| 100% |
With dichloro-R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ruthenium; hydrogen In ethanol |
|
| 99% |
With hydrogen In methanol at 50℃; for 24h; optical yield given as %ee; enantioselective reaction; |
|
| 99% |
With hydrogen In methanol at 50℃; for 24h; Autoclave; enantioselective reaction; |
|
| 98% |
With hydrogen In ethanol at 55℃; for 24h; |
|
| 98.5% |
With dichloro(benzene)ruthenium(II) dimer In methanol at 80℃; for 20h; Inert atmosphere; Autoclave; |
2 Example 2: Synthesis of ethyl (R)-3-hydroxybutyrate
Under a nitrogen atmosphere,In a 3-liter autoclave,The dichlorophenyl ruthenium (II) dimer [RuCl2 (benzene) 2](80mg, 160umol),(R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-dibenzofuranyl-8,8'-disulfonic acid dipotassium salt ligand (340umol)Ethyl 3-oxobutanoate (86 ml, 680 mmol) was dissolved in methanol (600 ml).Degassing under reduced pressure,After purging the autoclave with nitrogen,The hydrogenation reaction was carried out at 80° C. and a hydrogen pressure of 10 bar for 20 hours.Cool to room temperatureConcentrate to near dryness,A mixture of catalyst and ethyl (R)-3-hydroxybutyrate is obtained;Slowly warming up to 85°CObtained 88.4 g of colorless (R)-3-hydroxybutyrate,Yield 98.5%,The ee value is 94.5%.Recycling catalystCan be reused after regeneration.The concentrated methanol recovered can be used directly. |
| 97.4% |
With Acetobacter sp. CCTCC M209061 anti-Prelog carbonyl reductase mut-I147V/G152L mutant; isopropyl alcohol; NADH In aq. phosphate buffer at 35℃; for 4h; Enzymatic reaction; enantioselective reaction; |
|
| 95% |
With hydrogen In methanol at 70℃; for 2h; |
|
| 95% |
With D-glucose; broth E. coli HB101; pNTS1G; NADP In various solvent(s) at 30℃; for 20h; Enzymatic reaction; |
|
| 95% |
With hydrogenchloride; [RuCl2-((R)-binap)]*NEt3; hydrogen In methanol; water at 50℃; for 16h; optical yield given as %ee; enantioselective reaction; |
|
| 94% |
With hydrogenchloride; [(R)-Ru(BINAP)Cl2]2*NEt3 In methanol at 50℃; for 14h; |
(R)-Ethyl(-)-3-hydroxybutyrate (17)
Ethyl acetoacetate 7 (3 g, 23.05 mmol) and dry methanol (25 mL) were mixed and deoxygenated with flowing nitrogen for some time. The catalyst [(R)-Ru(BINAP)Cl2]2*NEt3 (24 mg, 0.1 mol %) was added along with 2N HCl (0.04 mL, 0.1 mol %) carefully. The mixture was then transferred to a standard Parr reactor apparatus and flushed with hydrogen several times. The apparatus was charged with H2 (100 psi) and heated at 50 °C with stirring for 14 h. After completion of reaction, it was cooled and concentrated under reduced vacuo. The crude was purified by column chromatographic purification with pet ether/ethyl acetate (9:1 v/v) as eluent to obtain pure (R)-alcohol 17. Yield: 94% (2.86 g), colorless liquid; [α]20D=-46.0 (c 1.0, CHCl3) {lit.11 [α]20D=-46.0 (c 1.0, CHCl3)}; IR (CHCl3, cm-1): υmax 1458, 1636, 1734, 2935, 2978, 3441; 1H NMR (200 MHz, CDCl3): δ 1.21-1.31 (m, 6H), 2.42-2.46 (m, 2H), 3.20 (d, J = 3.8 Hz, 1H), 4.12(t, J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 14.1, 22.6, 43.2, 60.5, 64.2, 172.5; HRMS (ESI): calc. for [(C6H12O3)H] (M+H) 133.0865, found 133.0861. |
| 93% |
With SmADH31 Enzymatic reaction; stereoselective reaction; |
|
| 89% |
With recombinant E. coli cells coexpressing carbonyl reductase and glucose dehydrogenase on cell surface In aq. phosphate buffer; dibutyl ether at 20℃; |
|
| 75% |
In water at 27℃; for 96h; Geotrichum candidum; |
|
| 47% |
With Leifsonia sp. S749 cells alcohol dehydrogenase; nicotinamide adenine dinucleotide; isopropyl alcohol In phosphate buffer at 25℃; for 24h; |
|
| 36% |
In water microbial reduction by the fungus Geotrichum candidum; |
|
|
With dimethylsulfide borane complex In tetrahydrofuran at 110℃; for 0.166667h; |
|
|
With Streptomyces sp. (IPV 2645) |
|
| 99 % Chromat. |
With hydrogen In ethanol at 23 - 30℃; for 58h; |
|
|
With hydrogen In ethanol for 51h; Ambient temperature; Yield given; |
