* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Journal of Organic Chemistry, 2001, vol. 66, # 19, p. 6495 - 6497
2
[ 936-59-4 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
With dimethylsulfide borane complex; C23H22BNO3 In tetrahydrofuran at 20℃; for 2 h;
Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH3-DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF was added dropwise to the reaction mixture. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropanol (yield: 75percent, 73percent ee) was obtained in the same manner as in Example 1.1.
77 % ee
With hydrogen In methanol at 60℃; for 24 h;
6.127 mg (8.0 μmol) of Cp*Ir(OTf)[(S,S)-MsDPEN] and 1.249 g (8.0 mmol) of β-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60° C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 77percent ee was produced in 12percent yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
80 % ee
With dimethylsulfide borane complex; (1R,2S,3R,5R)-2-(1',3',2'-dioxaborolan-2'-yloxy)apopinan-3-amine In tetrahydrofuran at 20℃; for 1 h;
General procedure: To a solution of 1 (0.005–0.01 mmol, 0.5–1 mol percent) in dry THF(3 mL) at room temperature, a solution of BH3SMe2 (10 M,100 lL, 1 mmol) in THF (2 mL) was added dropwise at a rate of3.2 mL per hour using a syringe pump. At the same time a solutionof ketone (1 mmol) in THF (2 mL) was also added to the reactionflask at a rate of 3 mL per hour. After the addition of both reagents,the reaction mixture was stirred for 20 min, quenched by the additionof MeOH (1 mL) at room temperature, and stirred for 30 min. Subsequently, the solvents were evaporated under vacuum and theproduct was isolated by column chromatography using hexane/EtOAc (4:1) as the eluent.
66 % ee
at 20℃; for 20 h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91percent isolated yield). The ee was measured by chiral GLC.
Reference:
[1] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0143; 0154; 0155
[2] Tetrahedron Letters, 2005, vol. 46, # 3, p. 495 - 498
[3] Tetrahedron Letters, 1993, vol. 34, # 26, p. 4145 - 4148
[4] Journal of the Chemical Society, Chemical Communications, 1986, # 13, p. 1018 - 1019
[5] Tetrahedron, 2002, vol. 58, # 6, p. 1069 - 1074
[6] Tetrahedron Asymmetry, 2001, vol. 12, # 16, p. 2323 - 2329
[7] Organic Letters, 2006, vol. 8, # 14, p. 2969 - 2972
[8] Tetrahedron Letters, 2007, vol. 48, # 33, p. 5799 - 5802
[9] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 8; 14
[10] Organic Letters, 2009, vol. 11, # 2, p. 305 - 308
[11] Organic Process Research and Development, 2012, vol. 16, # 4, p. 710 - 713
[12] Green Chemistry, 2014, vol. 16, # 5, p. 2680 - 2688
[13] Catalysis Letters, 2014, vol. 144, # 7, p. 1289 - 1295
[14] Chemistry - A European Journal, 2014, vol. 20, # 38, p. 12190 - 12200
[15] Tetrahedron Asymmetry, 2015, vol. 26, # 24, p. 1453 - 1458
[16] Organic and Biomolecular Chemistry, 2016, vol. 14, # 18, p. 4304 - 4311
[17] Journal of Molecular Catalysis A: Chemical, 2016, vol. 421, p. 138 - 145
[18] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 426 - 431
3
[ 108-22-5 ]
[ 18776-12-0 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
88 % ee
With Burkholderia species lipoprotein lipase; C51H77NO17; dextrin In toluene at 25℃; for 6 h; Enzymatic reaction
General procedure: In a typical procedure, isopropenyl acetate (1.5 equiv.) was added to a 4 mL-vial containing BSLPL-1c-D (3 mg), substrate (0.3 mmol), and anhydrous toluene (0.5 M). The resulting solution was then shaken at 25 °C until the reaction reached 46–50percent conversion. After being diluted with methylene chloride, the reaction mixture was filtered through a celite pad, concentrated, and then analyzed by HPLC to determine the enantiomeric excesses of remaining substrate and acetylated product. The enantioselectivity (E) was then calculated using the equation: E = ln[1−c(1+eep)]/ln[1−c(1−eep)] where c = ees/(ees+eep). The kinetic resolution of 4a: (S)-4a (82percent ee) and (R)-5a (97percent ee); 46percent conversion; E = >100. The kinetic resolution of 4b: (S)-4b (>99percent ee) and (R)-5b (97percent ee); 50percent conversion; E=>100.
