Promotion of a Reaction by Cooling: Stereoselective 1,2‐cis‐α‐Thioglycoconjugation by Thiol‐Ene Coupling at −80 °C

Abstract

The photoinitiated thiol-ene coupling reactions of 2-substituted glycals were studied as a generally applicable strategy for stereoselective 1,2-cis-α-thioconjugation. Although all glycals reacted with full α-selectivity, the efficacy of the reactions varied in a broad range depending on their configuration and glycals bearing axial acetoxy substituents reacted with very low efficacy at room temperature. The study revealed that the reaction progress could be promoted by cooling and inhibited by heating. At -80 °C, the equilibrium of the rapidly reversible addition of the thiyl radical to alkenes is shifted almost completely toward products, leading to efficient addition reactions. By exploiting this unique temperature effect a series of α-thio-l-fucosides, -d-galactosides, and d-GlcNAc derivatives were prepared with high efficacy and complete stereoselectivity.

Stereoselective Thioconjugation by Photoinduced Thiol‐ene Coupling Reactions of Hexo‐ and Pentopyranosyl d‐ and l‐Glycals at Low‐Temperature—Reactivity and Stereoselectivity Study

“…In the case of the above studied reactions, only few of the intermediates formed were sufficiently stable at room temperature to allow hydrothiolation in an acceptable efficacy. Similar to our recent results, we have found that freezing the intermediate radical is an adequate strategy to promote the reaction by preventing its degradation and thereby allowing it to react with a thiol in the hydrogen abstraction step. Although the cooling was beneficial in all reactions, the optimal reaction temperature was found to be varying depending on the configuration and substituents of the glycals, and also on the nature of the thiols.…”

“…As already observed in our previouse xperiments,e fficient thiol-ene couplings of 2 and 3 required lower temperatures than those of the d-gluco analogue 1. [28,29] Similar trends were observed when thiols 12 or 14 were coupled to 2,b eing À40 to À80 8Ct he optimal temperature range of these reactions. (Table 2).…”

“…In this context,t he radicalm ediated thiol-ene coupling emerged as ap owerful methodf or glycoconjugation [15][16][17] which, if unsaturated sugarsare applieda st he alkene partners, opens the way for the stereoselective synthesis of ab road range of thio-linked glycomimetics. [18][19][20][21][22][23][24][25][26][27][28][29][30] We demonstrated that the UV-light-initiated addition of various thiols including amino acid, peptide, and sugar thiols to 2-substitutedh exoglycals occursw ith complete stereoselectivity,p roviding an easy accesst o1 ,2-cis-a-linked thiodisaccharides and thioglycoconjugates. [26][27][28][29][30] Recently,w eh ave demonstrated that the reaction temperature profoundly influences the efficacy of the reactions by controlling the equilibrium of the reversible propagation step of the radical chain process.…”

“…[18][19][20][21][22][23][24][25][26][27][28][29][30] We demonstrated that the UV-light-initiated addition of various thiols including amino acid, peptide, and sugar thiols to 2-substitutedh exoglycals occursw ith complete stereoselectivity,p roviding an easy accesst o1 ,2-cis-a-linked thiodisaccharides and thioglycoconjugates. [26][27][28][29][30] Recently,w eh ave demonstrated that the reaction temperature profoundly influences the efficacy of the reactions by controlling the equilibrium of the reversible propagation step of the radical chain process. [28,29] Our study revealed that cooling promotes while heatingi nhibits the thiol-enec ouplings of 2-substitutedg lycals, and the unfavorable sterica nd electronic effects resulting in low conversionsa tr oom temperature could be overcome by conducting the reactions at À80 8C.…”

“…[26][27][28][29][30] Recently,w eh ave demonstrated that the reaction temperature profoundly influences the efficacy of the reactions by controlling the equilibrium of the reversible propagation step of the radical chain process. [28,29] Our study revealed that cooling promotes while heatingi nhibits the thiol-enec ouplings of 2-substitutedg lycals, and the unfavorable sterica nd electronic effects resulting in low conversionsa tr oom temperature could be overcome by conducting the reactions at À80 8C.…”