Asymmetric Hydrogenation Tandem Reaction Of Pyridone And Antibacterial Activity Of Nitrogen Heterocyclic Compounds

The direct catalytic asymmetric hydrogenation of pyridine compounds remains a challenge,mainly due to the high aromaticity and strong alkalinity of the pyridine ring,which hinders the reduction process.For this purpose,we use the strategy of activating substrates with Bronsted acid to connect the asymmetric hydrogenation of pyridine ketone with nitrogen alkylation reaction,and synthesize high enantioselectivity indolizidine and quinolizidine alkaloid derivatives through a "one pot" method.The catalytic cycling process was explored through mechanism research and DFT calculations,and the antibacterial activity of the nitrogen heterocyclic compounds involved was investigated.The main content is as follows:1.Synthesis of indolizidine alkaloid derivatives: Exploring the conditions for asymmetric hydrogenation nitrogen alkylation series reaction using pyridine 1a as substrate.The optimal condition is to use Ir-(R)-Binap as the catalyst,with additives such as trifluoroacetic acid,p-methoxybenzoic acid,sodium chloride,and crown ether.A total of 41 indolizidine alkaloid analogues with different substituents were obtained,with a maximum yield of 95% and enantioselectivity of 96%.Research has shown that p-methoxybenzoic acid can effectively reduce the production of intermediate(2a ’);The presence of chloride ions in the system can effectively prevent the substrate amine from directly coordinating with metals,thereby poisoning the catalyst and reducing cycle efficiency;The time control experiment indicates that the carbonyl portion in the substrate is preferentially reduced,and the formed chiral center participates in the subsequent construction of the chiral center.The deuterium substitution experiment found that the nitrogen alkylation process in the reaction is carried out through the nucleophilic substitution mechanism,and the spatial configuration does not flip under the induction of the chiral center of the substrate.2.Synthesis of quinorizidine alkaloid derivatives: Based on existing research,explore the optimal reaction conditions for pyridine 3a.On the basis of maintaining the addition of trifluoroacetic acid,the optimal reaction conditions were obtained by replacing the ligand(R)-DTBM-Seg Phos with larger steric hindrance and acidic additive(diisopropylethylamine hydrochloride).A total of three different substituents of quinolicidine alkaloid derivatives were obtained,with a maximum yield of 79% and enantioselectivity of 87%.3.Antibacterial activity evaluation: Using thiamethoxazole as a positive control,the inhibitory effect of 29 nitrogen heterocyclic compounds involved in the reaction process on 6 common plant pathogenic fungi was evaluated using filamentous growth method(drug concentration 50 μg/m L).It was found that 14 nitrogen-containing heterocyclic chalcone analogues could inhibit plant pathogenic fungi,and the inhibition rate of 2-bromo substituted azacyclic chalcone analogues 4f against Alternaria brassicae was as high as 95%.However,the antibacterial effects of alkaloid derivatives are poor,and there is no significant difference between the antibacterial effects of racemic compounds and optically pure compounds.Using ciprofloxacin as a positive control,the inhibitory effects of 33 nitrogen heterocyclic compounds involved in the reaction process on 11 bacteria were evaluated using filter paper diffusion method(drug loading of 20 μg).13 nitrogen heterocyclic substituted chalcone analogues were found to have poor inhibitory effects on 11 bacteria,with only 2-bromo substituted nitrogen heterocyclic chalcone analogues 4f exhibiting a 20 mm inhibitory zone against Xanthomonas oryzae.20 alkaloid derivatives have almost no inhibitory effect on 11 bacteria.