Catalyst-controlled glycosylation reactions

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Catalyst-controlled glycosylation reactions involve the reaction of an electrophilic glycosyl donor and nucleophilic glycosyl acceptor in the presence of a catalyst that controls the stereochemical and regiochemical outcome of the reaction.[1] Glycosylation is a nucleophilic substitution process in which the acceptor displaces a leaving group in the donor located at the 1-position (anomeric position). Because glycosyl donors are almost universally chiral, they exhibit an intrinsic preference for a particular product diastereomer. The requirement that catalysts for stereoselective glycosylation override this preference makes catalyst-controlled glycosylation challenging in general. Because reported methods typically have limited scope, several different classes of catalysts have been developed, including chiral Brønsted acids, Lewis acids, dual hydrogen-bonding organocatalysts such as thioureas, and transition metal complexes.

Mechanisms of glycosylation reactions lie on a continuum between a purely concerted SN2 process and a stepwise SN1 process. The latter involves an oxygen-stabilized carbocationic intermediate known as an oxocarbenium ion. Catalyst control can be particularly difficult when an SN1 mechanism is operative because acidic catalysts that assist in departure of the leaving group tend not to associate with the oxocarbenium ion and anchimeric assistance by an adjacent Lewis basic group in the donor can severely hinder one face of the anomeric carbon.

On the other hand, the SN2 mechanism is stereospecific, meaning that a mixture of anomers subjected to glycosylation conditions will produce a mixture of anomeric products. For this reason, strategies that prevent formation of an equilibrium mixture of anomers of the glycosyl donor are commonly employed when the SN2 mechanism is operative. Approaches that involve simultaneous activation of both the acceptor and donor mitigate many of these issues and can result in high selectivity for a single product anomer and high site selectivity when polyfunctional glycosyl acceptors are used.

References

  1. Jacobsen, E. N.; Levi, S. M. Org. React. 2019, 100, 13. (link)