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Synthesis 2022; 54(13): 3005-3014
DOI: 10.1055/s-0041-1737911
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Synthesis of Phosphoramidate Prodrugs of Phenolic Natural Products and Drugs by Ester Exchange

Jie Yao
a   Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
b   Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
,
Chengjie Huang
a   Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
b   Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
,
Fan Wu∗
a   Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
b   Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
,
Yufen Zhao
a   Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
b   Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
,
Feng Ni  ∗
a   Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
b   Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo, Zhejiang, 315211, P. R. of China
› Author AffiliationsSupported from the National Natural Science Foundation of China (91856126, 21778042), Scientific Research Grant of Ningbo University (215-432000282), and Ningbo Top Talent Project (215-432094250).
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Abstract

Drug development based on phenolic natural products as drug candidates against various diseases has gained much attention in recent years. However, most of those molecules lack therapeutic efficacy in clinical trials, usually due to poor bioavailability. Therefore, a prodrug approach was adopted to address the bioavailability problem of phenolic drugs. This paper describes a mild and convenient method for late-stage ProTide-type prodrug synthesis of phenolic pharmaceuticals, which gives various phosphoramidate prodrugs from unprotected phenolic natural products and drugs in high yield. More importantly, this reaction is amenable for the selective phosphorylation of the phenolic hydroxyl group in the presence of otherwise problematic nucleophilic functional groups like amines and alcohols. We also observed that the chemical release rate of the phenol can be substantially tuned by changing the amino acid residue on the phosphoramidate moiety.

Key words

ProTide technology - prodrugs - phenolic drugs - phosphor­yl­ation - drug release - phosphoramidates

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1737911.
  • Supporting Information


Publication History

Received: 11 January 2022

Accepted after revision: 14 February 2022

Article published online:
30 March 2022

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