Enantioselective epoxidation of protected allylic and homoallylic amines via chiral cationic ion-pairing catalysis

Abstract

Asymmetric epoxidation is one of the most versatile organic transformations as up to two stereogenic centre can be generated from the three member oxirane product in a single step. Although numerous reports on catalytic asymmetric epoxidation on allylic alcohols had been published in the literature since the first discovery by Katsuki and Sharpless in 1980s, there are only handful examples for allylic amines, largely due to competing N-oxidation as side reaction. The derivatives of the epoxidised product, amino alcohols, are present in scaffold of many drugs or nature products. Hence, an efficient and effective methodology for asymmetric epoxidation on allylic amines is highly desirable. Chiral ligand strategy was applied in the previous reports by Yamamoto and He’s group on asymmetric epoxidation of allylic amine type substrates. Electron donor on the ligand is typically required for coupling to metal centre which limits the design and scope of ligands used. Therefore, we seek for a novel methodology in which the reactivity of metal can be activated or modulated through ionic interaction instead of a chiral ligand. Recently, a chiral sp2- hybridized guanidinium salt, bisguanidinium developed by our group has been demonstrated to form ion pairs with several metallic anions for highly enantioselective dihydroxylation, oxohydroxylation, sulfoxidation or with silicates for alkylation. On the other hand, a compact, rigid ion-pairing catalyst which containing a sp3 ammonium centre with a spiro backbone was successfully synthesized and structure was determined by X-ray struct.ural analysis. Further optimization on the synthetic route to this new spiro ion-pairing catalyst is still underway. Herein, we wish to disclose an unprecedented ion-pairing strategy for highly enantioselective epoxidation of protected allylic and homoallylic amines using a catalytic oxidation system consisting of silver tungstate, sodium hydrogen sulfate, Bisguanidinium. Environmental friendly oxidant, hydrogen peroxide was used oxidant in the reaction. In the preliminary study, the unreacted starting material was recovered quantitatively and this rules out the N-oxidation pathway. Sulfonyl group in the tosyl protecting group may serve as a directing group as the presence of group is crucial for achieving high enantioselectivity. Excellent enantioselectivity (up 96%ee) and yield (up to 97%) could be achieved for 1, 1’-, 1, 2-substituted phenyl/naphthyl and tosyl protected allylic amines and 1, 2- substituted phenyl and tosyl homoallylic protected amines. The versatility and practicality of this methodology have been demonstrated by low catalyst loading (2.5mol %), ease of operation (under air), use of green oxidant and gram-scale synthesis.