Chiral Pyridoxal-catalyzed Asymmetric αC-H Addition Of Glycine Ester

With the continuous development of the economy and the progress of society,synthetic chemistry plays an increasingly important role in the national economy.However,current synthetic chemistry is plagued by issues such as low synthesis efficiency,harsh conditions,frequent use of protective groups,and cumbersome reaction steps,all of which contribute to deteriorating environmental pollution,necessitating chemists to devise new strategies for more efficient and environmentally friendly synthetic chemistry.Among them,biomimetic catalysis is a chemical catalysis technology that learns from nature and simulates the structure and function of enzymes,which can reduce pollution from the source.All these aspects belong to the category of green chemistry.It has the advantages of mild conditions,green and harmless,high catalytic efficiency and environmental friendliness,and can integrate the advantages of biocatalysis and traditional chemocatalysis to achieve high efficiency and precisely controlled chemical transformation under environmentally friendly conditions,which meets the national strategic needs of sustainable development of environmental protection.Inspired by the direct Aldol reaction between aldehydes and glycine catalyzed by L-threonine aldolase in living organisms,we have developed two types of chiral pyridoxal catalysts to catalyze the biomimetic asymmetric Michael addition reaction and the biomimetic asymmetricα-allylation reaction respectively,which provided new ideas for the synthesis of chiral pyroglutamic acid and glutamate derivatives.（1）Chiral pyroglutamic acids and their derivatives are a type of important compounds,which have been widely studied and applied in health and medicine,food,cosmetics,agriculture and other industries.It is of great significance to develop new methods for synthesizing pyroglutamic acids derivatives.Traditional synthetic methods have limitations such as long reaction steps,low atom utilization,and harsh reaction conditions,which extremely affect the efficiency of synthesis.Inspired by the Aldol reaction catalyzed by enzymes in biological systems,we designed and synthesized a chiral pyridoxal catalyst with an amide side chain,which successfully realized direct asymmetric conjugated addition at theα-C of glycinate withα,β-unsaturated esters,to produce various chiral pyroglutamic acid esters 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 with the same absolute configuration via tert-butyl group removal and subsequent Barton decarboxylation.This reaction provides a simple and efficient perspective for the synthesis of chiral polysubstituted pyroglutamic acid derivatives.It has the characteristics of high reaction efficiency,green and pollution-free,and meets the needs of green and sustainable development.（2）Chiral glutamic acids and their derivatives are a class of significant compounds with high bioactivities.Many medicinal and natural products contain the basic structural unit of glutamic acid.Therefore,it is of great significance to develop new methods for the synthesis of glutamic acid derivatives.The traditional method of synthesizing chiral glutamic acid derivatives necessitates the addition of additional protecting groups to protect the NH₂ group,is time-consuming,and does not meet the requirements of green and sustainable development.Based on carbonyl catalysis strategy,we designed and synthesized a chiral pyridoxal catalyst with an amide side chain at the C3 position of the naphthalene ring.Without protection of NH₂ groups,direct biomimetic asymmetric allylation at theα-C of glycinate with MBH acetate has been successfully realized,to produce a series of chiral multisubstituted glutamic acid esters with high yields and good stereoselectivities（yield as high as 86%,>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.This reaction provides a simple and efficient method for the synthesis of chiral multisubstituted glutamic acid derivatives.It has the characteristics of simple operation and environmental friendliness,and conforms to the concept of green and sustainable development.