Reference:
[1] Journal of Organic Chemistry, 2004, vol. 69, # 6, p. 1972 - 1977
[2] Journal of Molecular Catalysis B: Enzymatic, 2016, vol. 134, p. 148 - 153
4
[ 936-59-4 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
60.526 % ee
at 28℃; for 48 h; Microbiological reaction; Enzymatic reaction
General procedure: Fresh plates of each yeast strain were streaked from the frozen stock in PDA. A single colony was used to inoculate 100mL of YM Broth. The culture was incubated at 28°C and 150rpm for 48h and the cells were collected by centrifugation at 4000rpm and 4°C for 15min. The pellet was washed three times with 50mL physiological serum. Afterward, 2g of yeast cells (wet weight) were suspended in 20mL of 10percent dextrose solution and 30mg of the appropriate substrate were added. The culture was incubated at 28°C and 150rpm in an orbital shaker ZHICHENG ZHWY-211B for 48h.
23 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 6 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
Reference:
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 102, p. 94 - 98
[2] Tetrahedron Asymmetry, 2014, vol. 25, # 18-19, p. 1264 - 1269
5
[ 936-59-4 ]
[ 1565-74-8 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
21 %Chromat.
With yeast culture of Aphanocladium album KCh 417 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces cerevisiae KCh 464 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces pastorianus KCh 906 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Candida parapsilosis KCh 909 In acetone at 25℃; for 72 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
57 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Saccharomyces brasiliensis KCh 905 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 11, p. 1767 - 1769
14
[ 936-59-4 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With borane-THF; (S)-diphenylprolinol In tetrahydrofuran; toluene at 20℃; for 1.5 h;
Step 1: a flask was charged with (S)-(−)-α,α-diphenylprolinol (0.30 g, 1.19 mmol) and anhydrous toluene (7 ml). The mixture was placed under nitrogen by evacuation and filling three times. The borane tetrahydrofuran complex solution [BH3•THF; 1M solution in THF, stabilized with 5mM NaBH4] (0.35 ml, 3.56 mmol) was added in a dropwise fashion at 30°C and the clear solution was stirred for 30min. Step 2: to this stirred solution, 3-chloro-1-phenylpropan-1-one 12 (1 g, 5.93 mmol) in anhydrous toluene (1 ml) was added. The reaction mixture was then stirred at room temperature for 15min followed by the addition of BH3·THF (6 ml, 61.44 mmol) over a period of 3 min. After stirring for additional 9 0min, the reaction flask was cooled in ice bath and quenched successively with MeOH (10 ml), isopropanole (10 ml), and HCl (3 ml), and was passed through a pad of Celite. The filtrate was concentrated to dryness and crystallized from hexane. The title compound was obtained as white fluffy solid (4.91g). Yield: 97percent; m.p. 57–59°C; [α]D25=+ 25.7° (c 1, CHCl3); 1H NMR (400MHz, CDCl3): δ 2.07–2.16 (m, 2H), 2.20–2.32 (m, 1H), 3.51–3.62 (m, 1H), 3.71–3.80 (m, 1H), 4.91–4.98 (m, 1H), 7.37–7.43 (m, 5H), 13C NMR (400MHz, CDCl3): δ 41.45, 41.73, 71.34, 125.80, 127.94, 128.69, 143.71; MS (EI+) m/z: 170 [M+], 172 [M+2] showing relative intensity ratio∼3:1.
95%
With 2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2 h;
Preparative Example 2.2. Dissolving the 2-cat (1.78 mmol, 575 mg) prepared inaccordance with the 25 of THF and, after the addition of BH3 DMS (12.5 mmol,1.18 ), which was stirred for 7 minutes. Over a solution of 3-chloro-propiophenone(17.8 mmol, 3.0 g) was dissolved in THF 6 to the reaction mixture was addeddropwise a 10 minute dropwise. After reacting at room temperature for an 2 hour, thereaction was terminated by adding methanol. Example 1.1. And purified in the samemanner as (R) -3- chloro-1-phenyl-propanol to give the (yield: 95percent, 93percent ee).The compound was recrystallized from a nucleic acid of 99percent ee (R) -3- chloro-1-phenyl-propanol to give the (86percent recovery).
95%
With 2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2.16667 h;
Cat-2 (1.78 mmol, 575 mg) prepared in Preparation Example 1.2 was dissolved in 25 mL of THF, BH3-DMS (12.5 mmol, 1.18 mL) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropan-1-ol (yield 95percent, 93percent ee) was obtained in the same manner as in Preparation Example 2.2. The above compound was recrystallized from a nucleic acid to obtain (R) -3-chloro-1-phenylpropan-1-ol (86percent recovery) with 99percent ee.
