The Research On Synthesis Of Chiral Tetrahydroquinolin-4-ols And 6-H Phenanthridines

The first part of this paper: The study on the asymmetric synthesis of chiral 1,2,3,4-tetrahydroquinolin-4-olsObjective: To screen the efficient lipase with high activity and enantioselectivity as catalyst and synthesize the enantiocomplimentary chiral 1,2,3,4-terahydroquinolin-4-ols and its corresponding esters through kinetic resolution.Methods: N-Boc-1,2,3,4-terahydroquinolin-4-ol was choosed as model substrate to screen the lipases, acyl donors and solvents of enzymatic kinetic resolution, then the optimal reaction condition was obtained, last the relationship between different substrate structure and the reaction activity of enzymatic kinetic resolution was also investigated.Results:(1) The optimal asymmetric esterification system with Novozyme 435 as optimal biocatalyst, vinyl 2-chloroacetate as efficient acyl donor has been established.(2) Chiral 1,2,3,4-tetrahydroquinolin-4-ols and 2,3,4,5-tetrahydro-1H-benzo[b] azepin-5-ols could be synthesized in high yields with excellent enantioselectivities(up to 49% yield, >99% ee) in this systerm.(3) The absolute configuration of the product was determined by X-ray crystallographic analysis.(4) This protocol could be apply to the asymmetric acylation of 10 grams-scale of the racemic 1,2,3,4-tetrahydroquinolin-4-ol in 44% yield with 99% ee, as well as the chiral 1,2,3,4-tetrahydroquinolin-4-ol could be transformed into chiral 1,2,3,4-tetrahydroquinolin-4-amine with simple steps.Conclusion:(1) A practical and efficient methodology for the construction of chiral 1,2,3,4-tetrahydroquinolin-4-ols, 2,3,4,5-tetrahydro- 1H-benzo[b]azepin-5-ols and its corresponding esters through kinetic resolution has been developed.(2) 13 substrates could be smoothly supply the corresponding products in excellent yields with enantioselectivities through this method.(3) The 10 grams-scale enzymatic kinetic resolution also proceeded smoothly through this method.The second part of this paper: The study on the synthesis of 6-H phenanthridinesObjective: To develop an efficient method for the synthesis of 6-H phenanthridines.Methods: 6-H phenanthridines could be obtained with readily prepared N-Ms arylamines and commercially available 2-bromobenzyl bromide derivatives as starting materials through palladium-catalyzed nucleophilic substitution/C-H activation /aromatization cascade reaction.Results: The optimal reaction condition was obtained: Pd(TFA)2 as catalyst, PPh3 as P-Ligand, Cs2CO3 as base and DMF as solvent in 160 oC;(2) A range of 6-H phenanthridines could be obtained with 31%-85% yield through this method;(3) The structure of the product was determined by X-ray crystallographic analysis;(4) This method was also successfully applied to the synthesis of natural alkaloid trisphaeridine in 55% yield.Conclusion: Palladium-catalyzed nucleophilic substitution/C-H activation/ aromatization cascade reaction has been developed. A range of 6-H phenanthridines could be obtained with readily prepared and commercially available compounds as starting materials. Additionally, the possible mechanism for this cascade reaction was also proposed.