1,3,2-Benzodioxaborole

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1,2-Bis(4-(2-propyl)phenyl)acetylene (11.40 g, 43 mmol) was dissolved in 50 mL THF, catecholborane (1 M, 50 mL) in THF was added, and the mixture was heated at reflux for 30 hours. The mixture was cooled, then 4,6-diamino-5-iodo-pyrimidine, 30 mL saturated aqueous sodium bicarbonate, 20 mL 3N aqueous sodium hydroxide, and 1.00 g (0.87 mmol) tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated to reflux for 18 hours, cooled, diluted with water, then extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and the solvent evaporated. The residue was chromatographed on silica gel with 2.5% to 5% (19:1 ethanol:ammonium hydroxide) in ethyl acetate to give the desired product (4.53 g, 28% yield). the mixture was heated at reflux for 30 hours The mixture was cooled The mixture was heated to reflux for 18 hours cooled extracted with ethyl acetate dried with magnesium sulfate the solvent evaporated The residue was chromatographed on silica gel with 2.5% to 5% (19:1 ethanol:ammonium hydroxide) in ethyl acetate

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (5.60 g, 17.29 mmol) and (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 9 mL, 9.00 mmol) cooled to −78° C. was added catecholborane (5.6 mL, 54.0 mmol) dropwise. After 20 min, the reaction temperature was allowed to warm to −15° C. and stirred overnight. The reaction was quenched at 0° C. by careful addition of water and diluted with ether. The resulting suspension was filtered through Celite and washed with ether. The filtrate was washed successively with 1 M aq NaOH (3×50 mL), 1 M aq HCl (3×50 mL), satd aq NaHCO3 and brine, and dried over Na2SO4. The solution was filtered, the filtrate was evaporated under vacuum, and the residue was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (2.44 g) and (R)-tert-butyl 3-((S)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.21 g). MS: 348 (M+Na)+. The reaction was quenched at 0° C. by careful addition of water diluted with ether The resulting suspension was filtered through Celite washed with ether The filtrate was washed successively with 1 M aq NaOH (3×50 mL), 1 M aq HCl (3×50 mL) dried over Na2SO4 The solution was filtered the filtrate was evaporated under vacuum the residue was purified by preparative HPLC

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (5.60 g, 17.29 mmol) and (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 9 mL, 9.00 mmol) cooled to −78° C. was added catecholborane (5.6 mL, 54.0 mmol) dropwise. After 20 min, the reaction temperature was allowed to warm to −15° C. and stirred overnight. The reaction was quenched at 0° C. by careful addition of water and diluted with ether. The resulting suspension was filtered through Celite and washed with ether. The filtrate was washed successively with 1 M aq NaOH (3×50 mL), 1 M aq HCl (3×50 mL), satd aq NaHCO3 and brine, and dried over Na2SO4. The solution was filtered, the filtrate was evaporated under vacuum, and the residue was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (2.44 g) and (R)-tert-butyl 3-((S)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.21 g). MS: 348 (M+Na)+. The reaction was quenched at 0° C. by careful addition of water diluted with ether The resulting suspension was filtered through Celite washed with ether The filtrate was washed successively with 1 M aq NaOH (3×50 mL), 1 M aq HCl (3×50 mL) dried over Na2SO4 The solution was filtered the filtrate was evaporated under vacuum the residue was purified by preparative HPLC

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g, 35.64 mmol) in anhydrous toluene (120 mL) was cooled to −78° C. and (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107 mmol, 3 equiv) was added slowly. The reaction mixture was then transferred into the freezer (−14° C.) and left overnight. LC-MS (16 min) showed a 9:1 ratio of the R to the S isomer. The mixture was cooled to 0° C. and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), and brine (100 mL), and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystallized from an ether/hexanes mixture to afford (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) as a white solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min) tR=1.70 min; LC-MS (3 min) tR=10.62 min, m/z 314 (M+Na). 1H NMR (CDCl3) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s, free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H). was then transferred into the freezer (−14° C.) left overnight LC-MS (16 min) to quench the reaction washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), and brine (100 mL) dried over Na2SO4 After concentration the crude product was purified by flash chromatography on a 120-g silica gel column eluted with a 4-35% EtOAc in hexanes gradient The purified product was recrystallized from an ether/hexanes mixture

