H-bonding, not remote participation, explains the influence of remote substituents on stereoselectivity in α-galactosylations

Abstract

The underlying roles of remote substituents in the stereochemical control of the formation of acetals and related reactions have been heavily debated. The competing prevailing theories were inconsistent with some of the trends reported herein. Specifically, electron-poor benzoate groups at the 4-position of a galactosyl donor gave unexpectedly high α-stereoselectivities in galactosylations. A Hammett study and DFT calculations led us to propose that non-classical intramolecular hydrogen-bonding to the β-glycosyl triflate can rationalize the selectivities observed. Using a para-nitrobenzoate protecting group at position 4 of galactosyl donors gave high α-selectivities in the synthesis of galactosides. Benzyl, silyl, allyl and carbamate groups were tolerated. The utility of this protocol was demonstrated in >10 examples, including a gram-scale example and a trisaccharide.