“…Generation of compound 6 might imply nucleophilic opening of the oxazolidine ring with concomitant formation of the six-membered tiaazacycle. In fact, a similar compound 7 , whose structure was determined by X-ray crystallography, is the major compound isolated upon treatment of 1a with excess trimethylchlorosilane in the presence of SnCl 4 at room temperature, an observation that further stresses the necessity of subzero temperatures 3 Thermally Favored Formation of Side-Product 6 and Analogue 7 under Brønsted and Lewis Acid Conditions, Respectively, and a Plausible Interpretation of the Course of the Reaction 4 TFA-Promoted Sulfur Transfer Reaction in Cyclic α,β-Disubstituted Substrate Involving the Generation of Two Contiguous Stereocenters 5 Testing the Efficacy of Other Oxazolidine-2-thione Auxiliaries
3 Fitting the Best Brønsted Acid and Reaction Temperature a Brønsted acid T (°C) t (h)conversion (%)d.r.
The ability of Brønsted acids alone to efficiently promote the sulfur transfer process in N-enoyl oxazolidine-2-thiones to give beta-mercapto carbonyl derivatives is demonstrated. The reactions proceed with essentially perfect diastereocontrol for a range of alkyl-substituted N-enoyl oxazolidine-2-thiones (d.r. regularly above 98:2) and high selectivity for most aryl-substituted counterparts (d.r. typically above 92:8). Importantly, the reaction works remarkably well in beta,beta-disubstituted N-enoyl oxazolidine-2-thiones as well, giving rise to quaternary C-S stereocenters in selectivities usually above 95:5. The relative efficiency of a range of acids (trifluoroacetic, difluoroacetic, acetic, triflic) is assessed showing TFA and TfOH as the most efficient and acetic acid as a totally inefficient reaction promoter. The new procedure complements the Lewis acid promoted reaction previously described by our group in two aspects: First, stereodivergent results are obtained for the Lewis acid or Brønsted acid promoted reactions of beta,beta-disubstituted enoyl compounds. Second, while the Brønsted acid promoted reactions are stereospecific, providing a good correlation between the substrate E/Z configuration and products stereochemistry, the reactions mediated by Lewis acids (BF3/OEt2) provide invariant d.r. values regardless of the E/Z composition of the starting olefin. The synthetic value of the method is illustrated by (a) removal of the oxazolidinone moiety from the rearranged products under reducing conditions (NaBH4, H2O-THF) which yields beta-mercapto alcohols and (b) treatment with Sm(OTf)3 in MeOH which affords the corresponding beta-mercapto carboxylic esters, both categories of compounds being isolated in up to 97% ee. Remarkably, the method constitutes the first general approach to highly enantioenriched building blocks bearing a quaternary C-S stereocenter. On the other hand, spectroscopic and inhibition experiments are carried out that demonstrate the participation of protons also in the Lewis acid promoted reactions. Finally, the computational studies carried out at the B3LYP/6-31G* level give support for an activation of the substrate enoyl by complexation with two molecules of either the Brønsted or Lewis acid and serve to explain the stereochemical outcome of the reactions.
“…Generation of compound 6 might imply nucleophilic opening of the oxazolidine ring with concomitant formation of the six-membered tiaazacycle. In fact, a similar compound 7 , whose structure was determined by X-ray crystallography, is the major compound isolated upon treatment of 1a with excess trimethylchlorosilane in the presence of SnCl 4 at room temperature, an observation that further stresses the necessity of subzero temperatures 3 Thermally Favored Formation of Side-Product 6 and Analogue 7 under Brønsted and Lewis Acid Conditions, Respectively, and a Plausible Interpretation of the Course of the Reaction 4 TFA-Promoted Sulfur Transfer Reaction in Cyclic α,β-Disubstituted Substrate Involving the Generation of Two Contiguous Stereocenters 5 Testing the Efficacy of Other Oxazolidine-2-thione Auxiliaries
3 Fitting the Best Brønsted Acid and Reaction Temperature a Brønsted acid T (°C) t (h)conversion (%)d.r.
The ability of Brønsted acids alone to efficiently promote the sulfur transfer process in N-enoyl oxazolidine-2-thiones to give beta-mercapto carbonyl derivatives is demonstrated. The reactions proceed with essentially perfect diastereocontrol for a range of alkyl-substituted N-enoyl oxazolidine-2-thiones (d.r. regularly above 98:2) and high selectivity for most aryl-substituted counterparts (d.r. typically above 92:8). Importantly, the reaction works remarkably well in beta,beta-disubstituted N-enoyl oxazolidine-2-thiones as well, giving rise to quaternary C-S stereocenters in selectivities usually above 95:5. The relative efficiency of a range of acids (trifluoroacetic, difluoroacetic, acetic, triflic) is assessed showing TFA and TfOH as the most efficient and acetic acid as a totally inefficient reaction promoter. The new procedure complements the Lewis acid promoted reaction previously described by our group in two aspects: First, stereodivergent results are obtained for the Lewis acid or Brønsted acid promoted reactions of beta,beta-disubstituted enoyl compounds. Second, while the Brønsted acid promoted reactions are stereospecific, providing a good correlation between the substrate E/Z configuration and products stereochemistry, the reactions mediated by Lewis acids (BF3/OEt2) provide invariant d.r. values regardless of the E/Z composition of the starting olefin. The synthetic value of the method is illustrated by (a) removal of the oxazolidinone moiety from the rearranged products under reducing conditions (NaBH4, H2O-THF) which yields beta-mercapto alcohols and (b) treatment with Sm(OTf)3 in MeOH which affords the corresponding beta-mercapto carboxylic esters, both categories of compounds being isolated in up to 97% ee. Remarkably, the method constitutes the first general approach to highly enantioenriched building blocks bearing a quaternary C-S stereocenter. On the other hand, spectroscopic and inhibition experiments are carried out that demonstrate the participation of protons also in the Lewis acid promoted reactions. Finally, the computational studies carried out at the B3LYP/6-31G* level give support for an activation of the substrate enoyl by complexation with two molecules of either the Brønsted or Lewis acid and serve to explain the stereochemical outcome of the reactions.
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