Reaction Studies Of Asymmetric Alkylation Of 3-bromooxindoles With Indole Derivatives For The Construction Of Alkaloid Intermediates

Cyclotryptamine indole alkaloids are widely found in plants,animals,marine mosses and microorganisms and have a broad spectrum of biological activities（e.g.,antihypertensive,analgesic,anticonvulsant,antifungal,etc.）.Based on the number of hexahydropyrrolo[2,3-b]indole（HPI）units they contain,they can be simply classified into three categories:monomeric,dimeric and oligomeric.Among them,the key backbone and full-quaternary carbon stereocenter of C3-indole substituted monomeric cyclotryptamine alkaloids,and the continuous full carbon quaternary carbon center structure of C3a,C3a’-dimeric cyclotryptamine alkaloids all pose great challenges for their chemical synthesis.In this thesis,the asymmetric alkylation of indoles with 3-bromooxindoles was firstly developed to achieve the asymmetric construction of 3-indolyl oxindoles in a simple and efficient manner.After the screening of ligands,metal catalysts,solvents and bases,L₅/Ni（BF₄）₂·6H₂O was finally determined as the optimal catalytic system,DIPEA as the base and ethyl acetate as the solvent as the optimal reaction conditions.And a series of3-bromoindole oxide and indole derivatives with different substituents were investigated for their substrate suitability.Under the optimal conditions,all the C-3a-C-3a’oxindole-indole derivatives were obtained with excellent yields（up to 99%yield）and high enantioselectivities（up to>99%ee）.This method with mild conditions and stable gram-scale reaction can be used as a potential intermediate for the synthesis of3-indolylindole alkaloids.To further verify the synthetic potential,we achieved the synthesis of cyclic tryptamine alkaloids in the form of（+）-folicanthine in 3-step 55%overall yield from the obtained chiral 3-indolyl oxindoles ent-2-58t after simple methylation,oxidation and allylation reactions.Caulamidines A and Caulamidines B are a class of indole alkaloids from the marine mosquitoes with a novel indole-quinoline backbone and crowded neighboring all-carbon quaternary carbon centers,which show significant inhibition of both wild-type and resistant strains of P.falciparum at low micromolar concentrations.Structurally,how to stereoselectively construct adjacent high-resistance all-carbon quaternary carbon centers is also key to their chemical synthesis.Therefore,we further expanded the substrate range and developed the asymmetric alkylation of 3-bromooxindoles with 4-hydroxyquinolinones to stereoselectively construct indole-quinoline structures with continuous all-quaternary carbon centers.After the preliminary condition screening,the reaction was determined to be carried out at room temperature with L6/Ni（BF4）2-6H2O as the catalytic system,DIPEA as the base and ethyl acetate as the solvent as the better reaction conditions,38%yield and 92%ee under this condition.And the relative conformations of the products 3-37bb and the natural products caulamidines A and caulamidines B were determined by X single crystal diffraction.It provided a feasible strategy for the construction of key intermediates of caulamidines A,caulamidines B.