Chemoenzymatic Synthesis of Optically Active Alcohols Possessing 1,2,3,4-Tetrahydroquinoline Moiety Employing Lipases or Variants of the Acyltransferase from Mycobacterium smegmatis 

Abstract

The enzymatic kinetic resolution (EKR) of racemic alcohols or esters is a broadly recognized methodology for the preparation of these compounds in optically active form. Although EKR approaches have been developed for the enantioselective transesterification of a vast number of secondary alcohols or hydrolysis of their respective esters, to date, there is no report of bio- or chemo-catalytic asymmetric synthesis of non-racemic alcohols possessing 1,2,3,4-tetrahydroquinoline moiety, which are valuable building blocks for the pharmaceutical industry. In this work, the kinetic resolution of a set of racemic 1,2,3,4-tetrahydroquinoline-propan-2-ols was successfully carried out in neat organic solvents (in the case of CAL-B and BCL) or in water (in the case of MsAcT single variants) using immobilized lipases from Candida antarctica type B (CAL-B) and Burkholderia cepacia (BCL) or engineered acyltransferase variants from Mycobacterium smegmatis (MsAcT) as the biocatalysts and vinyl acetate as irreversible acyl donor, yielding enantiomerically enriched (S)-alcohols and the corresponding (R)-acetates with E-values up to 328 and excellent optical purities (>99% ee). In general, higher ee-values were observed in the reactions catalyzed by lipases; however, the rates of the reactions were significantly better in the case of MsAcT-catalyzed enantioselective transesterifications. Interestingly, we have experimentally proved that enantiomerically enriched 1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-2-ol undergoes spontaneous amplification of optical purity under achiral chromatographic conditions.

Beyond the Chemical Step: The Role of Substrate Access in Acyltransferase from Mycobacterium smegmatis

“…12−15 The acyltransferase from Mycobacterium smegmatis (MsAcT) is a versatile enzyme because it also accepts nonactivated esters such as ethyl acetate and shows an exceptionally wide substrate spectrum. 16,17 MsAcT has been successfully applied to synthesize a broad range of esters, 12,18,19 alcohols, 20 peracids, 21 and amides. 22−25 Previously, the potential of MsAcT as a catalyst for the enantioselective synthesis of cyanohydrins and secondary propargyl alcohols in aqueous media was assessed.…”

“…One subclass of hydrolases, the acyltransferases, catalyze the transesterification of activated acids such as thioesters in aqueous media, although hydrolysis is thermodynamically preferred in the presence of water . The observed high yield of ester product is caused by their kinetic preference of synthesis to hydrolysis. − The acyltransferase from Mycobacterium smegmatis ( Ms AcT) is a versatile enzyme because it also accepts nonactivated esters such as ethyl acetate and shows an exceptionally wide substrate spectrum. , Ms AcT has been successfully applied to synthesize a broad range of esters, ,, alcohols, peracids, and amides. − Previously, the potential of Ms AcT as a catalyst for the enantioselective synthesis of cyanohydrins and secondary propargyl alcohols in aqueous media was assessed …”

Lipase-Catalyzed Strategies for the Preparation of Enantiomeric THIQ and THβC Derivatives: Green Aspects

“…Although lipase-catalyzed kinetic resolution (KR) methods have been developed for the enantioselective acylation in a large number of primary and especially secondary alcohols or the hydrolysis of their corresponding esters, the first chemoenzymatic method for the preparation of optically active alcohols and esters possessing the 1,2,3,4-tetrahydroquinoline (THQ) moiety was published only recently [43]. The enantioselective transesterification (E values > 328) of racemic 1,2,3,4-THQ-propan-2-ols was performed with vinyl acetate (VA) in the presence of immobilized Candida antarctica lipase B (CALB) or Burkholderia cepacia lipase (BCL) or engineered acyltransferase variants from Mycobacterium smegmatis (MsAcT).…”