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

We present a new sustainable and efficient approach consists of a telescoped CDC/Mannich reaction in continuous flow to access enantiopure carbonyl derivatives of masked Non Proteinogenic Amino 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 a-enolizable ketones or aldehyde, activated by 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 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 durability of the system; furthermore; we were able to obtain 1.8 gr of the desired product of the benchmark reaction (gram scale) after cumulative runs. Furthermore, NMR measurements were employed to shine a light on deactivation of the catalysts during the operative conditions.