|
|
With dimethylsulfide borane complex; C11H17BNOP In toluene at 110℃; for 0.0833333h; |
|
|
With borane-THF; (2R,4S)-2-phenyl-1,3,2-oxazaphospholidine*borane In toluene at 110℃; |
|
|
With phosphate buffer; Pichia etchellsii CBS 2011 for 24h; |
|
|
In dichloromethane at 55℃; for 2.7h; |
|
|
In tetrahydrofuran; hydrogenchloride at 25℃; for 120h; |
|
|
With hydrogen; (+)-3-[2-(diphenylphosphino-5-methoxy)phenyl]-2-(diphenylphosphino)naphtho[2,1-b]thiophene In methanol at 40℃; for 40h; |
|
|
With hydrogen In methanol at 80 - 90℃; |
|
|
With hydrogen; (R)-4,4'-perfluorohexylBINAP In ethanol at 50℃; for 15h; |
|
|
With hydrogen In ethanol at 50℃; for 15h; |
|
|
With glucose dehydrogenase; ketoreductase; NADPH In dimethyl sulfoxide at 34℃; |
|
|
With hydrogen In methanol; water at 50℃; for 10h; |
|
|
With Candida magnoliae carbonyl reductase; D-glucose dehydrogenase; NADPH In water; dimethyl sulfoxide at 20℃; |
|
| 100 % Chromat. |
With hydrogen In dichloromethane at 70℃; for 24h; |
|
|
With hydrogen; 1-butyl-3-methylimidazolium Tetrafluoroborate In methanol at 20℃; for 20h; |
|
|
With hydrogen In ethanol; dichloromethane at 70℃; for 24h; |
|
| 100 % Spectr. |
With hydrogen In ethanol at 50℃; for 9h; |
|
|
With isopropyl alcohol In water at 25℃; for 24h; |
|
| 87.6 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
23
Complex 5A-a from Example 2 (2.6 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 86.2% conversion to ethyl (R)-3-hydroxybutyrate with 87.6% ee. |
| 81.7 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
29
Complex 5A-g from Example 9 (2.8 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 100% conversion to ethyl (R)-3-hydroxybutyrate with 81.7% ee. |
| 92.7 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
32
Complex 5A-i from Example 11 (2.8 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 33.5% conversion to ethyl (R)-3-hydroxybutyrate with 92.7% ee. |
| 95.4 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
36
Complex 5A-j from Example 12 (2.8 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 100% conversion to ethyl (R)-3-hydroxybutyrate with 95.4% ee. |
| 94.0 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
46
Complex 5A-k from Example 13 (3.0 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 59.2% conversion to ethyl (R)-3-hydroxybutyrate with 94.0% ee. |
| 92.5 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
52
Complex 5A-l from Example 14 (2.8 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 100% conversion to ethyl (R)-3-hydroxybutyrate with 92.5% ee. |
| 91.6 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
55
Complex 5A-n from Example 16 (2.7 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 100% conversion to ethyl (R)-3-hydroxybutyrate with 91.6% ee. |
| 92.7 % ee |
With hydrogen In ethanol at 20℃; for 6h; |
58
Complex 5A-o from Example 17 (2.7 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed ethanol (2 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetoacetate (64 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed ethanol was added and was washed in with 1.0 mL of argon-degassed ethanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 99.8% conversion to ethyl (R)-3-hydroxybutyrate with 92.7% ee. |
| 86.7 % ee |
With hydrogen In ethanol at 50℃; for 15h; |
10
Example 10: (U)-Ethyl 3-hydroxybutyrateIn a 15 mL autoclave under argon atmosphere RuCls (1.5 mg, 0.007 mmol), (-)-ligand Ib(4.3 mg, 0.007 mmol) and ethyl acetoacetate (0.15 g, 1.1 mmol) is dissolved in degassedethanol (7 mL). After flushing the autoclave with argon hydrogenation is carried out during15 h at 50°C and at 4 bar hydrogen pressure. After cooling to room temperature thereaction solution is directly analyzed by GC for conversion (column: HP-101 25 m /0.2 mm) and, after derivatization with trifluoroacetic acid anhydride, enantiomeric excess(column: Lipodex-E 25 m / 0.25 mm). Conversion is 98.3% at an ee of 86.7%. |
