Direct, stereoselective thioglycosylation enabled by an organophotoredox radical strategy

Abstract

While strategies involving a 2e^- transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or S_N side reactions of commonly used, labile glycosyl donors. Here we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp² and sp³ sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed.

Scheme 1. Selected examples of thioglycosides with α-1,2-cis-configuration.

Scheme 2. Ionic and radical thioglycosylation.

Scheme 3. Scope of thiosulfonates. ^aReaction conditions: unless specified, see footnote a of Table 1 and the ESI; isolated yield; the ratio of α and β anomers determined by crude ¹H NMR. ^bYield after hydrolysis of the acyl group. ^cDisulfide used. ^dToluenethiosulfonate used. ^eZ/E ratio determined by ¹H NMR.

Scheme 4. Scope of saccharides and selenoglycosylation. ^aReaction conditions: unless specified see footnote a of Table 1 and the ESI; isolated yield; the ratio of α and β anomers determined by crude ¹H NMR. ^b3.0 equiv. of glycosyl bromide used. ^cDisulfide used.

Scheme 5. Thiodiversification of pharmaceutically relevant structures. ^aReaction conditions: unless specified, see footnote a of Table 1 and the ESI; isolated yield; ratio of α and β anomers determined by crude ¹H NMR. ^bThe product after hydrolysis. ^cMethylthiosulfonate used. ^dDCE : H₂O (1.5 mL, 2 : 1, v/v) used as the solvent.

Scheme 6. Proposed mechanism and mechanism studies.