Acid-Base Catalysis in Glycosidations: A Nature Derived Alternative to the Generally Employed Methodology.

Inverting glycosyltransferases enforce in the active site an intramolecular, acid-base catalyzed glycosidation that, due to proximity of the donor anomeric carbon and the acceptor hydroxyl group, follows an SN2-type reaction. Spacers, tethering donor and acceptor via nonreacting functional groups, led in intramolecular glycosidations to excellent yields and, independent of the donor anomeric configuration, to either the α- or the β-anomer. The requirement of a demanding protecting group pattern confines the application of this efficient method. Only the method where the 2-hydroxyl group of a mannopyranosyl donor is tethered via an acetal spacer to the reacting acceptor functional group is used for β-mannopyranoside synthesis. The most elegant method, tethering donor and acceptor covalently to the spacer via the leaving group and the reacting functional group, was so far not as efficient as hoped. This method is very efficient when donor and acceptor are temporarily assembled through a hydrogen-bond facilitating a stretched hexagon-like transition state. This follows from the stereoselective O-glucopyranosyl trichloroacetimidate transformation into O-glucopyranosyl phosphate with dibenzyl phosphoric acid as acceptor that can be regarded as A═B-C-H acceptor type. Generalizing this concept to the use of alcohols as acceptors requires reversible generation of an A-B-C-H adduct where A-H represents the acceptor (RO-H) and B═C a catalyst that has to fulfill several criteria. Among these criteria are low affinity to nitrogen, avoiding glycosyl donor activation in the absence of acceptor, and high affinity to oxygen in order to generate the A-B-C-H adduct with increased proton acidity. Thus, hydrogen-bond mediated self-assembly of donor and acceptor and concomitant donor activation via a transition state is available, which enforces an acid-base catalyzed SN2-type reaction. It could be shown that PhBF2, Ph2BF, and PhSiF3 are such catalysts that fulfill the desired four functions: reversible adduct formation with the acceptor, hydrogen-bond mediated tethering of this adduct with the donor, and acid- and base-catalysis of the glycosidation. Also Lewis acidic metal salts, particularly the dimeric gold(III) chloride, turned out to exhibit excellent B═C type catalyst properties. Worth mentioning in this context is the ability of gold(III) chloride to regioselectively activate diols. As thioureas have high affinity to anions and also to neutral compounds through strong hydrogen bonds, their binding to alcohols and concomitant activation of O-glycosyl trichloroacetimidates was of interest. Yet, even the acidic N,N'-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea was unable to catalyze glycosidations. However, as a cocatalyst to acids, thiourea exerts a strong effect that, based on NMR studies, leads first to a hydrogen-bond mediated catalyst-cocatalyst-acceptor complex. This complex activates the donor in an intramolecular, acid-base catalyzed reaction that is again closely related to the action of inverting glycosyltransferases. Thus, from O-(α-glycosyl) trichloroacetimidates, good yields of the inversion products, that is, the β-glycosides, are obtained. This novel conceptual approach to glycosidation revealed that for retention of configuration in addition a catalytic nucleophile is required that enables formation of the α-glucoside from the α-trichloroacetimidate. Preliminary studies with a catalyst possessing this 5-fold function, that is, adduct formation with the acceptor, hydrogen-bonding between the reactants, acid and base catalysis, and a catalytic nucleophile as part of a chiral framework supporting facial selection, exhibited good chances for final success in this endeavor.