| 98% |
With sodium tertiary butoxide; <i>tert</i>-butyl alcohol; (S)-2,2',6,6'-tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine In toluene at 20℃; for 14h; enantioselective reaction; |
|
| 98% |
With di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium; hydrogen; C41H44N3O3P; barium(II) hydroxide In ethanol at 40℃; for 1h; Autoclave; enantioselective reaction; |
|
| 97% |
With bis(tricyclohexylphosphine)benzylidene ruthenium (IV) dichloride; hydrogen; C41H43N2O4P; barium(II) hydroxide In methanol at 30℃; for 2h; enantioselective reaction; |
|
| 96% |
With dodecacarbonyltri-iron; C52H58N4P2; hydrogen; potassium hydroxide In methanol at 45℃; for 5h; enantioselective reaction; |
|
| 95% |
With potassium hydroxide; <RuCl2(mesitylene)>2 (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine In isopropanol for 8h; Ambient temperature; |
|
| 93% |
With Debaryomyces hansenii P1 at 30℃; for 48h; Microbiological reaction; enantioselective reaction; |
|
| 91% |
With 2-(N-morpholino)ethanesulfonic acid buffer; nadide; isopropanol for 24h; Ambient temperature; acetone powder of Geotrichum candidum IFO4597(APG4); in the dark; |
|
| 91% |
With 2-(N-morpholino)ethanesulfonic acidbuffer; nadide; isopropanol at 30℃; for 20h; acetone powder of Geotrichum candidum; |
|
| 89% |
With Lactobacillus paracasei BD101 In aq. buffer at 30℃; for 48h; Microbiological reaction; enantioselective reaction; |
|
| 88% |
With n-hexan-2-ol In hexane; lithium hydroxide monohydrate at 30℃; for 24h; immobilized Geotrichum candidum; |
|
| 83% |
In lithium hydroxide monohydrate at 30℃; for 5h; Geotrichum candidum IFO4597 on a diluted medium (glycerol, yeast extract, polypeptone); |
|
| 82% |
With nadide; Sodium hydrogenocarbonate; isopropanol In carbon dioxide at 35℃; for 5h; Supercritical conditions; MES buffer; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; |
|
| 80% |
With D-glucose at 35℃; for 36h; Tris buffer; Microbiological reaction; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; |
4.6. Preparative scale production
General procedure: The preparative scale (large scale) production of (S)-1-phenylethanol 1b from acetophenone 1a by immobilized C. laurentii EBK-19 cells was also achieved. The reduction of 1a was carried out in a 1000-mL Erlenmeyer flask using beads prepared as described in Section 4.4. The cells were activated by suspending the beads in 300 mL tris buffer containing 4% glucose. After cell activation (3 h), acetophenone 1a (6 mM) was directly added to the mixture. During the 36 h reaction period, the beads were regularly separated by filtration, resuspended in tris buffer and glucose and reused for the same reaction without washing. At regular time intervals (36 h), the conversion and enantiomeric excess (ee) of the product were determined and the yields calculated. The run time of the beads was optimized for the production of 1b and found to be 27 days. |
| 80% |
With Lactobacillus kefiri P2 at 25℃; for 64h; Green chemistry; Enzymatic reaction; enantioselective reaction; |
General asymmetric bioreduction process
General procedure: Lactobacillus kefiri P2 was added from its glycerol stock by inoculation to 10mL MRS mixture (MgSO4.7H2O 11.5% (w/v), K2HPO4 2 g/L, pepton [Oxoid] 10 g/L, yeast extract 2% glucose, [Difco] 5 g/L, C2H3NaO2.3H2O 5 g/L, salt solution [MgSO4.7H2O 11.5% (w/v), triamonium citrate 2 g/L], Tween 80 1 mL/L) followed by 48 h growth at 37 °C. From this mixture, overnight grown bacterial cells were inoculated to 100m LMRS mixture at 10% concentration. Then, pH of medium was adjusted to 4.5 with 1M HCI. This mixture was shaken for 2 hours, and then 1 mmol of substrate (1-16) was directly added to this mixture and incubated