91%
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C55H92N6O4S(2+)*2I(1-); sodium formate In water
A solution of 1.3 mg (0.002 mmol) metal [RhCl2Cp*]2 and 5.2 mg (0.004 mmol) ligand XIV is in the thick wall of the test tube, add 5 ml water placed in the 40 °C activation stirring 2 hours. 0.4 mmol 3-chlorophenylacetone and 2 mmol sodium formate, stirring the reaction. The solution was extracted with ethyl acetate 5 ml × 3 extraction, combined the organic phase, dried with anhydrous sodium sulfate, the solvent was evaporated. Column chromatography purification (petroleum ether / ethyl acetate = 20/1). HPLC detection ee value. For the product passes through the derivatization ee value detected: the obtained product is dissolved in 5 ml dichloromethane in, adding 49 mg 4-dimethylaminopyridine (0.4 mmol) and 82 mg of acetic anhydride (0.8 mmol), stir at room temperature 3h. Processing, dichloromethane is used for solution 5 ml × 3 extraction, the combined organic phase, dried with anhydrous sodium sulfate, the solvent, then the GC detection ee value. Isolation yield 91percent, 95percent ee
86%
With dimethylsulfide borane complex In tetrahydrofuran for 2 h;
EXAMPLE 8R-(+)-3-chloro-1-phenylpropan-1-olFollowing similar procedure as before, BH3.SMe2 (10 M, 0.7 mL, 7 mmol) was added to a solution of complex derived from ethylene glycol and diphenyl prolinol (EG-DDP), catalyst 10, (323 mg, 0.1 mmol) in dry THF (35 mL) at room temperature. The reaction mixture was stirred for approximately one hour. A solution of dry 3-chloropropiophenone (1.69 g, 10 mmol) in dry THF (5 mL) was added by a syringe using infusion pump for 1 hour. (Rate: 6 mL/h). The 3-chloropropiophenone solution was light yellow but after adding to the complex, the total solution was clear. Following similar procedure as above for the work-up, the crude product was obtained: 1.66 g (97percent yield). The product was analyzed by 31P-NMR: 145.0 ppm (5.7percent), 134.5 ppm (94.3percent)-->88.6percent ee. The product was purified by column chromatography with 30 g of silica and a mobile phase of hexane/ethyl acetate (2:1).(Yield: 1.47 g, 86percent). The product was analyzed by 1H, 13C, and 31P-NMR (derivative with a phosphonate (CDA). 31P-NMR: 145.1 ppm (3percent), 134.6 ppm (97percent): 94percent ee; [α]20=+21.0 c=0.030 (CHCl3).
86.7%
With (+)-diiso-2-ethylapophosphate pinacylboraneheptane In tetrahydrofuran at -20℃; for 6 h;
3-Chlorophenylacetone (40 g) was dissolved in tetrahydrofuran (160 ml)(152 ml) of 65percent (+) diiso-2-ethylapopamate-pinacylborane n-heptane was added at -10 ° C,The reaction was carried out for 8 hours and concentrated under reduced pressure. The residue was added with diethyl ether (400 ml), followed by addition of diethanolamine (37.4 g), stirred for 2 h and filtered. (R) - (+) - 3-chlorophenyl propanol 7.4g, the yield was 86.7percent, mp56 ~ 57 (m), and the mixture was stirred at room temperature for 4 hours. ° C; [a] 23d = + 25.1, c = 1, CHC13; 99percent ee.
