. The chirality of the pentavalent phosphorous plays a significant role in the bioactivity of a ProTide molecule. Therefore, the efficient synthesis of such chemical scaffold in a highly enantioselective manner is very desirable and has intrigued great interests from both academia and pharmaceutical industry. In this review, based on the reactions employing optically pure P(V) precursors or P-racemic P(V) precursors, the recent advances on the stereoselective assembly of ProTide compounds are summarized. Various innovative strategies, including (dynamic) kinetic resolutions, were implemented to construct the vital P-stereogenic center with high regio- and stereo-selectivity. It is notable that several methods could be performed at kilogram scale, which are highlighted to showcase their practical values in the process chemistry. The asymmetric synthesis of enantiopure phosphoramidate precursors is illustrated in detail which will be informative for future drug development. Moreover, the clinical performance of some investigational ProTide drugs is also briefly discussed.

Key words: antiviral, asymmetric synthesis, nucleoside analogue, prodrug nucleotide (ProTide), P-stereogenic center