Direct α‐functionalization of NH2‐free glycinates with relatively weak electrophiles such as α,β‐unsaturated esters still remains a big challenge in organic synthesis. With chiral pyridoxal 5 d as a carbonyl catalyst, direct asymmetric conjugated addition at the α‐C of glycinate 1 a with α,β‐unsaturated esters 2 has been successfully realized, to produce various chiral pyroglutamic acid esters 4 in 14–96 % yields with 81–97 % ee's after in situ lactamization. The trans and cis diastereomers can be obtained at the same time by chromatography and both of them can be easily converted into chiral 4‐substituted pyrrolidin‐2‐ones such as Alzheimer's drug Rolipram (11) with the same absolute configuration via tert‐butyl group removal and subsequent Barton decarboxylation.

Owing to the strong nucleophilicity of the NH2 group, free‐NH2 glycinates react with MBH acetates to usually deliver N‐allylated products even in the absence of catalysts. Without protection of the NH2 group, chiral pyridoxal catalysts bearing an amide side chain at the C3 position of the naphthyl ring switched the chemoselectivity of the glycinates from intrinsic N‐allylation to α‐C allylation. The reaction formed chiral multisubstituted glutamic acid esters as SN2′–SN2′ products in good yields with excellent stereoselectivity (up to 86 % yield, >20 : 1 dr, 97 % ee). As compared to pyridoxal catalysts bearing an amide side arm at the C2 position, the pyridoxals in this study have a bigger catalytic cavity to enable effective activation of larger electrophiles, such as MBH acetates and related intermediates. The reaction is proposed to proceed via a cooperative bifunctional catalysis pathway, which accounts for the high level of diastereo‐ and enantiocontrol of the pyridoxal catalysts.

The direct asymmetric aldol reaction of glycinates represents an intriguing and straightforward strategy to make biologically significant chiral β‐hydroxy‐α‐amino‐acid derivatives. But it is not easy to realize the transformation due to the disruption of the reactive NH2 group of glycinates. Inspired by the enzymatic aldol reaction of glycine, we successfully developed an asymmetric aldol reaction of glycinate 5 and trifluoromethyl ketones 4 with 0.1–0.0033 mol % of chiral N‐methyl pyridoxal 7 a as the catalyst, producing chiral β‐trifluoromethyl‐β‐hydroxy‐α‐amino‐acid esters 6 in 55–82 % yields (for the syn‐diastereomers) with up to >20:1 dr and 99 % ee under very mild conditions. The reaction proceeds via a catalytic cycle similar to the enzymatic aldol reaction of glycine. Pyridoxal catalyst 7 a activates both reactants at the same time and brings them together in a specific spatial orientation, accounting for the high efficiency as well as excellent diastereo‐ and enantioselectivities.

Direct α‐functionalization of NH2‐free glycinates with relatively weak electrophiles such as α,β‐unsaturated esters still remains a big challenge in organic synthesis. With chiral pyridoxal 5 d as a carbonyl catalyst, direct asymmetric conjugated addition at the α‐C of glycinate 1 a with α,β‐unsaturated esters 2 has been successfully realized, to produce various chiral pyroglutamic acid esters 4 in 14–96 % yields with 81–97 % ee's after in situ lactamization. The trans and cis diastereomers can be obtained at the same time by chromatography and both of them can be easily converted into chiral 4‐substituted pyrrolidin‐2‐ones such as Alzheimer's drug Rolipram (11) with the same absolute configuration via tert‐butyl group removal and subsequent Barton decarboxylation.

Organocatalysis In their Communication on page 20166, Guoqing Zhao, Baoguo Zhao et al. describe a highly efficient asymmetric biomimetic aldol reaction of glycinates and trifluoromethyl ketones via carbonyl catalysis.