Tadaaki Ohtani

Practical application of the palladium-catalyzed amination in phenylpiperazine synthesis: An efficient synthesis of a metabolite of the antipsychotic agent aripiprazole

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.

Synthesis of a key intermediate, (S)-2-[(3-hydroxypropyl)sulfinyl]-1-(o-tolyl)imidazole, for the platelet aggregation inhibitor, OPC-29030 via lipase-catalyzed enantioselective transesterification

Abstract 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.

Identification of two novel reductases involved in equol biosynthesis in Lactococcus strain 20-92.

Lactococcus strain 20–92 is a bacterium that produces equol directly from daidzein under anaerobic conditions. In this study, we reveal that the transcription of the gene encoding daidzein reductase in Lactococcus strain 20–92 (L-DZNR), which is responsible for the first stage of the biosynthesis of equol from daidzein, is regulated by the presence of daidzein. We analyzed the sequence surrounding the L-DZNR gene and found six novel genes, termed orf-US4, orf-US3, orf-US2, orf-US1, orf-DS1 and orf-DS2. These genes were expressed in Escherichia coli, and the resulting gene products were assayed for dihydrodaidzein reductase (DHDR) and tetrahydrodaidzein reductase (THDR) activity. The results showed that orf-US2 and orf-US3 encoded DHDR and THDR, respectively. DHDR in Lactococcus strain 20–92 (L-DHDR) was similar to the 3-oxoacyl-acyl-carrier-protein reductases of several bacteria and belonged to the short chain dehydrogenase/reductase family. THDR in Lactococcus strain 20–92 (L-THDR) was similar to several putative fumarate reductase/succinate dehydrogenase flavoprotein domain proteins. L-DHDR required NAD(P)H for its activity, whereas L-THDR required neither NADPH nor NADH. Thus, we succeeded in identifying two novel enzymes that are related to the second and third stages of the biosynthetic pathway that converts daidzein to equol.

Enantioselective Synthesis of the Metabolites of Vasopressin V2 Receptor Antagonist OPC-31260 via Lipase-Catalyzed Transesterification

Abstract The optical isomers of 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-31260, 1) and its metabolites (2, 3, 4, 5 and 6) were enantioselectively synthesized. The chiral acetate 8b and alcohol 7a were prepared via the resolution of the racemic alcohol (±)-7 using the lipase-mediated transesterification in vinyl acetate. The compounds 8b and 7a were converted to the hydroxy metabolites (2a and 2b), the methylamine metabolites (3a and 3b), the dimethylamines (1a and 1b), and the amine metabolites (4a and 4b) in several steps while maintaining their absolute configurations. The 4,5-diol metabolites (5a, 5b, 6a and 6b) were synthesized from the key intermediates obtained by the lipase-catalyzed transesterification.

An efficient synthesis of optically active metabolites of platelet adhesion inhibitor OPC-29030 by lipase-catalyzed enantioselective transesterification

Abstract The optically active metabolites of ( S )-3,4-dihydro-6-[3-(1- o -tolyl-2-imidazolyl)sulfinyl-propoxy]-2(1 H )-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.

An efficient synthesis of a key intermediate towards (S)-(−)-nadifloxacin

Abstract 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 .

Efficient Synthesis of Functionalized Benzazepine Derivatives Utilizing Intramolecular Mitsunobu Reaction

The 5-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine derivative (2), which is a typical metabolite of mozavaptan (1) having the 2,3,4,5-tetrahydro-1H-benzazepine skeleton, was synthesized by utilizing the intramolecular Mitsunobu reaction of the corresponding 2-(4-hydroxybutyl)aniline derivative. In the intramolecular Mitsunobu reaction, effect of the substituent group on nitrogen atom, influence of the functional group applying to synthesis of the other metabolites (3, 4 and 5) and utilization of synthesis of 2-substituent benzazepine derivatives were investigated.