Chiral aldehyde-nickel dual catalysis enables asymmetric α−propargylation of amino acids and stereodivergent synthesis of NP25302

Abstract

The combined catalytic systems derived from organocatalysts and transition metals exhibit powerful activation and stereoselective-control abilities in asymmetric catalysis. This work describes a highly efficient chiral aldehyde-nickel dual catalytic system and its application for the direct asymmetric α−propargylation reaction of amino acid esters with propargylic alcohol derivatives. Various structural diversity α,α−disubstituted non-proteinogenic α−amino acid esters are produced in good-to-excellent yields and enantioselectivities. Furthermore, a stereodivergent synthesis of natural product NP25302 is achieved, and a reasonable reaction mechanism is proposed to illustrate the observed stereoselectivity based on the results of control experiments, nonlinear effect investigation, and HRMS detection.

Modular Chiral-Aldehyde/Palladium Catalysis Enables Atom-Economical α-Allylation of N-Unprotected Amino Acid Esters with 1,3-Dienes and Allenes

“…These results show that ZnCl 2 (i) accelerates Schiff base formation via the formation of stable Schiff-base–Zn complexes, (ii) enhances the α-carbon acidity of the Schiff base, facilitating subsequent deprotonation, and iii) strengthens stereoselective control in the transition state. These conclusions were in accordance with that we reported in our previous works. , …”

“…This combined catalysis realized the highly efficient asymmetric α-allylation of amino acid esters with inert allyl alcohol esters. Building on this discovery, asymmetric α-allylation of aza-aryl methylamines, asymmetric α-benzylation, and α-propargylation of amino acid esters were successively achieved (Figure b). We envisioned that the abovementioned transition-metal-catalyzed hydrometallation would operate well in combination with the formation of active α-imine carbanions by chiral-aldehyde catalysis, resulting in a novel platform for the asymmetric synthesis of optically active amines and amino acids in a completely atom-economical manner.…”

Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

“…The unique property of chiral aldehyde catalysis, [21][22][23][24] directly promoting the asymmetric functionalization of Nunprotected amino acid esters, has been demonstrated in alkylation, 25 Michael addition, [26][27][28] Mannich, [29][30] aldol, [31][32][33] allylation, [34][35][36] benzylation, 37 and propargylation 38 reactions. We envisioned that this strategy may be promising for the direct asymmetric hydrocarbylation of amino acid esters with halohydrocarbons.…”

Chiral Aldehyde–Palladium Catalysis Enables Asymmetric Synthesis of α-Alkyl Tryptophans via Cascade Heck-Alkylation Reaction

“…The organo/transition metal combining catalysis provides powerful solutions for achieving challenging organic transformations and has become one of the hottest research fields in current asymmetric catalysis . As an emerging catalytic strategy, the chiral aldehyde/transition metal combining catalysis has been successfully used in the catalytic asymmetric α-allylation, benzylation, and propargylation of NH 2 -unprotected primary amines, exhibiting a good perspective in the creation of optically active amino acids and amines. In this combined catalytic system, the transition metal responded to the formation of an active π-allyl–metal complex from corresponding alcohol esters.…”