A Telescoped Photo-/Organo-Catalyzed Cross Dehydrogenative Coupling (CDC) between Glycine Derivatives and Ketones to Afford Nonproteinogenic Amino Acids (NPAAs) Enabled by Heterogeneous Continuous Flow Catalysis

Abstract

We present a new sustainable and efficient approach that consists of a telescoped CDC/Mannich reaction in continuous flow to access enantiopure carbonyl derivatives of masked non-proteinogenic mmino acids (NPAAs). The protocol consists of two reactions: the C–H activation of glycine analogues enabled by mesoporous graphitic carbon nitride (mpg-CN), followed by a Mannich reaction between α-enolizable ketones or aldehyde, activated by a supported proline-like organocatalyst (Si-Ley), and the imine formed in the first step. The protocol was designed embracing the principles of green chemistry (metal-free catalysis, the reuse of medium and catalysts to reduce the E-factor, and the use of air for oxidation). Furthermore, good results were obtained in terms of yield and enantioselectivity (Y = up to 91% and ee = up to 99%). Long-term stability experiments and reactivation studies were performed providing excellent results in terms of the durability of the system; furthermore; we were able to obtain 1.8 g of the desired product of the benchmark reaction (gram scale) after cumulative runs. Furthermore, NMR measurements were employed to shine light on the deactivation of the catalysts during the operative conditions.