on an orbital shaker at 150 rpm with an incubation temperature of 25 °C for 64 h incubation period. After the catalytic reaction was complete, the supernatant was separated. The aqueous phase was saturated with NaCI and extracted with dichloromethane. After the organic phases were combined, they were dried over anhydrous Na2SO4 and filtered to remove the salt. The liquid was removed in a vacuum to remove dichloromethane and the crude product was characterizedby NMR analysis. After the crude product was purified using column chromatography, ee was determined using chiral HPLC. The absolute configurations of the alcohols were determined by comparing the literature values of the specific rotation. |
| 79% |
With D-glucose In lithium hydroxide monohydrate at 32℃; for 24h; Microbiological reaction; optical yield given as %ee; enantioselective reaction; |
|
| 77% |
With acetophenone reductase from Geotrichum candidum NBRC 4597; nadide; isopropanol In aq. buffer at 30℃; for 14h; Enzymatic reaction; enantioselective reaction; |
1.6 Preparative scale reduction of 2a-13a by GcAPRD wild type and Trp288Ala
General procedure: Reductions were performed in 50 mL of 100 mM HEPES-NaOH buffer (pH 7.2) consisting of1.4 mM NAD+, 0.23-0.39 mmol of 2a-13a, cofactor regeneration reagent written in Table S1, and purified GcAPRD with the amount written in Table S1. Reactions were done for 14 h at 30°C with a rotational speed of 130 rpm. The product was extracted with diethyl ether, dried over MgSO4, and evaporated under reduced pressure. Silica gel column chromatography (hexane:ethyl acetate 4:1) were performed to give the corresponding chiral alcohols 2b-13b. |
| 75% |
With n-hexan-2-ol; Geotrichum candidum IFO 4597 cells on BL-100 polymer In hexane at 30℃; for 24h; |
|
| 75% |
With C23H31ClN2O2RuS; potassium hydroxide In isopropanol at 24 - 25℃; for 24h; |
|
| 74% |
Stage #1: 1-(3-chlorophenyl)ethan-1-one With (1R,2R)-N,N’-bis(3,5-di-tert-butylbenzyl)-1,2-diphenylethane-1,2-diamine; methyldiethoxysilane; Zinc acetate In tetrahydrofuran at 25℃; for 24h; Inert atmosphere;
Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In tetrahydrofuran for 1h; enantioselective reaction; |
|
| 73% |
With Alternaria alternata EBK-4 In various solvent(s) at 28℃; for 24h; Microbiological reaction; |
|
| 66% |
With D-(+)-glucose In aq. phosphate buffer at 25℃; for 24h; Sealed tube; enantioselective reaction; |
3.4. Reduction of Ketones
General procedure: Reactions were all performed in 50-mL screw-capped plastic vials to prevent evaporation ofketones/alcohols. The reaction mixture contained 3 g of free resting cells (0.3 g/mL) or 4.5 gof immobilized cells (0.45 g/mL), 0.5 g of glucose in 10 mL Na2HPO4-KH2PO4 buffer (100 mM,pH 7.0), with the substrates of the final concentration of 10 mM. The solution was shaken at 25 Cfor 24 h. After separating from the cells by centrifugation, 2 mL of the obtained supernatant wassaturated with NaCl, and extracted with n-hexane/i-PrOH (95/5, v/v, 2 1 mL). The obtained organiclayer was dried over Na2SO4 and injected into HPLC for yield and ee measurement. |
| 64% |
With (S)-selective alcohol dehydrogenase whole-cell lyophilisate In aq. buffer enantioselective reaction; |
|
| 44% |
With seeds of Bauhinia variegata L. (Fabaceae) In lithium hydroxide monohydrate; dimethyl sulfoxide at 40℃; for 48h; Green chemistry; enantioselective reaction; |
|
| 37% |
With Synechococcus sp. PCC 7942 at 20℃; for 72h; Irradiation; |
|
| 26% |
With fruits of Ligustrum lucidum (glossy privet) In aq. phosphate buffer; dimethyl sulfoxide at 20℃; for 144h; enantioselective reaction; |
|
|
With [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]ruthenium; formic acid; triethylamine at 28℃; for 21h; Yield given; |