| 99 % ee |
With (R)-5,5'-perfluorohexylBINAP; hydrogen In ethanol at 50℃; for 15h; |
11
In order to evaluate the activities of these novel ligands and the influence of the perfluoro chains, the corresponding metal complexes were prepared by reaction with [RuCl2(benzene)]2 in accordance with the general procedure described by Noyori et al. [Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahedron Lett. 1991, 32, 4163]. The complexes were tested for the catalytic hydrogenation of several β-keto esters. The results are given in the following table: Substrate/ Ex. catalyst Conversion e.e. ref. Ligand Complex R in mol (%) (%) 10 ex 8[RuCl2(benzene)]2 Me 1000 100 99 11 ex 8[RuCl2(benzene)]2 Et 2000 100 99 |
| 83 - 90 % ee |
With hydrogen In ethanol at 50℃; |
14
Degassed anhydrous ethanol is added to the reactor in which the catalyst has just been prepared. The substrate is then added (in a defined catalyst/substrate ratio). The reactor is placed in an autoclave under a hydrogen pressure of 40 bar and at 50° C. Stirring is maintained overnight. The reactor is recovered and then centrifuged. The supernatant solution is recovered and then analyzed by gas chromatography. The determination of the enantiomeric excess is performed by chiral gas chromatography on a Lipodex A 25 m×0.25 mm column. The results obtained are given in the following table: Catalyst Substrate/catalyst Conversion e.e. (5,5'-polyNAP) in mol (%) (%) 5,5' 1000 100 83 5,5' 500 100 85 5,5' (recycled) 500 100 90 The hydrogenation of ethyl acetoacetate leads to ethyl 3-hydroxybutyrate. |
|
With dichloro(benzene)ruthenium(II) dimer; (R)-2,2'-bis(diphenylphosphanyl)-7,7'-dipropoxy-1,1'-binaphthalenyl; hydrogen In ethanol at 50℃; for 12h; optical yield given as %ee; enantioselective reaction; |
|
|
With ketoreductase from Lactobacillus kefir KefC; NADPH at 20℃; aq. buffer; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; |
|
| 86.7 % ee |
With (-)-6-dicyclohexylphosphanyl-2'-diphenylphosphino-2-methoxy-1,1'biphenyl; hydrogen In ethanol at 50℃; for 15h; |
18
In a 15 mL autoclave under argon atmosphere RuCl3 (1.5 mg, 0.007 mmol), (-)-ligand Ib (4.3 mg, 0.007 mmol) and ethyl acetoacetate (0.15 g, 1.1 mmol) is dissolved in degassed ethanol (7 mL). After flushing the autoclave with argon hydrogenation is carried out during 15 h at 50°C and at 4 bar hydrogen pressure. After cooling to room temperature the reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m /0.2 mm) and, after derivatization with trifluoroacetic acid anhydride, enantiomeric excess (column: Lipodex-E 25 m / 0.25 mm). Conversion is 98.3% at an ee of 86.7%. |
| 86.7 % ee |
With hydrogen In ethanol at 50℃; for 15h; |
14
Example 14: CR)-Ethyl 3-hydroxybutyrate; In a 15 mL autoclave under argon atmosphere RuCls (1.5 mg, 0.007 mmol), (-)-ligand Ib(4.3 mg, 0.007 mmol) and ethyl acetoacetate (0.15 g, 1.1 mmol) is dissolved in degassedethanol (7 mL). After flushing the autoclave with argon hydrogenation is carried out during15 h at 50°C and at 4 bar hydrogen pressure. After cooling to room temperature thereaction solution is directly analyzed by GC for conversion (column: HP-101 25 m /0.2 mm) and, after derivatization with trifluoroacetic acid anhydride, enantiomeric excess(column: Lipodex-E 25 m / 0.25 mm). Conversion is 98.3% at an ee of 86.7%. |
|
With isopropyl alcohol at 37℃; for 3h; aq. acetate buffer; Enzymatic reaction; optical yield given as %ee; enantioselective reaction; |
|
|
With hydrogen In methanol Inert atmosphere; |
|
|
With hydrogen In methanol at 50℃; for 24h; Autoclave; optical yield given as %ee; enantioselective reaction; |
|
|
With recombinant stereospecific carbonyl reductase 1 from Candida parapsilosis; NAD In aq. phosphate buffer at 30℃; for 6h; |
|
| 80 %Chromat. |
With Aspergillus flavus strain 4 at 35℃; for 72h; |
|
| 98.8 %Chromat. |
With hydrogen In ethanol at 60℃; for 6h; Inert atmosphere; Autoclave; enantioselective reaction; |