9%
With hydrogen In methanol at 60℃; for 24 h;
5.010 mg (8.0 μmol) of RuCl[(R,R)-TsDPEN](p-cymene) and 1.249 g (8.0 mmol) of β-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60° C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 90percent ee was produced in 9percent yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
Reference:
[1] Tetrahedron Letters, 1989, vol. 30, # 39, p. 5207 - 5210
[2] Synthetic Communications, 2009, vol. 39, # 15, p. 2737 - 2746
[3] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 3, p. 431 - 435
[4] Chemical Communications, 2015, vol. 51, # 26, p. 5725 - 5727
[5] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 157 - 172
[6] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0143; 0156-0158
[7] Patent: KR2016/44117, 2016, A, . Location in patent: Paragraph 0069-0072
[8] Organic and Biomolecular Chemistry, 2014, vol. 12, # 6, p. 1009 - 1017
[9] Patent: CN105061126, 2017, B, . Location in patent: Paragraph 0095; 0096; 0097; 0098; 0099
[10] Patent: US2008/200672, 2008, A1, . Location in patent: Page/Page column 7
[11] Patent: CN105732309, 2016, A, . Location in patent: Paragraph 0037; 0049; 0050
[12] Chinese Journal of Chemistry, 2013, vol. 31, # 3, p. 349 - 354
[13] Organic Letters, 2016, vol. 18, # 18, p. 4658 - 4661
[14] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 8; 14
[15] Journal of Organic Chemistry, 2001, vol. 66, # 19, p. 6495 - 6497
[16] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 11, p. 1767 - 1769
[17] Tetrahedron Asymmetry, 1992, vol. 3, # 4, p. 525 - 528
[18] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 4929 - 4931
[19] Organic Process Research and Development, 2012, vol. 16, # 4, p. 710 - 713
[20] Advanced Synthesis and Catalysis, 2015, vol. 357, # 8, p. 1697 - 1702
[21] Chemical Communications, 2015, vol. 51, # 86, p. 15728 - 15731
[22] Advanced Synthesis and Catalysis, 2018, vol. 360, # 11, p. 2119 - 2124
[23] Angewandte Chemie - International Edition, 2018, vol. 57, # 32, p. 10231 - 10235[24] Angew. Chem., 2018, vol. 130, p. 10388 - 10392,5
15
[ 936-59-4 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
With dimethylsulfide borane complex; C23H22BNO3 In tetrahydrofuran at 20℃; for 2 h;
Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH3-DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF was added dropwise to the reaction mixture. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropanol (yield: 75percent, 73percent ee) was obtained in the same manner as in Example 1.1.
77 % ee
With hydrogen In methanol at 60℃; for 24 h;
6.127 mg (8.0 μmol) of Cp*Ir(OTf)[(S,S)-MsDPEN] and 1.249 g (8.0 mmol) of β-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60° C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 77percent ee was produced in 12percent yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
80 % ee
With dimethylsulfide borane complex; (1R,2S,3R,5R)-2-(1',3',2'-dioxaborolan-2'-yloxy)apopinan-3-amine In tetrahydrofuran at 20℃; for 1 h;
General procedure: To a solution of 1 (0.005–0.01 mmol, 0.5–1 mol percent) in dry THF(3 mL) at room temperature, a solution of BH3SMe2 (10 M,100 lL, 1 mmol) in THF (2 mL) was added dropwise at a rate of3.2 mL per hour using a syringe pump. At the same time a solutionof ketone (1 mmol) in THF (2 mL) was also added to the reactionflask at a rate of 3 mL per hour. After the addition of both reagents,the reaction mixture was stirred for 20 min, quenched by the additionof MeOH (1 mL) at room temperature, and stirred for 30 min. Subsequently, the solvents were evaporated under vacuum and theproduct was isolated by column chromatography using hexane/EtOAc (4:1) as the eluent.
66 % ee
at 20℃; for 20 h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91percent isolated yield). The ee was measured by chiral GLC.
Reference:
[1] Patent: KR2015/116956, 2015, A, . Location in patent: Paragraph 0143; 0154; 0155
[2] Tetrahedron Letters, 2005, vol. 46, # 3, p. 495 - 498
[3] Tetrahedron Letters, 1993, vol. 34, # 26, p. 4145 - 4148
[4] Journal of the Chemical Society, Chemical Communications, 1986, # 13, p. 1018 - 1019
[5] Tetrahedron, 2002, vol. 58, # 6, p. 1069 - 1074
[6] Tetrahedron Asymmetry, 2001, vol. 12, # 16, p. 2323 - 2329
[7] Organic Letters, 2006, vol. 8, # 14, p. 2969 - 2972
[8] Tetrahedron Letters, 2007, vol. 48, # 33, p. 5799 - 5802
[9] Patent: US2009/62573, 2009, A1, . Location in patent: Page/Page column 8; 14
[10] Organic Letters, 2009, vol. 11, # 2, p. 305 - 308
[11] Organic Process Research and Development, 2012, vol. 16, # 4, p. 710 - 713
[12] Green Chemistry, 2014, vol. 16, # 5, p. 2680 - 2688
[13] Catalysis Letters, 2014, vol. 144, # 7, p. 1289 - 1295
[14] Chemistry - A European Journal, 2014, vol. 20, # 38, p. 12190 - 12200
[15] Tetrahedron Asymmetry, 2015, vol. 26, # 24, p. 1453 - 1458
[16] Organic and Biomolecular Chemistry, 2016, vol. 14, # 18, p. 4304 - 4311
[17] Journal of Molecular Catalysis A: Chemical, 2016, vol. 421, p. 138 - 145
[18] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 426 - 431
16
[ 108-22-5 ]
[ 18776-12-0 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
Yield
Reaction Conditions
Operation in experiment
88 % ee
With Burkholderia species lipoprotein lipase; C51H77NO17; dextrin In toluene at 25℃; for 6 h; Enzymatic reaction
General procedure: In a typical procedure, isopropenyl acetate (1.5 equiv.) was added to a 4 mL-vial containing BSLPL-1c-D (3 mg), substrate (0.3 mmol), and anhydrous toluene (0.5 M). The resulting solution was then shaken at 25 °C until the reaction reached 46–50percent conversion. After being diluted with methylene chloride, the reaction mixture was filtered through a celite pad, concentrated, and then analyzed by HPLC to determine the enantiomeric excesses of remaining substrate and acetylated product. The enantioselectivity (E) was then calculated using the equation: E = ln[1−c(1+eep)]/ln[1−c(1−eep)] where c = ees/(ees+eep). The kinetic resolution of 4a: (S)-4a (82percent ee) and (R)-5a (97percent ee); 46percent conversion; E = >100. The kinetic resolution of 4b: (S)-4b (>99percent ee) and (R)-5b (97percent ee); 50percent conversion; E=>100.