|
|
With D-glucose; D-glucose dehydrogense; Pyrococcus furiosus alcohol dehydrogenase In dimethyl sulfoxide at 37℃; |
|
|
With 1,4-dihydronicotinamide adenine dinucleotide; (S)-alcohol dehydrogenase; formate dehydrogenase from C. boidini; Rhodococcus erythropolis (E.coli) In phosphate buffer Enzymatic reaction; |
|
|
With 1,4-dihydronicotinamide adenine dinucleotide; (S)-alcohol dehydrogenase from Rhodococcus erythropolis In phosphate buffer at 30℃; |
|
|
With D-glucose; D-glucose dehydrogenase; NADPH In dimethyl sulfoxide at 20℃; |
|
|
With C49H57ClFeN2OsP2; potassium-t-butoxide; hydrogen In methanol at 60℃; for 1h; optical yield given as %ee; enantioselective reaction; |
|
|
With Aspergillus terreus SSP 1498 at 32℃; for 48h; aq. phosphate buffer; Microbiological reaction; optical yield given as %ee; enantioselective reaction; |
|
|
With carrot (Daucus carota L.) In ethanol; lithium hydroxide monohydrate at 33℃; for 28h; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; |
|
|
With phenylsilane; copper (II) acetate; (S)-2,2',6,6'-tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine In toluene at -20℃; for 12h; stereoselective reaction; |
|
|
With ADH-A from Rhodococcus ruber; NAD<SUP>+</SUP> In aq. phosphate buffer; isopropanol at 30℃; for 72h; enantioselective reaction; |
|
| 99.9 % ee |
With 5'-GGTATTGAGGGTCGCGCGGGCGCGGGCGCGATGTCAATTCCATCAAGCCAGTACGGATT-3'; nicotinamide adenine dinucleotide; anhydrous zinc chloride In aq. phosphate buffer at 30℃; for 0.05h; stereoselective reaction; |
|
| > 99.9 % ee |
With tripotassium phosphate tribasic; Candida parapsilosis aldo-keto reductase CPAR4; NADPH at 30℃; for 8h; Enzymatic reaction; enantioselective reaction; |
2.7 Asymmetric reduction of carbonyl compounds
General procedure: Asymmetric reductions of various carbonyl compounds by the purified enzymes were carried out at 30°C for 8h with mild shaking in a reaction mixture containing 0.1M potassium phosphate buffer (pH 6.5), 1gL-1 substrate, 10mM NADPH, and the purified enzyme of appropriate amount in a total volume of 2mL. In order to determine the absolute configuration of chiral alcohols, the reaction products were extracted with ethyl acetate or hexane and the organic layer was used for analysis. The optical purity of the reaction products were determined by chiral HPLC (HP 1100, Agilent, USA) equipped with Chiralcel OB-H column (4.6mm×250mm; Daicel Chemical Ind. Ltd., Japan) or chiral GC (7890A, Agilent, USA) equipped with FID detector and Chrompack Chirasil-Dex CB chiral capillary column (25m×0.25mm; Varian, USA) [21]. |
| 99 %Chromat. |
With alcohol dehydrogenase from Escherichia coli In isopropanol at 30℃; for 24h; Enzymatic reaction; stereoselective reaction; |
|
| >99% ee |
With glucose; glucose dehydrogenase from Bacillus subtilis CGMCC 1.1398; medium-chain dehydrogenase from Kuraishia capsulate CBS1993; nadide In aq. phosphate buffer for 16h; Enzymatic reaction; enantioselective reaction; |
Substrate scope and enantioselectivity determination
General procedure: Substrate scope and enantioselectivity determination The relative activities of 26 substrates were measured using thepreviously described assay protocol with adjusted ratio of enzymeand substrate concentration. The a-chloroacetophenone activitywas assumed 100%.Enantioselectivity was determined by examining the reductionof aromatic ketones using an NADH-regeneration system consist-ing of the puried KcDH and glucose dehydrogenase (GDH) fromBacillus subtilis CGMCC 1.1398. The 1-mL reaction mixture con-tained 0.5 mM NAD+, 10 mM ketone, 1 U KcDH, 50 mg glucoseand 2 U GDH in 50 mM potassium phosphate buffer (pH 7.0). After16 h, the reaction sample was equally separated into two parts,with one terminated by adding an equal volume of methanol, fol-lowed by HPLC analysis to determine the conversion ratio, and theother extracted with ethyl acetate, followed by ee analysis. Meth-ods used for analysing chiral products using HPLC or GC aredescribed in Supplementary Table S1. |
