Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

Abstract

Owing to the strong nucleophilicity of the NH 2 group, free-NH 2 glycinates react with MBH acetates to usually deliver N-allylated products even in the absence of catalysts. Without protection of the NH 2 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 S N 2'-S N 2' 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.Organocatalytic allylic substitution of Morita-Baylis-Hillman (MBH) adducts is a very useful synthetic transformation, which is capable to transfer various nucleophiles into optically active compounds bearing multiple functional groups. [1][2][3][4][5] When glycinates, a type of important synthons [6] for constructing non-natural amino acids, serve as the nucleophiles, N-addition products 4 and/or 5 are easily formed due to the high nucleophilicity of NH 2 group (Figure 1a). [7] Protecting of the NH 2 group leads to α-C allylation to give S N 2' products 4-alkylidenyl glutamic acid derivatives 7 or S N 2'-S N 2' products 4-methylene glutamic acid derivatives 7' when in the presence of chiral organo-

The chiral pyridoxal-catalyzed biomimetic Mannich reaction: the mechanism and origin of stereoselectivity

“…Inspired by the role of transaminase based on the PLP-Lys active structure, Zhao's group designed and synthesized a variety of axially chiral organocatalysts for realizing biomimetic asymmetric transamination reactions. 30–32,65 Notably, they developed an enantioselective Mannich reaction with an axially chiral pyridoxal catalyst for generating diamino acid ester in 93% yield with a >20 : 1 diastereomeric ratio (dr) and 98% enantiomeric excess (ee). 33 These kinds of biomimetic asymmetric reactions have achieved great progress in the biomimetic catalysis field, but the corresponding mechanistic study still lags behind.…”