Reference:
[1] Journal of Organic Chemistry, 2004, vol. 69, # 6, p. 1972 - 1977
[2] Journal of Molecular Catalysis B: Enzymatic, 2016, vol. 134, p. 148 - 153
17
[ 936-59-4 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
60.526 % ee
at 28℃; for 48 h; Microbiological reaction; Enzymatic reaction
General procedure: Fresh plates of each yeast strain were streaked from the frozen stock in PDA. A single colony was used to inoculate 100mL of YM Broth. The culture was incubated at 28°C and 150rpm for 48h and the cells were collected by centrifugation at 4000rpm and 4°C for 15min. The pellet was washed three times with 50mL physiological serum. Afterward, 2g of yeast cells (wet weight) were suspended in 20mL of 10percent dextrose solution and 30mg of the appropriate substrate were added. The culture was incubated at 28°C and 150rpm in an orbital shaker ZHICHENG ZHWY-211B for 48h.
23 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 6 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
Reference:
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 102, p. 94 - 98
[2] Tetrahedron Asymmetry, 2014, vol. 25, # 18-19, p. 1264 - 1269
18
[ 936-59-4 ]
[ 1565-74-8 ]
[ 613-87-6 ]
[ 100306-34-1 ]
[ 100306-33-0 ]
[ 93-55-0 ]
Yield
Reaction Conditions
Operation in experiment
21 %Chromat.
With yeast culture of Aphanocladium album KCh 417 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces cerevisiae KCh 464 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33 %Chromat.
With yeast culture of Saccharomyces pastorianus KCh 906 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Candida parapsilosis KCh 909 In acetone at 25℃; for 72 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
57 %Chromat.
With yeast culture of Candida viswanathii KCh 120 In acetone at 25℃; for 144 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Saccharomyces brasiliensis KCh 905 In acetone at 25℃; for 24 h; Microbiological reaction
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3–7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With dimethylsulfide borane complex; C23H22BNO3; In tetrahydrofuran; at 20℃; for 2h;
Cat-5 (0.05 mmol, 20 mg) prepared in Preparation Example 2.5 was dissolved in 1 ml of THF, BH3-DMS (0.42 mmol, 0.04 ml) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (0.6 mmol, 100 mg) in 0.45 ml of THF was added dropwise to the reaction mixture. After reacting at room temperature for 2 hours, the reaction was terminated by the addition of methanol. (R) -3-chloro-1-phenylpropanol (yield: 75%, 73% ee) was obtained in the same manner as in Example 1.1.
With hydrogen;Cp*Ir(OTf)[(S,S)-Msdpen]; In methanol; at 60℃; under 7600.51 Torr; for 24h;Product distribution / selectivity;
6.127 mg (8.0 mumol) of Cp*Ir(OTf)[(S,S)-MsDPEN] and 1.249 g (8.0 mmol) of beta-chloropropiophenone were introduced in an autoclave, and the mixture was subjected to argon substitution. 3.3 mL of methanol was introduced and deaeration was performed, then hydrogen gas was introduced at 10 atm and the resulting mixture was maintained at 60 C. for 24 hr while stirring. The solvent was distilled off under reduced pressure to give a crude product. GC analysis of the reactant confirmed that 3-chloro-1-phenylpropane-1-ol with optical purity of 77% ee was produced in 12% yield. Comparison with Example E-1 demonstrated the superiority of the asymmetric reduction using a potassium formate solution as the hydrogen source.
