Matched/Mismatched Cases in Proline-Catalyzed Cascade Reactions with Carbohydrates: A Computational Insight into the Role of d- and l‑Proline

The cascade reactions of carbohydrates with methyl ketones in the presence of proline feature complex running reaction steps. By extensive quantum mechanical simulation, a coherent reaction mechanism was identified matching the experimental data. The present calculations indicate a Mannich reaction/proline hydrolysis/retro aza-Michael cascade to form an intermediate α,β-unsaturated ethyl ketone. This key precursor yields C-glycosides by a final intramolecular amine-catalyzed oxa-Michael addition. Additionally, the formation of this intermediate determines the rate and selectivity of the overall cascade reaction. Strongly matched and mismatched cases were observed when used with d- or l-proline. They are consistent with the calculated energy barriers of the corresponding transition states.