Dynamic Kinetic Resolution of 1,2-Diarylethanols by Enzyme-Metal Combination

DoctorDynamic kinetic resolution (DKR) provides a practical method for the conversion of racemic substrates to single enantiomeric products. In the last decade, Kim and Park’s group and others have developed various DKR systems consist of enzymes and metals. For example, the DKR of a wide range of racemic secondary alcohols can be achieved with a lipase-ruthenium combination. Ruthenium complexes are used as a racemization catalyst in DKR and have been remarkably improved by some leading groups including ours. On the other hand, the use of enzymes is relatively limited that only a few enzymes have been practically introduced to DKR. Particularly, enzymes generally fail to resolve secondary alcohols possessing two similar-in-size substituents at the hydroxymethine center. The objective of this work thus was to develop the practical procedures for the DKR of sterically demanding secondary alcohols using enzyme-metal combination.I have investigated the enzymatic kinetic resolution (EKR) of seventeen 1,2-diarylethanols as sterically demanding secondary alcohols. It was found that all of them were accepted by PSL with high enantioselectivities. Addition of inorganic base such as potassium phosphate or potassium carbonate increased the activity of PSL but also caused a chemical acylation reaction. The racemization of chiral 1,2-diarylethanols was successfully completed by ruthenium complex. I conducted the DKR of 1,2-diarylethanols using PSL and ruthenium catalyst to obtain optically pure 1-acetoxy-1,2-diarylethanols. The DKR reactions were performed with solutions containing substrate (0.2 mmol), ruthenium catalyst (8 mol%), PSL (120 mg / mmol), isopropenyl acetate (1.5 equiv), and K2CO3 (1 equiv) in toluene at 25 oC. All of 1,2-diarylethanols were successfully transformed into their acetates with high yields (95-99%) and excellent enantiopurities (96-99%).I also have explored the (S)-selective DKR of 1,2-diarylethanols. First, I examined the EKR of 1-phenyl-2-arylethanols by Candida antarctica lipase A (CALA). CALA was immobilized on Celite with sucrose to improve its activity. It showed a good activity and (S)-selectivity toward 1-phenyl-2-arylethanols. CALA’s substrate scope was relatively more restricted than that of PSL. Replacing the 1-phenyl ring of 1-phenyl-2-arylethanols by a smaller furyl ring enhanced the enantioselectivity in general. I have tried to improve the activity of CALA by coating the enzyme with triphenylphosphine oxide (TPPO). The TPPO-coated CALA showed an improved activity relative to Celite-immobilized CALA. And then, I explored the (S)-selective DKR of 1-phenyl-2-arylethanols using TPPO-activated CALA and a ruthenium catalyst. The DKR reactions were carried out with solutions containing substrate (0.1 mmol), ruthenium catalyst (8 mol%), CALA (60 mg), trifluoroethyl butyrate (1.5 equiv), and K2CO3 (1 equiv) in toluene at 25 oC. Five 1-phenyl-2-arylethanols were subjected to DKR. All of them were converted efficiently to their butyrates with good yields (82-91%) and satisfactory enantiopurities (87-94%). Finally, I explored the preparation of readily recyclable homogeneous transition metal catalyst. At first, I used single-walled carbon Nanotubes (SWNTs) as a solid supporter for a ruthenium complex possessing a pyrene moiety which can interact with the surface of SWNTs. I could not obtain a satisfactory result because the interaction between SWNTs and ruthenium complex was not strong enough. The second strategy was to introduce a fluorous tag to a catalyst. A fluorine-rich molecule was prepared and coupled with a ruthenium catalyst. A new fluorous-tagged ruthenium complex showed an increased activity in racemization reaction. However, it was more soluble in organic solvents than fluorous solvent so that it cannot be used for recycling