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The optically active metabolites of (S)-3,4-dihydro-6-[3-(1-o-tolyl-2-imidazolyl)sulfinyl-propoxy]-2(1H)-quinolinone (OPC-29030, 1), which is a new anti-platelet agent (platelet adhesion inhibitor), were effectively synthesized by the enzyme-catalyzed enantioselective transesterification of the racemic sulfinyl metabolites. The enzymes can recognize a stereogenic sulfur atom remote from the reaction site.

A metabolite of Aripiprazole (1), 7-[4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (2), was prepared by the coupling reaction of 1-(4-benzyloxy-2,3-dichlorophenyl)-piperazine (11) with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 was efficiently prepared using the palladium-catalyzed amination of phenyl bromide 15 with piperazine.

Optically active 2-[(3-hydroxypropyl)sulfinyl]-1-( o -tolyl)imidazole (S)- 2 was synthesized by kinetic resolution of (±)- 2 with lipase and hydrolysis of the acetate (S)- 3 with potassium carbonate. The reaction mixture of the lipase-catalyzed transesterification was converted to the phthalic acid derivative (R)- 4 , and this (R)- 4 and the unreacted acetate (S)- 3 were fractionated without use of column chromatography. The unrequired recovered alcohol (R)- 2 was also racemized and (±)- 2 was repeatedly submitted to the lipase-catalyzed transesterification.

An efficient and highly enantioselective synthesis of ( S )-(−)-5,6-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (4b) , a key intermediate in the synthesis of ( S )-(−)-nadifloxacin ( 2 ), was carried out by using a cross-coupling reaction. Also α,β-acetylenic ketones 14a,b underwent an asymmetric reduction using various chiral reagents to afford the corresponding propargylic alcohols 8a,b in good yield and excellent enantiomeric excess, which can be easily converted to butanol 9 .

A metabolite of Aripiprazole (1), 7-[4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (2), was prepared by the coupling reaction of 1-(4-benzyloxy-2,3-dichlorophenyl)-piperazine (11) with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 was efficiently prepared using the palladium-catalyzed amination of phenyl bromide 15 with piperazine.

As an efficient and enantioselective synthesis of the 4,5-dihydroxy-benzazepine compounds, the syntheses of optically active 5-0-protected trans-4,5-dihydroxybenzazepine derivatives were accomplished. The trans-7-chloro-4-hydroxy-5-methoxymethoxy-1 -(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(±)-4] was kinetically resolved by lipase-catalyzed transesterification. The optically active 4* was isomerized into the cis compound (6*) utilizing the Mitsunobu esterification followed by hydrolysis. The chiral compounds (4* and 6*) were converted to the 4,5-bismethoxymethoxy compounds (7*-10*), which were the intermediates for the compounds (2a, b and 3a, b).

The optically active enantiomers of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061, 1) were enantioselectively synthesized. The asymmetric transfer hydrogenation of the ketone (2), which is the precursor of 1, gave the corresponding secondary alcohols in good yield and excellent enantiomeric excess.