Chiral Aldehyde Catalysis-Enabled Asymmetric α-Functionalization of Activated Primary Amines

The development of catalytic activation modes provides a reliable and effective platform for designing new enantioselective reactions and preparing chiral molecules with diverse structures. Chiral aldehyde catalysis is an attractive concept in asymmetric catalysis, which utilizes a chiral aldehyde catalyst to promote the asymmetric hydroamination of allylic amines, the asymmetric alpha-functionalization of primary amines, or the asymmetric transamination of alpha-keto esters. Typically, the chiral aldehyde-catalyzed asymmetric alpha-functionalization of primary amines provides an efficient and straightforward method for the synthesis of alpha-functionalized chiral amines, which does not require any additional protection or deprotection manipulations of the amine group. However, achieving catalytic stereoselective transformations with high efficiency and enantioselectivity by this strategy has remained an intractable challenge. This Account summarizes our endeavors in the development and application of chiral aldehyde catalysis. Using a chiral aldehyde as a catalyst, we reported the catalytic asymmetric alpha-C alkylation of 2-aminomalonate with 3-indolylmethanol in 2014, which represents the first chiral aldehyde-catalyzed asymmetric alpha-functionalization of an activated primary amine. Subsequently, several axially chiral aldehyde catalysts were continuously prepared by using chiral BINOL as the starting material, and their applications in asymmetric synthesis were explored. On the one hand, they were used as organocatalysts to realize the various transformations of alpha-amino acid esters, such as asymmetric 1,4-addition toward conjugated enones/alpha,beta-unsaturated diesters and cyclic 1-azadienes as well as asymmetric alpha-arylation/allylation and benzylation with corresponding halohydrocarbons. Notably, taking advantage of the difference in the distribution of catalytic sites between two chiral aldehyde catalysts, we disclosed chiral aldehyde-catalyzed diastereodivergent 1,6-conjugated addition and Mannich reactions. On the other hand, the potential for the cooperative catalysis of a chiral aldehyde with a transition metal has also been demonstrated. Enabled by the combination of a chiral aldehyde, a palladium complex, and a Lewis acid, the enantioselective alpha-allylation of amino acid esters with allyl alcohol esters was established. Moreover, the ternary catalytic system has been successfully used for the alpha-functionalization of amino acid esters with 1,3-dienes, allenes, allenylic alcohol esters, 1,3-disubstituted allyl alcohol esters, and arylmethanol esters as well as the asymmetric cascade Heck-alkylation reaction. The combination of a chiral aldehyde and nickel complex allows for the asymmetric alpha-propargylation of amino acid esters with propargylic alcohol esters and provides excellent enantioselectivities. These transformations provide a large library of optically active amines and amino acids. With those chiral amino acid esters as key building blocks, the synthesis or formal synthesis of multiple natural products and biologically significant unnatural molecules was accomplished. This includes the stereodivergent synthesis of natural pyrrolizidine alkaloid NP25302 and the formal synthesis of natural product (S)-hypoestestatin 1 and manzacidin C, clinical candidate compound (+)-AG-041R, and somatostatin mimetics. It is fully anticipated that chiral aldehyde catalysis will soon witness rapid expansion both in the development of novel asymmetric transformations and in innovative applications for constructing optically active nitrogen-containing molecules with significant values.