Chemoenzymatic Dynamic Kinetic Resolution of Functionalized Secondary Alcohols

Sammanfattning: Dynamic kinetic resolution (DKR) is the combination of a kinetic resolution with an in situ racemization and is a powerful method for obtaining optically active compounds. In this thesis various secondary alcohols are transformed to their corresponding enantiomerically enriched acetates by employing immobilized lipases as resolution catalysts and transition metal complexes as racemization catalysts. In the first part 3-hydroxypiperidines and 3-hydroxypyrrolidines are transformed to their corresponding acetates in high yields and high enantiomeric excesses using the DKR method. This was the first report of DKR on these types of N-heterocycles. It was found that the immobilization method used has a significant impact on the enzyme selectivity and reactivity. In the second part, cyclic allylic alcohols are investigated as substrates for DKR. After optimization, the amount of enone by-product could be reduced to <10% and a range of allylic alcohols could be converted to enantiomerically pure allylic acetates in high ee. The possibility of further transformation of an iodo-substituted substrate was investigated and initial results obtained are promising. Electron-rich allylic alcohols are not suitable for this method due to competing formation of homo coupled ether. DKR has also been applied in the total synthesis of Duloxetine, the active species of the pharmaceutical CymbaltaTM. CymbaltaTM is administered as a drug against physical disorder like depression, stress urinary incontinence, and obsessive compulsive disorder. By performing a sixs tep synthesis, utilizing DKR in the enantiodetermining step, Duloxetine could be isolated in an overall yield of 37% and an enantiomeric excess above 96%.