(R,S)‐Azolides as Novel Substrates for Lipase‐Catalyzed Hydrolytic Resolution in Organic Solvents

Abstract

Azolides, that is, N-acylazoles, as versatile acylation reagents are well characterized in the literature, in which the azole structure can not only act as a better leaving group but also make the carbonyl carbon more electrophilic and susceptible to nucleophilic attack. It is therefore desirable to combine this unique property and lipase resolution ability in the development of a new resolution process for preparing optically pure carboxylic acids. With the Candida antarctica lipase B (CALB)-catalyzed hydrolysis of (R,S)-N-profenylazoles in organic solvents as the model system, (R,S)-N-profenyl-1,2,4-triazoles instead of their corresponding ester analogues were exploited as the best substrates for preparing optically pure profens, i.e., 2-arylpropionic acids. The structure-reactivity correlations for the (R,S)-azolides in water-saturated methyl tert-butyl ether (MTBE) at 45 8C coupled with a thorough kinetic analysis were further employed for elucidating the rate-limiting formation of a tetrahedral adduct without C À N bond breaking or with moderate C À N bond breaking concerted with C À O bond formation in the acylation step. The advantages of easy substrate preparation, high enzyme reactivity and enantioselectivity, and easy recovery of the product and remaining substrate by aqueous extraction demonstrate the potential of using (R,S)-azolides as novel substrates for the enzymatic resolution process.

Quantitative Improvements and Insights into CALB‐Catalyzed Resolution of trans‐ and cis‐2‐Phenylcyclopropyl Azolides

“…By furthermore replacing 3 by 2 and 1 (Figures S1c and 1a), the resultant E trans values slightly decreased to 83 and 95, yet with enhancements of 7.3‐fold of V RR0 ( E t ) −1 ( S RR ) 0 −1 and 8.3‐fold of V SS0 ( E t ) −1 ( S SS ) 0 −1 for 1 owing to the easy‐leaving capability of 1,2,4‐triazole moiety. Similar kinetic behaviors have been reported for CALB‐catalyzed hydrolysis of ( R,S )‐2‐arylpropionic azolides in MTBE ,. By considering the high enzyme activity and enantioselectivity and easy product separation via extraction, we have selected 1 as the best substrate for the following investigations.…”

“…Similar kinetic behaviors have been reported for CALB‐catalyzed hydrolysis of ( R,S )‐2‐arylpropionic azolides in MTBE ,. By considering the high enzyme activity and enantioselectivity and easy product separation via extraction, we have selected 1 as the best substrate for the following investigations.…”

“…A substrate model (Figure C in reference 8c) has been proposed on predicting CALB stereopreference for substrates with the acyl part containing a chiral center at the alpha or beta position. Accordingly, CALB would preferentially hydrolyze (R,S)‐2‐phenylpropyl 1,2,4‐triazolide and (R,S)‐3‐phenylbutyl 1,2,4‐triazolide for obtaining (R)‐2‐phenylpropyl acid and (R)‐3‐phenylbutyl acid, respectively –. It is then logical to predict the order of kinetic parameters as k 2RR K mRR −1 > k 2RS K mRS −1 > k 2SR K mSR −1 > k 2SS K mSS −1 , or k 2RR K mRR −1 > k 2SR K mSR −1 > k 2RS K mRS −1 > k 2SS K mSS −1 , if the substrate mixture consists of trans ‐ and cis ‐2‐methyl‐3‐phenylbutyl 1,2,4‐triazolides ( trans ‐ and cis ‐MPBT).…”

Pd‐Catalyzed Regioselective Hydroesterification of Olefins with 2,2,2‐Trifluoroethyl Formate

“…Ester 3a (Table , entry 1): Light yellow oil; IR (film): 1756, 1167 cm –1 ; 1 H NMR (400 MHz, CDCl 3 ) δ = 7.37–7.23 (m, 5H), 4.54–4.42 (m, 1H), 4.42–4.31 (m, 1H), 3.81 (q, J = 7.2 Hz, 1H), 1.53 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ = 173.2, 139.5, 128.9, 127.7, 127.65, 123.1 (q, J = 275.5 Hz), 60.6 (q, J = 36.3 Hz), 45.3, 18.5; 19 F NMR (376 MHz, CDCl 3 ) δ = –73.8; HRMS (EI) Calcd for C 11 H 11 F 3 O 2 [M] + : 232.0706, found 232.0708.…”

A Review on Geotrichum Lipases: Production, Purification, Immobilization and Applications

“…The versatility of lipases allows applications in reactions such as hydrolysis, esterification, interesterification and transesterification, alcoholysis, acidolysis and aminolysis. Several modern bioprocessesuse lipases, such as: biodiesel production 6,7 , food industry 8,9 , medicine 10,11 , in pharmaceutical and cosmetic industries 12,13 , pretreatment of industrial wastewaters 14,15 , detergents formulation 16,17 , and many others 18 . Lipases can replace alkaline catalyzers in biodiesel production facilitating the glycerol recovery and the purification of fatty methyl esters.…”