Glycosyl chloride

Glycosyl Chlorides, Bromides and Iodides 59 Suvarn S. Kulkarni, Jacquelyn Cervay-Hague... 

Donors possessing other halogens as leaving groups, such as glycosyl chloride and bromide, are not effectively activated in contrast to glycosyl fluoride. 

Sn2 Reactions Owing to their inherent stability, glycosyl chlorides are appropriate candidates for SN2 reactions offering complementary stereoselectivity compared to that of bromides and iodides. They are therefore useful precursors for various glycosyl donors. The following examples are noteworthy. 

Selenoglycosides of sialic acid have been successfully prepared in excellent yields from the corresponding peracetylated glycosyl chloride with phenylselenol in the presence of N,N-di-isopropylethylamine [519]. This reagent combination succeeded where others were less effective or failed (Scheme 4.98 [520]. 

From a historic perspective glycosyl chlorides and bromides introduced, respectively, by Michael [2] and Koenigs and Knorr [3] were the most widely used donors in the saccharide synthesis for a very long time. The introduction of 1,2-orthoesters in 1964 [4] was the first important attempt to find an alternative to the Koenigs-Knorr method. However, Paulsen in his 1990 review of reliable donors for glycosyl... 

Deoxy-a-D-ribosyl-l-phosphate 20, a key substrate in the preparation of 2 -deoxynucleosides, was stereoselectively prepared by crystallization-induced asymmetric transformation in the presence of an excess of ortho-phosphoric acid and tri( -butyl)amine under strictly anhydrous conditions (Scheme 2).7 Initial Sn2 displacement of Cl in ot-glycosyl chloride 16 by phosphoric acid resulted in a 1 1 a/p anomeric mixture of 17 and 18 due to the rapid anomerisation of the a-chloride in polar solvents. Under acidic conditions, in the presence of an excess of H3P04, an equilibration between the a and p anomers gradually changed in favour of the thermodynamically more stable a-counterpart. By selective crystallization of the mono tri( -butyl)ammonium salt of the a-phosphate from the mixture, the equilibrium could be shifted towards the desired a-D-ribosyl phosphate 18 (oc/p = 98.5 1.5), which was isolated as bis-cyclohexylammonium salt 19 and deprotected to furnish compound 20. 

Scheme 11 Reaction of glycosyl chlorides with organolithium reagents.

Specifically, Paulsen recognized that glycosyl halides bearing C2-benzylethers were much more prone to hydrolysis than the corresponding C2 esters. Similarly, Paulsen noted that the glycosyl iodides were more prone to hydrolysis than glycosyl bromides, and these bromides were more reactive than glycosyl chlorides. 

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