2.4. Catalytic hydrogenation
General procedure: Catalytic hydrogenation reactions were carried out in a 50 mL autoclave equipped with a magnetic bar. The reaction temperature was controlled by an electric heater and maintained at a set temperature. All reaction temperatures were 60 ◦C, and the hydrogen pressure was set at 40 bar. Prior to use, all substrates and solvents were degassed at reduced pressure with an aspirator. Under inert atmosphere conditions, catalyst, degassed solvent, and substrate were introduced sequentially into the reactor. The reactor was connected to a hydrogenation apparatus and purged with hydrogen (3 bar) five times before stirring was initiated. The reaction was initiated by introducing hydrogen at a pressure of 40 bar. Samples were obtained at predetermined time intervals from the reaction mixture to determine the reaction rate and enantioselectivity. The products were analyzed by gas chromatography (HP 6890) using a Rtx-1701 column. Enantiomeric excess was determined by GC using a Chiraldex G-TA column. |
| > 99 % ee |
With D-glucose; D-glucose dehydrogenase; Pichia guilliermondii; nicotinamide adenine dinucleotide phosphate In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 12h; Enzymatic reaction; enantioselective reaction; |
|
|
With hydrogenchloride; dichloro-di-μ-chloro-bis(R-2,2'-bis(diphenylphosphine)-1,1'-binaphtyl)diruthenium(II); hydrogen; triethylamine In methanol; water at 50℃; for 16h; Inert atmosphere; |
9 Exam pie 9: (R)-Ethyl (-)-3-hydroxybutyrate, (43)
[00059] Ethyl acetoacetate (7.5g) and dry methanol (25 mL) were mixed and deoxygenated with flowing nitrogen for five minutes. The catalyst [(R)-Ru(BINAP)C12]2 NEt3 (0.1 mol %) was added along with 2N HCI (0.1 mol %). The mixture was transferred to a standard Parr reactor apparatus and flushed by evacuating and refilling with hydrogenseveral times. The apparatus was heated at 50 °C with stirring under 100 psi of hydrogen for 16 h. After completion of reaction (monitored by TLC) the reaction was cooled and concentrated under reduced pressure. The residue was subjected to column chromatographic purification with petroleum ether/ethyl acetate (9:1 v/v) to get pure (R)alcohol 43 as a colorless liquid.[a]025 -46.0 (c 1.0, CHC13); lit.” [a]025 -46.0 (c 1.0, CHCI3); 98% ee (Mosher ester); IR (CHCI3, cm’) 3441.7, 2978.6, 2935.7, 1734.0, 1636.1, 1458.1; ‘H NMR (200 MHz, CDCI3): ö 4.12-4.22 (m, 3H), 3.20 (d, J 3.8 Hz, 1H), 2.42-2.45 (m, 2H), 1.21-1.31 (m, 6H); ‘3C NMR (50 MHz, CDCI3): ö 172.5,64.2, 60.5, 43.2, 22.6, 14.1. Analysis: C6H,203 requires C, 54.53; H, 9.15; found C, 54.56; H, 9.35%. |
| ~ 95 % ee |
With baker's yeast In water; glycerol at 20℃; for 72h; Microbiological reaction; enantioselective reaction; |
|
| 94 % ee |
With hydrogen; acetic acid In tetrahydrofuran at 100℃; for 20h; Autoclave; enantioselective reaction; |
General procedure: Nickel powders (5 μm) purchased from Aldrich were directly subjected to chiral modification without any pretreatment, such as hydrogen activation. The chiral modification was performed under the conditions optimized previously for this type of catalyst.26 Thus, the non-activated nickel powders (0.5 g) were immersed in an aqueous solution (50 cm3) of (R,R)-tartaric acid (0.5g) and NaBr (2.0 g) at 100 °C, the pH of which was pre-adjusted to 3.2 with an aqueous 1M NaOH solution. NaBr was added to the modification solution to block the non-enantiodifferentiating sites of tartaric acid/Ni catalyst, thus preventing the generation of racemic products.39 After immersion for 1 h, the modification solution was removed by decantation and the catalyst was successively washed once with deionized water (10 cm3), twice with methanol (25 cm3), and twice with tetrahydrofuran (THF) (10 cm3). The modified catalyst was added to a mixture of alkyl acetoacetate (43 mmol for methyl ester and 21.5 