|Budget Amount *help
¥29,700,000 (Direct Cost: ¥29,700,000)
Fiscal Year 1995: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1994: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1993: ¥23,500,000 (Direct Cost: ¥23,500,000)
The side effects caused by Salidomide drug promoted scientists to investigate the selective synthetic methods and catalytic asymmetric reactions because that only its one enantiomer caused physical deformity. But, almost chiral medicines at 1990 in Japan were under development as racemates, mainly from lack of suitable efficient synthetic methods to produce homochiral medicines.
The typical chiral skeletons of the developing medicines were 1,4-dihydropyridines, glycerol derivatives and beta-aminoethanols. We have developed novel efficient methods catalyzed by chiral metal catalysts only for asymmetric synthesis of beta-aminoiethanols. But, efficient catalytic asymmetric synthesis of 1,4-dihydropyridine-type and glycesol-type mediceneswas not developed until now.
We started to develop the catalytic asymmetric synthesis of these medicines by using enzymes and micro-organisms as catalysts. For large scale production, substrate solubility is most important factor. So, we selected to investig
ate catalytic asymmetric reactions in organic solvents, based on new designing concept that enzymes are both catalyst and macromoleculars having substrate-specific asymmetric space, resulting that when the reaction does not complete, new reagent should be used to remove the the reaction equiblium point and when the reaction does not occur, new functional groups suitable to enzymes should be added to start the asymmetric reactions.
We have developed new methodologies based on our new concepts for asymmetric synthesis of homochiral 1,4-dihydropyridines, glycerol-type medicines, d-alpha-tocopherol, barbiturates, beta-lactams and hydantoions.
Vinyl acetate methodology and meso-racemic diol methodology for homochiral alcohols, succinic anhydride methodology for resolution of racemic alcohols, acyloxymethyl methodology, carbamoyl methodology and point mutation methodology for asymmetric synthesis of 1,4-dihydropyridines, oxalate methodology and intra-molecular asymmetric cyclization methodology for asymmetric synthesis of d-alpha-tocopherol and remote recognition methodology for chiral synthesis were established. Less