Developments of Lipase-Catalyzed Resolution Platform by Uisng (R,S)-Azolides as Novel Substrates

  • Tsai, Shau-Wei (PI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Enzyme-catalyzed kinetic resolution is to enantioselectively resolve the racemate such that the resulting chiral product can be separately from remaining chiral substrate via conventional unit operation processes. For the past years, this laboratory has employed approaches of medium engineering, immobilized enzyme techniques, and substrate engineering for developing lipase-catalyzed resolution processes. However, there still exists a bottleneck that the rate-determining step will change and leads to reduced enantioselectivity, when employing conventional racemic acids, alcohols, amines, estes, amides and thioesters as the substrates. However recently, we have found that by combining the azoles chemistry with lipase resolution ability on using (R,S)-N-acylazoles (i.e. (R,S)-N-azolides) as the substrate, the bottleneck can be overcome, and thus induce our motivation to submit the research proposal. In the following three years, we will focus on developing the lipase-catalyzed resolution platform for preparing chiral carboxylic acids, alcohols and amines. In the first year, the combinatorial resolution for (R,S)-N-azolides containing an α-chiral center is studied, in which effects of the acyl and leaving alcohol azole containing substituents on the enzyme performance will be investigated and compared with those using simple azoles without containing the substituent. Moreover, the kinetic analysis will be carried out to elucidate the optimal enantioselectivity when varying the leaving azole moiety. In the second year, (R,S)-azole-N-carboxylates are first synthesized from (R,S)-alcohols and then employ for performing the lipase-catalyzed hydrolytic resolution. This approach is different from the conventional resolution of using (R,S)-alcohol as an acyl acceptor, i.e. the (R)- and (S)-alcohol of (R,S)-azole-N-carboxylate as an acyl donor allocating in the acyl pocket of the catalytic active site. In the third year, the research will be extended to the resolution (R,S)-amines. However, new derivatives of (R,S)-N-oxalamic azoles from (R,S)-amines, oxayl dichloride and azole will be synthesized, and then are employed as the substrate for lipase-catalyzed hydrolysis. It stresses that this approach is also different from the conventional resolution of using (R,S)-amine as an acyl acceptor, i.e. the (R)- and (S)-amine of (R,S)-N-oxalamic azoles as an acyl donor allocating in the acyl pocket of the catalytic active site (details are described in the following section).

Project IDs

Project ID:PB9907-12643
External Project ID:NSC99-2221-E182-028
StatusFinished
Effective start/end date01/08/1031/07/11

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