NOTE * E-mail: fwliu@zzu.edu.cn Received January 17, 2013; accepted March 4, 2013; published online April 3, 2013. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300045 or from the author. Chin. J. Chem. 2013, 31, 855—860 © 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 855 DOI: 10.1002/cjoc.201300045 Directly Regioselective Protection of Secondary Hydroxyl Group on Ribosides in Aqueous Solution Ruigang Xu, Fei Liu, Yingju Liu, Beiqing Chen, and Feng-Wu Liu* School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China Selective benzoylation of secondary hydroxyl on sugar moiety of various ribosides including N-ribosides, O-ribosides and 2'-deoxy-N-riboside was investigated by using benzoyl chloride and Na 2 CO 3 in aqueous CH 3 CN. The influence of the aglycone and sugar moiety on the selectivity of benzoylation was discussed as well. A most ef- ficient method for preparation of 2',3'-O-dibenzoylnucleosides was developed. Keywords selective benzoylation, ribosides, deoxyribosides, secondary hydroxyl group, protection Introduction Nucleosides and nucleotides are abundant in nature and often play an important role in life process. Devel- opment of novel nucleoside analogs has attracted much attention for decades. Protection and deprotection of hydroxyl groups on sugar moiety is often needed in the modification strategy. While syntheses of fully benzoy- lated nucleoside analogs are fairly simple by using various acylating reagent, such as benzoic anhydride, [1] benzoyl chloride [2] or benzoyl cyanide, [3] synthesis of monobenzoate, [4,2e] dibenzoate, [5] or 2'-deoxy-monoben- zoate [6] still suffers from tedious protection and depro- tection steps which involve much complicated work-up procedures. Monobenzoate and dibenzoate could also be obtained through partial deprotection of fully benzoy- lated riboside derivatives in the presence of CH 3 ONa, [7] t-BuOK, [8] hydrazine hydrate [9] or hydroxylaminium acetate. [10] However, its application is limited due to forming large amount of by-products. Therefore, di- rectly regioselective introduction of benzoyl groups to the desired hydroxyl groups in ribosides is an alternative and highly efficient approach. N-Acylimidazole [11] is widely used to prepare 2'-O-acyl or 5'-O-acyl derivatives respectively in the presence of various bases, such as MDCAI or TEAH. Vinyl benzoate [12] is also applied to selectively protect 3'-OH of 2'-deoxyribosides furnish- ing 2'-deoxy-3'-monobenzoate in considerable yield by utilization of enzymes (PSL-C) and 1-butyl-2,3-dimeth- ylimidazolium hexafluorophosphate ([C 4 MMIm]PF 6 ) as additives. Organic tin reagent [13] is used in selective protection to give 3'-O-acyl derivatives in high yield, but its application is restricted due to its toxicity. Fur- thermore, 2',3'-di-O-benzoylriboside is a key interme- diate in the modification of 5'-OH of ribosides or modi- fied ribosides [14] among all the important intermediates of protected ribosides. Enzymatic selective 5'-deacyla- tion of 2',3',5'-tri-O-acylriboside gave 2',3'-di-O-acyl analogs, [15] but its disadvantage is that the expensive immobilized enzyme and multi-steps are involved. Re- gioselective benzoylation of ribosides to give 2',3'-di-O- benzoylribosides directly was scarcely reported. Maruyama et al. reported that 6-chloropurine-2',3'- di-O-benzoylriboside could be directly synthesized by regioselective 2',3'-dibenzoylation of 6-chloropurine ribonucleoside with benzoyl chloride in aqueous solu- tion in high yield, [16] but further extensive research on other ribosides with this convenient and environ- mental-friendly trait has not been reported. Based on its advantages over traditional methods, we have done an extending research to investigate the generality of this method in different ribosides, including N-ribosides, O-ribosides and 2'-deoxy-N-ribosides and developed a most convenient and efficient protocol to regioselec- tively protect 2',3'-OH of ribonucleosides. Herein we describe the related study work. Results and Discussion In our on-going project, we need various benzoy- lated riboside or deoxyribosides intermediates with free 5'-OH. A variety of ribosides were firstly used to pre- pare 2',3'-dibenzoylated analogs in aqueous solution by following the literature procedures, [16] the results were concluded in Table 1. Benzoylation of N-ribosides (ribo-nucleoside) in aqueous solution afforded corre- sponding 2',3'-O-dibenzoylribonucleosides in moderate to good yield (Entry 1－5) whenever the nucleobase is purine or pyrimidine. Ribavirin (Entry 3) was most eas- ily selectively protected in the highest 82% yield.