Abstract
An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.
Highlights
Some nucleoside analogues can function as both nucleoside analogue reverse transcriptase inhibitors (NRTIs) and polymerase inhibitors for other viruses (e.g., Entecavir for hepatitis B) [20]
Less selective nucleoside analogues are used as chemotherapeutic agents to treat cancer, such as the orally administered Capecitabine [21], which is used to treat metastatic breast and colorectal cancers, and Cytarabine [22], which is mainly used in the therapy of white blood cell carcinomas (Figure 1)
Well-established strategies of preparing N-nucleosides include the following: (1) Fischer and Helferich reported that purine nucleosides could be synthesized by coupling purines with acetobromoglucose and applying silver or mercury salts as catalysts [23,24]; (2) the improved silyl-Hilbert-Johnson reaction [25,26], the most widely used synthetic method, involves the coupling of per-silylated heterocyclic bases with per-acylated sugars in the presence of Friedel-Crafts catalysts (e.g., SnCl4 or TMSOTf)
Summary
Nucleoside analogs represent a potentially important class of antiviral anticancer agents [1,2,3,4,5]with antimicrobial and cholinesterase inhibitory activities [6,7,8,9,10] and are commonly used to treat hepatitis B virus [11,12], hepatitis C virus [13,14], herpes simplex [15,16], Human ImmunodeficiencyVirus (HIV) and neoplasms [17,18]. Well-established strategies of preparing N-nucleosides include the following: (1) Fischer and Helferich reported that purine nucleosides could be synthesized by coupling purines with acetobromoglucose and applying silver or mercury salts as catalysts [23,24]; (2) the improved silyl-Hilbert-Johnson reaction [25,26], the most widely used synthetic method, involves the coupling of per-silylated heterocyclic bases with per-acylated sugars in the presence of Friedel-Crafts catalysts (e.g., SnCl4 or TMSOTf). This reaction has been the dominant method for the preparation of pyrimidine, purine and other heterocyclic nucleosides. Despite these available methods [8,9,27,28,29,30], a facile and Molecules 2017, 22, 84; doi:10.3390/molecules22010084 www.mdpi.com/journal/molecules green synthetic strategy, whichstrategy, avoids which the use of costly andofhazardous synthesizing a facile and green synthetic avoids the use costly and catalysts, hazardousfor catalysts, for nucleosides remains an urgent need
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