Asymmetric reduction using enzymes and chiral chemical reagents

• Main Author: Valente, Edward
• Published: University of Strathclyde 1984
• Subjects: 541; Physical chemistry
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371116

This thesis is concerned with the asymmetric reduction of achiral substrates to chiral products on a preparative scale. In the first case dihydrofolate reductase was used to catalyse the conversion of 7,8-dihydrofolic acid into (6S)- 5,6,7, B-tetrahydrofolic acid. The required coenzyme,NADPH, was recycled 1100 fold in situ using coupled enzyme techniques. The reaction was quantitative and complete stereospecificity was demonstrated using chiral naphthyl isocyanates and HPLC. (6R)- 5,10-Methenyltetrahydrofolate was isolated in 28% yield and hydrolysed to give (6S)-5-formyltetrahydrofolate. The necessary enzymeswere immobilised for recovery and re-use. However, despite extensive experimentation, a sufficiently active immobilised dihydrofolate reductase could not be obtained. This was primarily due to the low intrinsic activity of the enzyme. To complement the enzymic studies the chiral chemical reduction of dihydrofolic acid was investigated. The sepamtion of the C6 epimers was thus particularly important for the assessment of the efficiency of the chiral reagents. Two types were investigated a) borate complexes of ?-amino alcohols and b) triacycloxyborohydrides prepared from chiral amino acids. The fomer gave modest chiral induction (up to 18% isomeric excess) whilst the latter were inert. The enzymic route would therefore seemto be the best available. In the second case tetrahydropyran-3-one was reduced using the chiral catalytic properties of the enzyme horse liver alcohol dehydrogenase. The coenzyme, NADH, was recycled 800 fold using the same methodology as for NADPH. Tetrahydropyran-3-o1 was obtained in 49% enantiomeric excess. Acetolysis of the chiral brosylate was undertaken to ascertain whether Rv(2)0v(3) anchiomeric assistance was operating duxing the reaction. This suggestion had previously been surmised from kinetic results. Racemisation occurred during the solvolysis arguing against neighbouring group participation.