With dimethylsulfide borane complex; (1R,2S,3R,5R)-2-(1',3',2'-dioxaborolan-2'-yloxy)apopinan-3-amine; In tetrahydrofuran; at 20℃; for 1h;
General procedure: To a solution of 1 (0.005-0.01 mmol, 0.5-1 mol %) in dry THF(3 mL) at room temperature, a solution of BH3SMe2 (10 M,100 lL, 1 mmol) in THF (2 mL) was added dropwise at a rate of3.2 mL per hour using a syringe pump. At the same time a solutionof ketone (1 mmol) in THF (2 mL) was also added to the reactionflask at a rate of 3 mL per hour. After the addition of both reagents,the reaction mixture was stirred for 20 min, quenched by the additionof MeOH (1 mL) at room temperature, and stirred for 30 min. Subsequently, the solvents were evaporated under vacuum and theproduct was isolated by column chromatography using hexane/EtOAc (4:1) as the eluent.
With silver tetrafluoroborate; diethoxymethylane; C26H29N3O2*Cl(1-)*Ir(1+)*C8H12; at 20℃; for 20h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91% isolated yield). The ee was measured by chiral GLC.
With Burkholderia species lipoprotein lipase; C51H77NO17; dextrin; In toluene; at 25℃; for 6h;Enzymatic reaction;
General procedure: In a typical procedure, isopropenyl acetate (1.5 equiv.) was added to a 4 mL-vial containing BSLPL-1c-D (3 mg), substrate (0.3 mmol), and anhydrous toluene (0.5 M). The resulting solution was then shaken at 25 C until the reaction reached 46-50% conversion. After being diluted with methylene chloride, the reaction mixture was filtered through a celite pad, concentrated, and then analyzed by HPLC to determine the enantiomeric excesses of remaining substrate and acetylated product. The enantioselectivity (E) was then calculated using the equation: E = ln[1-c(1+eep)]/ln[1-c(1-eep)] where c = ees/(ees+eep). The kinetic resolution of 4a: (S)-4a (82%ee) and (R)-5a (97% ee); 46% conversion; E = >100. The kinetic resolution of 4b: (S)-4b (>99%ee) and (R)-5b (97% ee); 50% conversion; E=>100.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 24h;
STEP 1: 4-[(1S)-3-CHLORO-1-PHENYLPROPYL]OXY}-(4-PHENOXY)BENZENE: A mixture of 4-phenoxyphenol (1.86 g, 10.0 mmol), (R)-(-)-3-chloro-phenyl-1-propanol (1.70 g, 10.0 mmol), triphenylphosphine (2.62 g, 10.0 mmol), diethyl azodicarboxylate (1.57 ML, 10.0 mmol) in 5.0 ML of THF was stirred at room temperature for 24 h.. The reaction mixture was concentrated in vacuo.. The residue was washed with pentane (*3) and the combined pentane extracts were concentrated and chromatographed (silica with hexanes-EtOAc 97:3 as the eluent) to give the desired product as a thick oil which solidified on standing (2.51 g, 75.7%): 1H NMR (400 MHz, CDCl3) delta 7.4-7.23 (m, 7H), 7.03 (apparent t, 1H, J=7.3 Hz), 6.91 (apparent dm, 2H, J=7.8 Hz), 6.93 (apparent q, 4H, J=7.8 Hz), 5.31 (apparent dd, 1H, J=4.5, 8.6 Hz), 3.82 (m, 1H), 3.62 (apparent quintet, 1H, J=5.6 Hz), 2.47 (m, 1H), 2.20 (m, 1H).
4-Chloro-2-[(1R)-3-(cyclopropylamino)-1-phenylpropyl]oxy}-5-fluorobenzonitrile oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; N-methyl-acetamide; methanol; water; mineral oil;
EXAMPLE 25 4-Chloro-2-[(1R)-3-(cyclopropylamino)-1-phenylpropyl]oxy}-5-fluorobenzonitrile oxalate (R)-alpha-(2-Chloroethyl)benzenemethanol (341 mg, 2 mmol) was dissolved in tetrahydrofuran (10 ml) and treated with sodium hydride as a 60% suspension in mineral oil (480 mg, 3 mmol) followed after 10 minutes by <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (347 mg, 2 mmol). The mixture was stirred at room temperature for 18 h before being treated with methanol (1 ml) and then water (10 ml). The tetrahydrofuran was then removed via heating the vessel to 80 C. and applying a nitrogen stream. Once the tetrahydrofuran was evaporated the residue was extracted into dichloromethane, dried over magnesium sulphate and concentrated in vacuo. The resultant material was re-dissolved into dimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03 mmol), triethylamine (565 mul, 4.06 mmol) and cyclopropylamine (114 mg, 2 mmol) before being heated to 60 C. for 5 days. The mixture was filtered and purified via RPHPLC on the crude reaction material. The purified compound was then treated with 50% saturated oxalic acid in ether to produce 74 mg of a white powder that was collected via filtration. MS APCI+ve m/z 345/347 [(M+H)+]. 1H NMR 400 MHz (d6-DMSO) 7.97-7.87 (m, 1H), 7.53-7.25 (m, 6H), 5.69 (m, 1H), 3.28-3.07 (m, 2H), 2.80-2.68 (m, 1H), 2.45-2.29 (m, 1H), 2.29-2.12 (m, 1H), 0.85-0.74 (m, 4H).
