Enzymatic Resolution Of Chiral Diamines And Derivative Synthesis

Optically active amine compounds are important chiral intermediates,and play an important role in the synthesis of chiral compounds.Chiral amines can also be used as biological functional molecules,which are widely used in chiral medicine,chiral pesticides,chiral flavors,and other fine chemicals.For example,chiral cyclohexane diamine is a widely used chiral amine compound,which is mainly used in the field of chiral small molecule catalysts,and the synthesis of chiral drugs.This study focuses on the synthesis of chiral cyclohexane diamine,and its derivatives.Candida antarctica lipase B(Novozym 435)was firstly selected as a biocatalyst,and the trans 1,2-cyclohexanediamine,and dimethyl malonate were used as reaction substrates,where an asymmetric amination reaction catalyzed by Novozym 435 was established.The reaction was checked by thin layer chromatography,and product was purified by fast column chromatography.The qualitative and quantitative of products were detected by high-performance liquid chromatography.After the target product was determined,the enzyme-catalyzed reaction conditions were subsequently optimized to obtain the optimum reaction results.Under the optimum reaction conditions including 1,4-dioxane as the reaction solvent,Novozym 435 additive concentration of 50 mg/m L,substrate molar ratio(cyclohexane diamine: dimethyl malonate=1:1),reaction temperature of 30 °C,the yield of chiral diamide ester obtained was 17.8%(maximum theoretical yield of 50%),and the optical purity was 90%.The final(R,R)-1,2 could be obtained by hydrolysis of diamide ester,and its optical purity remained unchanged.Using the obtained chiral cyclohexane diamine as the central building block,six kinds of chiral small molecule cyclohexane diamine derivatives were successfully prepared,which can be used as basic catalysts to be used.The chiral bifunctional thiourea catalyst could be designed,and synthesized with threonine as a starting material.The excellent reaction yields could be obtained through the study of experimental conditions,and the structure of products were also characterized.Five kinds of more important organic reactions were selected for preliminary evaluation of the synthesized catalysts,and some thiourea compounds showed good catalytic performance.Especially the threonine-derived chiral thiourea catalyst showed high catalytic activities,and the reaction yield of 63%,and ee value of 93% could be obtained in the asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone and nitrostyrene.These bi-functional thioureas have high enantioselectivity and good tunability,and have great potential for further application in asymmetric organic catalysis.