Synthesis Of Chiral Nitrogen Heterocyclic Compounds By Iridium-Catalyzed Intramolecular Asymmetric Reductive Amination And Its Fungal Activity Against Plant Pathogens

Optically active nitrogen heterocyclic compounds are widely present in natural products and pharmaceutically active structures,and are also used in many fields such as pesticides,dyes,conductive materials,perfumes,and surfactants.For example,the well-known low toxicity insecticide Nornicotine,the analgesic Oxycontin and the antithrombotic drug Plavix are all the optically active nitrogen heterocyclic compounds.Therefore,it is very necessary to develop methods to efficiently synthesize the chiral nitrogen heterocyclic compounds.At present,the asymmetric catalysis involved in transition metals is widely used in the synthesis of chiral nitrogen heterocyclic compounds due to its low catalyst loading,high catalytic efficiency and flexible stereoselective control.Among them,the intramolecular asymmetric reductive amination avoids the disadvantage that the imine or enamine instability which causes the difficulty in separation and synthesis,and improves atomic economy.In this thesis we have synthesized four kinds of chiral nitrogen heterocyclic compounds and investigated the antifungal activity of three of them.The main contents are as follows:1.Synthesis of chiral 1-substituted tetrahydroisoquinolines:the intramolecular asymmetric reductive amination reaction was carried out after removing the protecting group of N-Boc-2-benzoylethyl ester under trifluoroacetic acid（TFA,6 equiv.）conditions.From the screening of solvents,additives,ligands and temperature,the optimal reaction conditions are[{Ir（H）[（R）-SegPhos]}₂（μ-I）₃]⁺I^-as catalyst,titanium tetraisopropanolate（Ti（OⁱPr）₄,1.2 equiv.）,p-toluenesulfonic acid（TsOH,0.1 equiv.）and iodine（I₂,0.1 equiv.）as additives.We have obtained 17 tetrahydroisoquinoline products（up to 99%yield and99%ee）in total.Studies have shown that the combination of the additive tetraisopropyl titanate and the iodine molecule contributes to the formation of the imine intermediates and the stereo-control of the products.2.Synthesis of chiral 2-substituted tetrahydropyrrole:The intramolecular asymmetric reductive amination reaction was carried out by removing the protecting group of the N-Boc-（4-oxo-4-phenylbutyl）amino acid ester under the conditions of trifluoroacetic acid（TFA,6 equiv.）.The reaction conditions were optimized on the basis of the addition of tetraisopropyl titanate and iodine.The addition of bicyclo（2.2.2）-1,4-diazaoctane（DABCO,0.2 equiv.）might promote the heterogeneous cleavage of the hydrogen molecule increases the catalytic activity.Sixteen tetrahydropyrrole products（up to 98%yield and 92%ee）were obtained using[Ir（COD）Cl]₂/L2 as a catalyst in total.3.Synthesis of chiral 2-substituted tetrahydroquinoline:based on previous research,we envisage that the protective group removal process can be carried out simultaneously with the asymmetric hydrogenation process by adding a suitable Br?nsted acid,to simplify the synthesis procedure.At present,the optimal reaction condition is[Ir（COD）Cl]₂/（R）-BINAP as catalyst and toluene as solvent under the action of TsOH（2.0 equiv.）.The yield of2-phenyltetrahydroquinoline was 91%,and the enantioselectivity was 79%.4.Synthesis of chiral cycloamides:twelve aryl substituted 3-aryl iso-1-ketones（up to99%yield and 96%ee）were synthesized by asymmetric hydrogenolysis of3-aryl-3-hydroxyindoline-1-one with iridium-phosphite ligand（L3i）as catalyst and3,5-difluoromethylphenylboronic acid（1.2 equiv.）as additive.The reaction conditions of aliphatic substituent products are still under optimization.5.Antibacterial activity evaluation:with carbendazim as positive control,the antibacterial effect for three types of chiral amines（36 samples）was determined using the mycelial linear growth rate method.At 50 ug/mL,there was no significant difference between racemic compounds and their optical isomers in the screening of bacteriostatic activities of tetrahydroisoquinoline and tetrahydropyrrole compounds,and the bacteriostatic rate was lower（<50%）.Cycloamide compounds showed good bacteriostasis.The inhibition rate of compound 12f on 6 pathogens was 80%and the inhibition rate on fusarium solani was as high as 96%.