4-Bromo-2-[(1R)-3-(cyclopropylamino)-1-(phenyl)propyl]oxy}-5-fluorobenzonitrile oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.2%
With oxalic acid;
EXAMPLE 28 4-Bromo-2-[(1R)-3-(cyclopropylamino)-1-(phenyl)propyl]oxy}-5-fluorobenzonitrile oxalate Prepared by the method of Example 25 using (R)-alpha-(2-chloroethyl)benzenemethanol and <strong>[133541-45-4]4-bromo-2,5-difluorobenzonitrile</strong> initially before converting into the title compound via in situ conversion to the iodo compound and treatment with cyclopropylamine. The free base was treated with a 50% saturated solution of oxalic acid in ether. The resultant white solid was collected via filtration to yield the title compound (41 mg, 4.2%). MS APCI+ve m/z 390 [(M+H)+]. 1H NMR 400 MHz (d6-DMSO) delta7.96 (d, 1H), 7.49 (d, 1H), 7.45-7.39 (m, 3H), 7.39-7.31 (m, 2H), 5.82-5.74 (m, 1H), 3.16-3.00 (m, 2H), 2.74-2.64 (m, 1H), 2.38-2.25 (m, 1H), 2.24-2.11 (m, 1H), 0.79-0.64 (m, 4H).
(c) 4-Bromo-2-[[(1R)-3-chloro-1-phenylpropyl]oxy]-5-fluorobenzonitrile This was prepared by the method of Example 43(a) using <strong>[133541-45-4]4-bromo-2,5-difluorobenzonitrile</strong> and (R)-alpha-(2-chloroethyl)benzenemethanol. 1H NMR 300 MHz (CDCl3) 8.02 (1H, s), 7.42-7.26 (5H, m), 7.06-7.03 (1H, m), 5.46-5.43 (1H, m), 3.82-3.62 (1H, m), 3.75-3.60 (1H, m), 2.75-2.5 (1H, m), 2.55-2.30 (1H, m).
(R)-(-)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.6%
With sodium hydroxide In N,N-dimethyl acetamide at 60 - 80℃;
4.1 Step 1: Preparation of intermediate 1
168.8g of 1-naphthol (SM2), 800mL of DMA, and NaOH were put into the reaction bottle. After stirring uniformly, the temperature was raised to 60-80 degrees, and then (R) -3-chlorophenylpropanol (SM1) 200g was dissolved in DMA 200mL, and slowly added dropwise. After the dropwise addition, continue the reaction for 10 to 25 hours, and stop the reaction (sampling point [1]). The reaction droplet was dropped into 10L of ice water (control about 1.5 hours after the addition was completed), and a pale pink solid was precipitated (sampling point [2]). Continue to stir for 3h and filter to get wet product. The wet product is beaten with pure water for 1 to 4 hours (sampling point [3]) and filtered; the resulting solid is beaten with n-heptane for 1 to 4 hours (sampling point [4]) and filtered to obtain a light red wet product. The product was dried in vacuum (45 ° C, 10-40 hours) to obtain 1280.2g of intermediate (sampling point [5]). The yield was 85.6% and the purity was 98.2%.
74%
Stage #1: α-naphthol With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice;
Stage #2: (1R)-3-chloro-1-phenylpropanol In N,N-dimethyl-formamide for 1h; Cooling with ice;
7 Preparation of (κ) - (-) - 3-α-naphthyloxy) -propyl alcohol from (R)-(+)-3-chlorophenylpropanol
16.8 g of NaH was added to DMF (160 ml) in a 500 ml three-necked flask under ice-cooling, and a solution of 92 g of a naphthol in DMF (200 ml) was slowly added dropwise,After the reaction for lh, 100 g of (R) - (+) - 3-chlorophenylpropanol in 100 ml of DMF was added,After the reaction was completed, the reaction was slowly poured into 400 ml of ice water and stirred for 1 h. The solid was washed off and the crude product was filtered off and recrystallized from n-hexane at a ratio of n-hexane = 1:118 g of (R) - (-) - 3- (l-naphthyloxy) -1-propanol was obtained in 74% yield, mp 76-78 ° C.
