A Highly Reactive and Enantioselective Bifunctional Organocatalyst for the Methanolytic Desymmetrization of Cyclic Anhydrides: Prevention of Catalyst Aggregation

TLDR: A thermally robust sulfonamide-based bifunctional organocatalysts I is presented, which shows unprecedented catalytic activity and excellent enantioselectivity in the methanolytic desymmetrization of meso cyclic anhydrides.

Abstract: At present, there is much interest in organocatalysts, as they tend to be less toxic and more environmentally friendly than traditional metal-based catalysts. Although much progress has been made, the development of chiral organocatalysts that are as reactive and stereoselective as some of the best transition-metal catalysts remains a considerable challenge. To attain reasonable reaction rates and stereoselectivity with organocatalysts, a large catalyst loading is often required. One way to address this difficulty is to design bifunctional or multifunctional organocatalysts with functional groups that work cooperatively to stabilize the transition state and accelerate the rate of the reaction. It has been shown that ureaor thiourea-based bifunctional organocatalysts are effective in facilitating a variety of useful organic reactions, including the methanolytic desymmetrization of cyclic anhydrides. However, we showed recently that ureaand thiourea-based organocatalysts can form hydrogen-bonded aggregates, which results in a strong dependence of reactivity and enantioselectivity on concentration and temperature. X-ray crystal structures of monofunctional and bifunctional (thio)urea derivatives show that they form aggregates through hydrogen bonding between the (thio)urea NH groups and the (thio)urea sulfur or oxygen atom in an intermolecular fashion. A recent NMR spectroscopic study also showed that the thiourea IV exists as a dimer, even in solution. Furthermore, thiourea groups tend to degrade under thermal conditions. Herein we present a thermally robust sulfonamide-based bifunctional organocatalyst I (Scheme 1), which shows unprecedented catalytic activity and excellent enantioselectivity in the methanolytic desymmetrization of meso cyclic anhydrides. A detailed mechanistic and computational approach to the design of I resulted in a catalyst that does not self-aggregate to any appreciable extent. To the best of our knowledge, I is the first quinineand sulfonamide-based bifunctional organocatalyst. The quinuclidine group of I may be able to function as a general-base catalyst to activate the nucleophile, and the sulfonamide group may be able to activate the electrophile simultaneously by hydrogen bonding. To investigate the catalytic activity and enantioselectivity of the cinchona-alkaloid-based sulfonamide catalyst I, we examined the asymmetric methanolysis of cis-1,2-cyclohexanedicarboxylic anhydride (1a) in Et2O with various amounts of I at ambient temperature. The results are summarized in Table 1, together with the results obtained with other cinchona-alkaloid-based catalysts (quinine (II), (DHQ)2AQN (III), and the quinine-based thiourea catalyst IV; Scheme 1). The desymmetrization of 1a with I (10 mol%) proceeded surprisingly fast; the reaction was complete within 1 h to Scheme 1. Structures of cinchona-alkaloid-based organocatalysts.