Study On The Synthesis And Biological Activity Of Active Natural Products Base On Asymmetric Catalytic Reaction

Chirality is one of the basic attributes of nature and life,and chiral compounds widely exist in nature.Chiral drug synthesis had become a hot issue in academic research and biopharmaceuticals.Asymmetric catalytic reaction is one of the most economical,efficient and green method for preparing chiral drugs.This thesis selected three reaction types in the asymmetric catalytic reaction that can be used to construct the CC,CO,and CN bonds in chiral drug molecules.They are asymmetric allylic alkylation reaction,asymmetric transfer hydrogenation ofα-hydroxyl-α,β-unsaturated carboxylic acid,and asymmetric catalytic hydrogenation of acyclicarylimine.These reactions were applied to the synthesis of active natural products and chiral drugs and the antioxidant bioactivities of some compounds were investigated.Alpha-hydroxy carboxylic acid is a common chemical structure in nature and is found in many active natural products and medicines.Aryllactic acid compounds are important intermediates for the synthesis of chiral drugs and active natural products.For the first time,a chemical catalytic system for the synthesis of aryllactic acid through asymmetric hydrogen transfer reaction with Ru Cl（P-Cymene）（TS-DPEN）as catalyst,methanol as solvent and triethylamine and formic acid as hydrogen source was successfully developed.And through the expansion of the substrates,the catalytic system could obtain aryl lactic acid compounds with high efficiency（conversion rate:>99%）and high enantioselectivity（up to 94%ee）.The catalytic system could also be used for preparation of heterocyclic substituted lactic acid compounds with sustained high efficiency（99%）and high enantioselectivity（up to 92%）.In the meantime,the catalytic reaction was also applied to the synthesis of Danshensu,and a new chemical synthesis route of optical pure Danshensu was established.Three Danshensu derivatives were synthesized by this route and their antioxidant activities were preliminarily studied.The experimental results showed that the three danshensin derivatives at different concentrations could reduce the ROS and MDA contents in cells during t-BHP induced cell injury,and the antioxidant effect was concentration-dependent.Among them,the antioxidant activity of compound 187q was the closest one to that of Danshensu.A preliminary study on the mechanism of the asymmetric transfer hydrogenation was conducted,and we noticed that under alkaline conditions,α-hydroxy-α,β-unsaturated carboxylic acid first undergoes enol and keto tautomerism,resulting in the ketone molecule interacts with the catalyst to generate an asymmetric transfer hydrogenation,and finally generates anα-hydroxycarboxylic acid compound.Chiral amines are ubiquitous in many bioactive compounds and drugs witch are important intermediates in the synthesis of many biologically active compounds.A new type of chiral P,P-ligands containing dinaphthalene blocks of axial chirality to the asymmetric catalytic hydrogenation of iridium-catalyzed acyclic aromatic N-arylimine was applied.According to comparison with the classical Josiphos ligands of the same type,enantioselectivity was related to groups attached to phosphorous atoms of the ligands;meanwhile,the axial chirality of the naphthalene ring played a key role in the asymmetric induction.In the iridium-catalyzed asymmetric hydrogenation of acyclic aromatic N-arylimine,the reaction conditions of toluene at 50℃and 50 atm H₂ in the presence of TFA and TBAI were the best,with L2 as the ligand and[Ir（COD）Cl]₂ as the metal precursor were determined.This catalytic system can be applied to the asymmetric catalytic hydrogenation of various acyclic imines to obtain corresponding chiral amines with excellent enantioselectivity（up to>99%ee）.In addition,this catalytic system had be also applied to the preparation of key chiral intermediates for calcium-sensitive receptor modulators.According to experimental results,the catalytic system supports efficient and highly-enantioselective synthesis of chiral arylamine intermediates at the gram level,which intermediates can be used to synthesize calcium-sensing receptor modulators of multiple chiral aryl alkylamines.Asymmetric allyl alkylation can be used to construct chiral C-C bonds in many active natural products and chiral drugs.A new class of chiral N,P-ligands（10 kinds in total）based on ferrocene was designed and synthesized.The structure was confirmed by NMR and HRMS.The catalytic effect of their palladium complex catalysts in the asymmetric allylic alkylation reaction was preliminarily discussed.At room temperature,a chiral complex of 2 mol%[Pd（C₃H₅）Cl]₂ and 5 mol%chiral ligand was used as a catalyst,dried toluene was used as the reaction solvent,and K₂CO₃ was used as an additive to obtain a chemical conversion rate of up to 99%in various examples and excellent stereoselectivity（up to 98%ee）.By looking into the reaction mechanism,we noticed the spatial effect between the substituents on phosphorous atoms and imine of such chiral N.P-ligands decided the activity and stereoselectivity of the ligands.Among them,the ligands L12,L14and L15 showed the best catalytic activity and excellent stereoselectivity,which is worthy of further research.Further studies on these ligands will be carried out in the follow-up work.It is expected to be used in the synthesis of natural products and chiral drugs.By developing three asymmetric catalytic systems that can be used for the synthesis of chiral drugs and biologically active molecules,the results of excellent asymmetric catalytic reactions are applied to the synthesis of Danshensu and its derivatives,and calcium-sensitive receptor modulators.The anti-oxidant activity of the obtained Danshensu derivatives was studied.The way to obtain active natural products and chiral drugs was expanded,and the support for the further research of active natural products and chiral drugs was provided.