67.2%
With sodium hydroxide In water; N,N-dimethyl-formamide; toluene at 90 - 95℃; for 2h; Large scale reaction;
With potassium hydroxide In acetone at 0℃; Inert atmosphere; Reflux;
1.1 Step 1:
Nitrogen protection, cooling 3 L of acetone to -10-5 ° C, adding 314 g of potassium hydroxide, and stirring. 734 g of 1-naphthol was dissolved in 1.5 L of acetone and dropped into the above reaction solution.The internal temperature t < 0 ° C was maintained during the dropwise addition. Then, 1 kg of 1-phenyl-3-chloropropanol was dissolved in 2 L of acetone, and the mixture was dropped into the above reaction liquid to maintain an internal temperature t < 0 °C. Heat to reflux and react for 20-24 h.TLC detection (EA: PE = 1:5), 1-naphthol reaction was completed, 10% activated carbon was added to reflux for 1 h, filtered, concentrated under reduced pressure, and the residue was stirred with 5 L of water and ethyl acetate (1.5 L) 3) The organic phases were combined and concentrated under reduced pressure.The obtained solid is added to a mixed solvent of 4 volumes of ethyl acetate/n-hexane (1:20), heated to reflux, and then cooled to 0-5 ° C, stirred and crystallized, and filtered to give (R) -3- (1-naphthyloxy)-1-phenyl-1-propanol;
With yeast strain Aureobasidium pullulans CQA; at 28℃; for 48h;Microbiological reaction; Enzymatic reaction;
General procedure: Fresh plates of each yeast strain were streaked from the frozen stock in PDA. A single colony was used to inoculate 100mL of YM Broth. The culture was incubated at 28C and 150rpm for 48h and the cells were collected by centrifugation at 4000rpm and 4C for 15min. The pellet was washed three times with 50mL physiological serum. Afterward, 2g of yeast cells (wet weight) were suspended in 20mL of 10% dextrose solution and 30mg of the appropriate substrate were added. The culture was incubated at 28C and 150rpm in an orbital shaker ZHICHENG ZHWY-211B for 48h.
30%Chromat.; 23%Chromat.
With yeast culture of Candida viswanathii KCh 120; In acetone; at 25℃; for 6h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Aphanocladium album KCh 417; In acetone; at 25℃; for 144h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33%Chromat.
With yeast culture of Saccharomyces cerevisiae KCh 464; In acetone; at 25℃; for 144h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
33%Chromat.
With yeast culture of Saccharomyces pastorianus KCh 906; In acetone; at 25℃; for 24h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Candida parapsilosis KCh 909; In acetone; at 25℃; for 72h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
28%Chromat.; 57%Chromat.
With yeast culture of Candida viswanathii KCh 120; In acetone; at 25℃; for 144h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
With yeast culture of Saccharomyces brasiliensis KCh 905; In acetone; at 25℃; for 24h;Microbiological reaction;
General procedure: Erlenmeyer flasks (300 ml), each containing 100 ml of the mediumconsisting of 3 g glucose and 1 g aminobac dissolved in water,were inoculated with a suspension of microorganisms and then incubated for 3-7 days at 25 C on a rotary shaker (190 rpm). After full growth of the culture 20 mg of a substrate dissolved in 1 ml of acetone was added. After 1, 3, 6, 9, 12 h and 1, 3, 6, 9 days of incubation under the above conditions, portions of 5 ml of the transformation mixture were taken out and extracted with CHCl3(3*10 ml). The extracts were dried over MgSO4, concentrated in vacuo, and analyzed by GC. All the experiments were repeatedthree times.
(R)-2-(3-(3-chloro-1-phenylpropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 72h;
Step 1. (R)-2-(3-(3-Chloro-1 -phenylpropoxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane. (0316) To a solution of (S)-3-chloro-1 -phenylpropan-1 -ol (1 g, 5.86 mmol) in dry THF (10 ml_), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (1 .94 g, 8.79 mmol) and triphenylphosphine (2.31 g, 8.79 mmol) were added. The reaction solution was cooled to 0 C and DIAD (1 .78 g, 8.79 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at r.t. for 3 days. The solvent was removed under reduced pressure and the residue purified by combiflash chromatography (neutral alumina, CH/EtOAc up to 30%) to give the title compound (623 mg, 29% yield).