Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

Abstract

Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.

Fig. 1

Strategies for catalytic glycosylation. (A) Catalyst-controlled stereoselective glycosylation. (B) Catalyst-mediated stereospecific glycosylation. (C) Glycosyltransferase-catalyzed stereospecific glycosylation. (D) Anion-binding catalysis with oxocarbenium intermediates.

Fig. 2

Evaluation of reaction components. (A) Catalyst optimization. (B) Effect of glycosyl chloride configuration at the anomeric center. (C) Effect of nucleophile chirality.

Fig. 3

Substrate Scope. Isolated yields are reported. Diastereomeric ratios were determined by NMR or HPLC analysis of crude material. * Reaction run at 40 °C. †Reaction run with 10 mol% catalyst. ‡Reaction run at 0°C with (S,S)-6. §Reaction run in toluene (0.1 M) at −40 °C. ||Reaction run in dichloromethane.

Fig. 4

Mechanistic studies. (A) Amide substituent effects. * reaction run for 18 hours. † reaction run run for 48 hours. Secondary deuterium kinetic isotope effects were determined from intermolecular competition experiments at low conversion (ca. 10–20%). (B) Transition state calculated using M06-2X/6-31G*/PCM (polarized continuum model, benzene).