Effect of a 2-O-acetyl substituent on the stereoselectivity of Koenigs-Knorr reactions involving 1,2-cis-glucopyranosyl bromides.

by Wallace, Jerry E.

Reactions of 2,3,4,6-tetra-0-methyl-a-D-glucopyranosyl bromide and the 2-0-acetyl analog with cyclohexanol in the presence of Hg(CN)2 in nitromethanebenzene (l:l, vol.) were investigated. Primary emphasis was on reactions at 10°C having a concentration ratio of 15:1:1 [ROH:RBr:Hg(CN) 2 ; RBr., ca. 6 x 10- 3M]. However, the effects of the reaction temperature (2-25°C) and the concentrations of the reactants were also studied. Products were measured quantitatively by GLC, and initial rates were determined by polarimetric analyses. Under all conditions employed, the 2-0-acetyl derivative selectively formed the B-glucoside (93-98% of the glucosidic product). In contrast, the reaction of the 2-0-methyl derivative was less selective (73-82% --glucoside), and the selectivity was significantly dependent on the alcohol concentration and the reaction temperature. Both glucosyl bromide reactions exhibited first-order kinetic dependence on the glucosyl bromide and Hg(CN) 2 concentrations but not on the alcohol concentration. Thus, it is concluded that the reactions occur by a Lewis acid-catalyzed unimolecular mechanism in which the rate-determining step:is heterolysis of the carbon-bromine bond, assisted by the Hg(CN)2' The observed autocatalysis indicates that other acids are formed which also assist in heterolysis of the carbon-bromine bond. These species could include HgCNBr, HgBr 2 , HCN, HBr, and H+, all of which can potentially be formed by the reaction of Hg(CN) 2 with bromide ion. It was shown that HgBr2 is a more effective catalyst for the reactions than Hg(CN) 2. For both reactions the initial mole ratio of 0-glucoside increased as the alcohol concentration was increased, indicating that the departing anion -2partially shielded the a-side of the carbonium ion from reaction with the alcohol. Therefore, glucoside formation occurred as the result of reaction of the alcohol with either the ion pair to give (-glucoside or the free carbonium ion to give a- and B-glucosides. In addition, an intermediate, shown to be 1,2-0-(l-cyclohexoxyethylidene)-3,4,6-tri-0-methyl-a-D-glucopyranose, was partially responsible for formation of glucosides in the 2-0-acetyl substituted bromide reaction. Reaction of the C-2 acetoxy carbonyl oxygen with the carbonium ion and subsequent reaction of the resultant 1,2-dioxolenium ion with the alcohol yielded the orthoester. Supporting evidence for the formation of an orthoester intermediate was obtained by NMR analysis of an analogous reaction employing ethanol in which 1,2-0-(1-exo-ethoxyethylidene)-3,4,6-tri-O-methyla-D-glucopyranose was detected. The reaction of the 2-0-acetyl substituted bromide in the presence of HgO, added to neutralize any acids formed and thereby stabilize the orthoester, yielded ca. 45% orthoester. In addition, the orthoester did react with cyclohexanol in the presence of Hg(CN) 2 and HBr to selectively form the B-glucoside. Thus, ca. 45% of the glucoside formation in the 2-0acetyl bromide reaction occurred via the orthoester intermediate. Initial product distributions indicated that the 2-0-acetyl carbonyl oxygen reacted five times faster with the a-side of the carbonium ion than did the alcohol. This and the fact that the orthoester intermediate selectively formed the B-glucoside were the main reasons for the high degree of stereoselectivity observed in the 2-0-acetyl substituted bromide reaction. -3-