Asymmetric Catalytic Synthesis Of Thioheterocyclic Compounds Based On Aromatic Aldehydes And Their Biological Activitie

Sulfur-containing heterocyclic compounds have important agricultural biological activities such as antifungal,antibacterial,insecticidal,and antiviral,which widely present in living organisms.Sulfur-containing thiazine heterocycles are an important class of active lead frameworks,and exploration of the activity of such frameworks has always been a significant research area for medicine and pesticide workers.Chiral pesticides are a crucial way to develop high-efficiency,low-toxicity green pesticides.The simple and efficient asymmetric synthesis of such skeletons is of great significance and research value.Therefore,N-Heterocyclic Carbene（NHC）was used to synthesize sulfur-containing heterocyclic compounds with a single chirality,and the pesticide activity was tested.Then study the biological activity of its different configurations（such as:R/S）,and carry out scientific issues such as mechanism of action through modern bioinformatics methods such as proteomics,laying a foundation for subsequent research and providing theoretical guidance.We first synthesized a series of chiral isoquinoline-sulfonamides and chiral indole-sulfonamides.Through preliminary activity tests,Xanthomonas oryzae pv.oryzae,Ralstonia solanacearum,and Xanthomonas axonopodis pv.citri,it was found that none of rice bacterial blight（Xoo）,tobacco bacterial wilt（R.s）and citrus canker（Xac）had obvious antibacterial activity.Therefore,we optimized and upgraded the structure,changed which increased the flexibility of the molecule,expanded the core skeleton,and improved structural diversity.The five-membered ring into a six-membered ring and designed a one-step efficient construction of chiral thiazide compounds from simple raw materials which increased the flexibility of the molecule,expanded the core skeleton,and improved structural diversity.Then,activity tests were performed,a new chiral lead structures with higher activity were screened out by in vitro,in vivo and scanning electron microscopy analysis,the mechanism was studied by label-free quantitative proteomics analysis.Through the iterative optimization of the structure of three generations of compounds,we finally found that the chiral thiazide compounds have good antibacterial activity,especially the best antibacterial activity against rice bacterial blight.The following are my main research contents.（1）Route a,a new activation mode of NHC was realized-NHC catalyzed direct carbon-hydrogen functionalization and（4+2）cyclization atγ-position across the benzene ring.Twenty-two novel chiral isoquinoline-sulfonamide functional group splicing compounds were synthesized,and the reaction mechanism was studied in depth.and the reaction mechanism was studied in depth.Through DFT calculation,it was found that the participation of NHC in the catalytic reaction can effectively activate the benzylic carbon-hydrogen bond to form o-QDM intermediates.（2）Route b,a new remoteδ-HOMO activation and[4+2]cycloaddition across the indole ring was realized;19 new splicing structures of chiral indole-sulfonamide active fragments were obtained.This is the first time in the field of NHC catalysis that theδ-position remote activation mode of aryl aldehydes has been realized,which provides an important theoretical support for the long-range activation mode of aryl aldehydes realized by NHC.The method has mild conditions,simple operation,high yield,and high stereoselectivity control.It can providean important technical means for the creation of new drugs and the splicing of active structures.（3）Route c,using the catalytic activation reaction of NHC catalysts,we realized the concise,efficient and rapid construction of 29 chiral thiazinone heterocyclic functional molecules with simple starting materials.An NHC-copper（II）synergistic mode of catalysis is realized for one-step construction of single-chiral thiazide-like compounds.In conventional copper-catalyzed reactions,monovalent copper is often used as a catalyst for catalytic reactions,while NHC has strong coordination ability and is often used as a ligand in metal catalysis.Therefore,the general catalytic theory holds that in the metal catalytic system,it is difficult for NHC to act as a catalyst for synergistic reactions without deactivation.In our study,only using NHC as a catalyst could not achieve a better control of stereoselectivity.With the continuous optimization of reaction conditions,we found that the addition of divalent copper can effectively improve the stereoselectivity of reactions,and also achieve higher chemical yields.（4）A series of synthetic compounds were tested for biological activity.The results showed that the thiazide series of structures exhibited good inhibitory activity against Xoo.especially,the compounds 3-3o,3-3p,3-3t,and 3-3u.Then,the racemate and the other two configurations of the highly active compound were evaluated by EC₅₀,then we found the compound 3-3p-S configuration has the highest activity(EC₅₀=1.9μg/m L);therefore,different configurations of 3-3p were studied.In vivo experiments were carried out,at a concentration of 200μg/m L,and it was found that compound 3-3p-S had a higher protection activity（48.5%）than the control agent bismerthiazol（29.1%）.Finally,the effect of the of compound 3-3p-S on Xoo was observed by scanning electron microscope,and it was found that compound 3-3p could fold and rupture the surface of the bacteria;this kind of structure has the value of continuing development,so we further study the Xoo in vivo for label-free quantitative proteomic analysis.The study of its mechanism of action,through non-quantitative proteomics analysis,the compound 3-3p-S may be involved in the metabolic pathway of sulfur-containing amino acids,interfering with the normal metabolic process,thus showing a certain biological activity.The next step is still in the methodical further research of our group.