Angelw: Huang Yong research group, School of chemistry, Shenzhen Graduate School, Peking University develops an asymmetric proton transfer strategy based on "transient stability" to prepare β - chiral amides

Amide is the core functional group in synthetic chemistry It not only mediates the construction of heterocyclic framework, but also widely exists in bioactive molecules and drug frameworks Among them, the peptides modified by chiral amides can reduce their polarity, improve their metabolic stability and membrane permeability, and become an important natural amino acid residue replacement unit β - chiral amides are usually prepared under strong reducing conditions: asymmetric Michael addition of organometallic reagents, or asymmetric hydrogenation of unsaturated amides, which has low applicability to heteroatom substrates with metal coordination ability Huang Yong research group of School of chemical biology and biotechnology, Shenzhen Graduate School of Peking University is committed to the development of bionic proton transfer strategy, and the development of efficient synthesis of chiral fragments through precise space-time regulation of "the smallest electrophilic reagent" - proton Previously, based on this idea, the research group developed the first non covalent catalytic model of azacarbene based on proton transfer catalysis, and successfully realized the asymmetric construction of C-C, C-S and C-N bonds On this basis, the research team further developed the asymmetric β - protonation reaction and realized the asymmetric hydroesterification of olefin aldehyde Recently, in order to solve the interference of basic amines on proton migration, the research team designed the transient acyl trap, developed the bionic asymmetric proton migration based on azacarbene catalysis, and efficiently constructed a series of chiral carboxylic acid derivatives such as β - amide The results were published online in angew Chem Int ed., entitled "enantioselective" hydroamidation of enals by trapping of a transientacyl species”（ DOI: 10.1002/anie.201803556）。 In order to obtain high asymmetric β - protonation and active acyl intermediates with certain stability, the reaction system has strict requirements for the acidity and nucleophilic of "transient stable" reagents Through the systematic study of reaction variables, the team found that triazole derived from aminoindenol was used as carbene precursor, bridgehead amine as proton shuttle, imidazole (or carbazole) as "transient steady-state" reagent, which could obtain β - chiral acyl "steady-state" intermediates with high optical activity, and could be used as aliphatic amines, aromatic amines, hydrazides, hydrazides, alcohols, peroxyalcohols, phenols, water and A series of nucleophiles, such as mercaptan, were captured in situ to form a wide range of β - chiral carboxylic acid derivatives These products can be used to construct chiral heterocyclic segments and modify peptides at N-terminal The above work is under the guidance of Professor Huang Yong / Chen jie'an, Shenzhen Graduate School, Peking University, and Professor Zhao Jin, Nanjing University The doctoral student yuan Pengfei Completed, relying on the joint construction of the National Key Laboratory of cancer chemical genomics by the Ministry and the province, and supported by the National Natural Science Foundation of China, China Postdoctoral special funding project and Shenzhen Science and Technology Innovation Committee.