Synthesis Of Chiral N-aryl-α-amino Acids By Pd Catalyzed Couplings Of Aryl Chloride

N-aryl amino acids, especially chiral N-aryl amino acids, have important applications. They are many core structures of some bioactive compounds, such as the inhibitor of protein kinase C indolactam-V8 and its analogs, the benzolactam-V8; the antagonist of fibrinogen acceptor SB 2148573; the antagonist of NMDA acceptor L6895604 and so on. N-aryl amino acids are also used as agricultural chemicals, such as a pesticide of metalaxyl. Therefore, developing the preparation method of N-aryl amino acids is important.There are several reports of the new synthetic methods of N-aryl amino acids following the group of Ma who report the preparation method of palladium-copper catalyze the aryl iodine and bromo and amino acid into N-aryl amino acid. Whereas, there are no news of using the palladium only catalyze aryl chlorine and amino acid.We adopted palladium(0) and single dentate triarylphosphine ligands with amino acids which used to make the C-N cross coupling reaction and prepare the N-aryl amino acids. In order to get the best conditioned response, we research the conditions on the kinds of palladium source and ligands, the amount of catalysts,the different base, the time and the temepreture. In the first, we attempt the reaction of L-valine and chlorobenzene, then get the optimal conditions: the time was one hour, the temepreture was 70℃, and with the Pd2(dba)3 and Johnphos. And,α-amino acids/ chlorinated aromatic/ catalyst/ ligand/ base=1.3:1.0:0.02:0.05:2.4(mmol). What's more, we try to make lots ofα-amino acids(there are L-valine, D-valine, L-Isoleucine, L-Leucine, L-Proline and L-Phenylalanine)with the chlorobenzene and L-valine with different substituent aryl chlorobenzene(there are 4- nitro chlorobenzene, 4- chloro cyanobenzene, 2- chloro cyanobenzene, 4- chloro toluene, 4 - chloro anisol, 2 - chloro anisol and 3- chloro anisol reacted. It proved that when the catalyst lows to 2(mmol)%, the time of the reaction only was 10 60 minutes, the temperature was 70 to 100 degrees, excepted the adjacent bits of chlorinated aromatic, the yields all fall on 40%⁷5%. The enantiomeric excess of N-aryl amino was higher than 70%. And we use the luminosity, infrared, NMR, mass spectrometry to characterize.We attempted to synthesize two chiral ligands, which will be used in enantioselective sulfoxidation and asymmetrical allyl substitution reaction. The hydroxyl groups of (R)-(+)-BINOL were protected by chloromethyl methyl ether to give BINOL-2MOM. The BINOL-2MOM was otho-lithiated with n-BuLi and then reacted with Ph₂CO to form diphenyl hydroxymethyl group on the ortho position. The crude product was purified through column chromatograhy to give the product.In the presense of p-tolyene sulfonic acid (R,R)-1,2-diphenyl ethylenediamine was reacted with ethyl formate to form formyl group on the amino groups. Then lithium aluminium hydride was used to reduce the formamide to give the target product.