Mapping the Reactivity of the C═C Bond of Cyclic Enol Ether Derivatives of Sugars: Nucleophilicity Parameters of Glycals

Abstract

ABSTRACT Glycals are unsaturated sugar derivatives constituting a large family of polyhydroxylated synthons which are widely exploited as synthetic intermediates in the synthesis of natural products and as final molecules for biochemical applications. We report the first investigation in the understudied area of structure–reactivity relationship and quantitative mapping of reactivity in endo ‐ and exo ‐glycals compounds. For quantifying the nucleophilicity of the C═C double bond of a series of endo ‐ and exo ‐glycals, we performed kinetic investigations of their C─C bond formation with reference electrophiles of known electrophilicity parameters. Fast spectroscopic techniques experiments (stopped‐flow and laser‐flash photolysis) enabled us to determine the rate constant of hundreds of reactions, which allows the first comprehensive mapping and structure–reactivity analysis of the nucleophilic reactivity of this wide family of cyclic enol ethers. Quantum–chemical calculations corroborate with kinetic investigations and highlight the crucial role of ring strain variations to explain the relative nucleophilicity of endo ‐ and exo ‐glycals. We examined also the influence of substitution and showed that alkoxy substituents decrease nucleophilicity through inductive effects and hyperconjugation.