mmol for other esters), acetic acid (0.1g), and THF (10 cm3) placed in an autoclave equipped with a magnetically coupled mechanical stirrer. The hydrogenation was run for 20h at 100 or 110 °C and at a hydrogen pressure of 9MPa. The hydrogenation product, a mixture of alkyl (R)- and (S)-3-hydroxybutyrates, was isolated from the reaction mixture by distillation. The conversion was determined by gas-liquid chromatography (GLC) on a GL Science model GC-4000 equipped with a CP Chirasil DEX-CB capillary column (0.25 mm × 25 m) at 90 °C, while the enantioselectivity was determined by chiral GLC after acetylation of the reaction product using acetyl chloride and pyridine. A portion of the acetylated sample was subjected to the chiral GLC analysis on a CP Chirasil DEX-CB column (0.25 mm × 25 m) operated at 90 °C. The ee value was calculated from the peak integration of the corresponding enantiomer peaks. The reproducibility of the ee value was found to be within ±2%. |
| 93 % ee |
With dichloro(benzene)ruthenium(II) dimer; hydrogen In methanol at 52℃; for 24h; enantioselective reaction; |
|
|
With hydrogenchloride; [RuCl2-((R)-binap)]*NEt3; hydrogen In methanol; water at 50℃; for 16h; Inert atmosphere; |
9 (R)-Ethyl(-)-3-hydroxybutyrate, (43)
Ethyl acetoacetate (7.5 g) and dry methanol (25 mL) were mixed and deoxygenated with flowing nitrogen for five minutes. The catalyst [(R)-Ru(BINAP)Cl2]2NEt3 (0.1 mol %) was added along with 2N HCl (0.1 mol %). The mixture was transferred to a standard Parr reactor apparatus and flushed by evacuating and refilling with hydrogen several times. The apparatus was heated at 50° C. with stirring under 100 psi of hydrogen for 16 h. After completion of reaction (monitored by TLC) the reaction was cooled and concentrated under reduced pressure. The residue was subjected to column chromatographic purification with petroleum ether/ethyl acetate (9:1 v/v) to get pure (R)-alcohol 43 as a colorless liquid. [α]D25 -46.0 (c 1.0, CHCl3); lit. [α]D25 -46.0 (c 1.0, CHCl3); 98% ee (Mosher ester); IR (CHCl3, cm-1) 3441.7, 2978.6, 2935.7, 1734.0, 1636.1, 1458.1; 1H NMR (200 MHz, CDCl3): δ 4.12-4.22 (m, 3H), 3.20 (d, J=3.8 Hz, 1H), 2.42-2.45 (m, 2H), 1.21-1.31 (m, 6H); 13C NMR (50 MHz, CDCl3): δ 172.5, 64.2, 60.5, 43.2, 22.6, 14.1. Analysis: C6H12O3 requires C, 54.53; H, 9.15. Found C, 54.56; H, 9.35%. |
| > 99 % ee |
With glucose dehydrogenase; alpha-D-glucopyranose; BgADH1 enzyme; nicotinamide adenine dinucleotide phosphate In water at 30℃; Enzymatic reaction; enantioselective reaction; |
|
| > 99 % ee |
With aldo-keto reductase CaAKR; NADH In aq. phosphate buffer at 30℃; for 10h; Enzymatic reaction; enantioselective reaction; |
2.8 Substrate specificity
General procedure: The bioreduction was performed in 1.5 mL Eppendorf tubes containing 200 mmol/L potassium phosphate buffer (pH 7.0), 1 mmol/L of each substrate, 0.5 mmol/L NADH, and 1 mg/mL purified CaAKR in a total volume of 1.0 mL, shaking for 10 h at 30 °C. The reaction mixture was extracted twice with an equivalent volume of 300 μL ethyl acetate. The extracts were combined, dried with anhydrous sodium sulfate. The concentrations for each product were determined by GC or HPLC analysis. |
| 94 % ee |
With hydrogen; sodium bromide In tetrahydrofuran; methanol at 99.84℃; for 20h; Autoclave; enantioselective reaction; |
|
| 99.9 % ee |
With recombinant alcohol dehydrogenase from Stenotrophomonas maltophilia SmADH2; isopropyl alcohol; NADH In aq. phosphate buffer at 30℃; Green chemistry; Enzymatic reaction; stereoselective reaction; |
|
| 95.1 % ee |
With dichloro(benzene)ruthenium(II) dimer; hydrogen In methanol at 50℃; for 20h; Inert atmosphere; Autoclave; enantioselective reaction; |
|
| 99.6 % ee |
With D-Glucose; cobalt(II); BaSDR1 reductase variant Q139G; NADH In aq. phosphate buffer at 35℃; Enzymatic reaction; enantioselective reaction; |
|
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