Stereoselective glycosylation reactions with 2-deoxyglucose: a computational study of some catalysts.

ABSTRACT

2-Deoxy glycosides are important components of many oligosaccharides with antibiotic and anti-cancer activity, but their synthesis can be very challenging. Phenanthrolines and substituted pyridines promote stereoselective glycosylation of 1-bromo sugars via a double SN2 mechanism. Pyridine reacting with α-bromo, 2-deoxyglucose was chosen to model this reaction. The first step involves displacement of bromide by pyridine which can be rate limiting because bromide ion is poorly solvated in the non-polar solvents used for these reactions. We examined a series of small molecules to bind bromide and stabilize this transition state. Geometry optimization and vibrational frequencies were calculated using M06-2X/6-31+G(d,p) and SMD implicit solvation for diethyl ether. More accurate energies were obtained with M06-2X/aug-cc-pVTZ and implicit solvation. Urea, thiourea, guanidine and cyanoguanidine bind bromide more strongly than alkylamines, (NH2CH2CH2)nNH3-n. Compared to the uncatalyzed reaction, urea, thiourea and cyanoguanidine lower the free energy of the transition state by 3 kcal/mol while guanidine lowers the barrier by 2 kcal/mol.