Friday, 24 June 2016

Lewis Acid Triggered Regioselective Magnesiation and Zincation of Uracils, Uridines, and Cytidines


Abstract Image

The Lewis acid MgCl2 allows control of the metalation regioselectivity of uracils and uridines. In the absence of the Lewis acid, metalation of uracil and uridine derivatives with TMPMgCl·LiCl occurs at the position C(5). In the presence of MgCl2, zincation using TMP2Zn·2LiCl·2MgCl2 occurs at the position C(6). This metalation method provides easy access to functionalized uracils and uridines. Using TMP2Zn·2LiCl·2MgCl2 also allows to functionalize cytidine derivatives at the position C(6).

The selective functionalization of uridines is an important synthetic goal because of the biological relevance of many substituted uridines. They are known to display antibiotic, antifungal, anticancer, and antiviral activity. Knochel and co-workers at Ludwig-Maximilians-Universität extended their investigation of metalation of heterocyclic systems to uridines. They reported the regioselective metalation of uridines at the C(5) or C(6) position and the subsequent functionalization of these metalated nucleoside derivatives with electrophiles ( Org. Lett. 2016, 18, 1068). Metalation of a protected uridine (A) with a slight excess of TMPMgCl·LiCl afforded the C(5) magnesiated uridine (C(5):C(6) = 98:2) in quantitative yield. The presence of MgCl2 inversed the regioselectivity of the metalation. Zincation of a protected uridine (A) with 1.2 equiv of TMP2Zn·2LiCl·2MgCl2 produced the C(6) bis-zincated uridine (C(5):C(6) = 3:97) also in quantitative yield. The C(5) or C(6) metalated uridines were then functionalized with a variety of electrophiles. This chemistry was successfully extended to the regioselective C6 metalation and functionalization of cytidines. The deprotection of the substituted uridines and cytidines afforded the corresponding functionalized nucleosides.


Lewis Acid Triggered Regioselective Magnesiation and Zincation of Uracils, Uridines, and Cytidines

Department Chemie, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 München, Germany
Org. Lett., 2016, 18 (5), pp 1068–1071
DOI: 10.1021/acs.orglett.6b00190

////////////////Lewis Acid,  Regioselective Magnesiation, Zincation, Uracils, Uridines, Cytidines

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