Catalytic Stereoselective 1,4-Addition Reactions Using CsF on Alumina as Solid Base: A Heterogeneous Platform for Continuous-Flow Synthesis of Glutamic Acid Derivatives

A novel methodology using CsF·Al2O3 as a highly efficient, environmentally benign and reusable solid base catalyst was developed to synthesize glutamic acid derivatives via stereoselective 1,4-addition of glycine derivatives to α,β-unsaturated esters. CsF·Al2O3 showed not only great selectivity toward 1,4-addtion reactions by suppressing undesired formation of pyrrolidine derivations via [3+2] cycloaddition, but also offered high yields for the 1,4-adduct with excellent anti diastereoselectivities. The catalyst was well characterized by using XRD, 19F MAS-NMR, 19F NMR, FT-IR, CO2-TPD, and XPS, and highly basic F from the Cs3AlF6 was identified as the most probable active basic site for the 1,4-addition reactions. Continuous-flow synthesis of 3-methyl glutamic acid derivative was successfully demonstrated by using the solid base-catalyzed methodology.