|
Multi-step reaction with 2 steps
1: (1R,2R)-N,N’-bis(3,5-di-tert-butylbenzyl)-1,2-diphenylethane-1,2-diamine; Zinc acetate / neat (no solvent) / 6 h / 25 °C / Inert atmosphere; Sealed tube
2: N,N,N-tributylbutan-1-aminium fluoride / tetrahydrofuran / 0.08 h / 0 °C / Inert atmosphere |
|
| 95 % ee |
With N,N'-((1S,2S)-cyclohexane-1,2-diyl)bis(2-(diphenylphosphino)benzamide); ruthenium(III) trichloride hydrate; hydrogen; anhydrous sodium carbonate In methanol at 20℃; for 22h; Autoclave; enantioselective reaction; |
|
| 98 %Chromat. |
With C50H47Cl2N6O5PRuS2; potassium isopropoxide; isopropanol at 28℃; for 0.0333333h; Inert atmosphere; enantioselective reaction; |
|
|
With D-glucose; NADH In aq. phosphate buffer; dimethyl sulfoxide at 30℃; Enzymatic reaction; |
1.A Step A: (S)-1-(3-chlorophenyl)ethanol
A stock solution of 9 g Glucose (25 g/L), 1.10 g ADH-RE (3 g/L), 360 mg NAD (1 g/L), 720 mg GDH (2 g/L), and 360 mg LDH (1 g/L) in 360 mL 0.1M phosphate buffer was prepared beforehand. 90 mL of the stock solution was quickly added to a solution of 1-(3-chlorophenyl)ethanone (1.0 g, 6.5 mmol) in 10 mL of DMSO, and stirred overnight at 30° C. The reaction showed >98% conversion and >99% e.e. by HPLC [ZORBAX Eclipse Plus C18 50×4.6 mm, 1.8 uM, 10% to 95% B (A=0.1% phosphoric acid, B=acetonitrile), 1.5 mL/min., 210 nM, 25C, 8 min. run time]; therefore, 100 mL of MTBE was added followed by 2 mL of 5N NaOH. The reaction was agitated, centrifuged, and separated. The aqueous layer was re-extracted with 50 mL of MTBE followed by agitation, centrifuge, and separation. The MTBE layers were combined and washed with 50 mL of brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by ISCO COMBIFLASH chromatography (12 g silica gel, 30 mL/min, 254 nM, 0% to 100% EtOAc/hexane over 24 CV. The desired product elutes at 22% EtOAc/hexane). |
| 96 % ee |
With di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium; C49H67FeN2O2PS; hydrogen; lithium tert-butylate In isopropanol at 20℃; for 12h; Inert atmosphere; Autoclave; |
10 Preparation of 1-m-chlorophenylethanol from m-chloroacetophenone (S/C=10000)
In a high-purity argon atmosphere, [Ir(COD)Cl]2 (3.4 mg, 0.005 mmol)The chiral ligand L6 (9.2 mg, 0.011 mmol) was dissolved in isopropanol (1 mL).Stirring for 3 hours at room temperature gives an orange clear solution. 20 μL (0.001 mol %) of the orange solution was taken with a micro syringe and added to m-chloroacetophenone (2 mmol),In a mixed system of isopropanol (2 mL) and lithium t-butoxide (1 mol %). Place the reaction system in an autoclaveStir at room temperature under H2 (20 atm) for 12 hours. Remove the solvent under reduced pressureColumn chromatography (silica gel column, eluent: ethyl acetate) to give pure 1-chlorobenzene-ethanol,The product was analyzed by HPLC and found to have an ee value of 96%. |
| 96 % ee |
With di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium; C49H67FeN2O2PS; hydrogen; lithium tert-butylate In isopropanol at 25 - 30℃; for 12h; Autoclave; enantioselective reaction; |
|
| 88 %Chromat. |
With tris-(dibenzylideneacetone)dipalladium(0); copper(I) thiophene-2-carboxylate; triethyl phosphite In isopropanol at 30℃; for 24h; |
|
| 95 % ee |
With hydrogen; C32H12BF24(1-)*C39H43IrN2P(1+) In isopropanol at 20℃; for 0.5h; enantioselective reaction; |
|
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