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (10.3 g, 35.64 mmol) in anhydrous toluene (120 mL) was cooled to −78° C. and (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 17.8 mL, 17.8 mmol, 0.5 equiv) was added slowly. After 5 min, catecholborane (11.4 mL, 107 mmol, 3 equiv) was added slowly. The reaction mixture was then transferred into the freezer (−14° C.) and left overnight. LC-MS (16 min) showed a 9:1 ratio of the R to the S isomer. The mixture was cooled to 0° C. and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), and brine (100 mL), and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel column eluted with a 4-35% EtOAc in hexanes gradient. The purified product was recrystallized from an ether/hexanes mixture to afford (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)piperidine-1-carboxylate (4.45 g, 43%) as a white solid with the ratio of R/S isomers 23.5:1. LC-MS (3 min) tR=1.70 min; LC-MS (3 min) tR=10.62 min, m/z 314 (M+Na). 1H NMR (CDCl3) δ 7.28 (m, 5H), 4.46 (d, 1H), 3.87 (d, 1H), 3.89-3.51 (br s, free exchange 1H), 3.00 (m, 2H), 2.68 (t, 1H), 2.52 (t, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (m, 1H), 1.42-1.20 (m, 10H). was then transferred into the freezer (−14° C.) left overnight LC-MS (16 min) to quench the reaction washed with 5% aq NaOH (2×150 mL), water (150 mL), 5% aq HCl (100 mL), and brine (100 mL) dried over Na2SO4 After concentration the crude product was purified by flash chromatography on a 120-g silica gel column eluted with a 4-35% EtOAc in hexanes gradient The purified product was recrystallized from an ether/hexanes mixture

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5-phenylpent-1-yne (0.38 ml, 2.58 mmol) was added catecholborane (500 mg, 1.72 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. After the reaction solution was cooled down to room temperature, toluene (5.0 ml), 4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one (500 mg, 1.72 mmol) obtained in Example 1 (f), bis(triphenylphosphine)palladium chloride (119 mg, 0.17 mmol), and sodium ethoxide (0.83 ml, 20% ethanol solution) were added thereto at room temperature. The reaction mixture was stirred for 2 hours at 60° C., cooled down to room temperature, and then 1N sodium hydroxide was added thereto. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (378 mg, 68% yield). After the reaction solution was cooled down to room temperature at room temperature The reaction mixture was stirred for 2 hours at 60° C. cooled down to room temperature The resulting mixture was extracted with ethyl acetate the organic layer was washed with water After the ethyl acetate layer was dried over anhydrous sodium sulfate the solvent was evaporated in vacuo The residue was purified by preparative thin-layer chromatography (elution solvent; hexane:ethyl acetate=1:1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5-phenylpent-1-yne (0.38 ml, 2.58 mmol) was added catecholborane (500 mg, 1.72 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. After the reaction solution was cooled down to room temperature, toluene (5.0 ml), 4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one (500 mg, 1.72 mmol) obtained in Example 1 (f), bis(triphenylphosphine)palladium chloride (119 mg, 0.17 mmol), and sodium ethoxide (0.83 ml, 20% ethanol solution) were added thereto at room temperature. The reaction mixture was stirred for 2 hours at 60° C., cooled down to room temperature, and then 1N sodium hydroxide was added thereto. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (378 mg, 68% yield). After the reaction solution was cooled down to room temperature at room temperature The reaction mixture was stirred for 2 hours at 60° C. cooled down to room temperature The resulting mixture was extracted with ethyl acetate the organic layer was washed with water After the ethyl acetate layer was dried over anhydrous sodium sulfate the solvent was evaporated in vacuo The residue was purified by preparative thin-layer chromatography (elution solvent; hexane:ethyl acetate=1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of catecholborane (107 mg) in toluene (1 mL) was added (S)-2-methyl-CBS-oxaborolidine (1M in toluene, 0.89 mL) under N2 at −78° C. and the mixture was stirred at the temperature for 1 h. Isopropyl 7-{(4R)-4-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-en-1-yl]-2-oxo-1,3-oxazinan-3-yl}heptanoate (200 mg) in toluene (2 mL) was added via a cannula slowly and the mixture was stirred for an additional hour and quenched with 1N HCl. The mixture was allowed to warm to room temperature and extracted with DCM (2×). The organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (80-100% ethyl acetate/hexanes) to give the title compound. MS (+ESI): m/z 454 (M+1)+. the mixture was stirred for an additional hour quenched with 1N HCl extracted with DCM (2×) The organic layers were dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue purified by column chromatography (80-100% ethyl acetate/hexanes)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5.55 g (24.7 mmol) of the ketone from Step A dissolved in 100 mL of toluene was added 3.7 mL (3.7 mmol, 1M in toluene) of (R)-2-methyl-CBS-oxazaborolidine catalyst and the resultant mixture was stirred at ambient temperature for 15 min. The mixture was cooled to −78° C. and 4.0 mL (37.1 mmol) of catecholborane in 30 mL of toluene was added dropwise over 30 min. After the addition, the slurry was stirred at −78° C. for 60 min while slowly turning homogeneous. The solution was then stirred at −78° C. an additional 4 h (reaction time varies from 4-24 h) until TLC revealed complete disappearance of starting material. Next, the reaction mixture was diluted with 100 mL of water and the resultant mixture was extracted with three 100-mL portions of diethyl ether. The organic phases were then combined and washed with two 100-mL portions of 1 N NaOH aqueous solution, two 100 mL portions of 5% hydrochloric acid solution, 100-mL portions of saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude waxy solid. The crude material was then purified by flash chromatography on a Biotage® system (silica gel, 0 to 20% ethyl acetate/hexanes gradient) to give the alcohol as a colorless crystalline solid. This compound was recrystallized in hexanes to yield the alcohol as colorless crystals (96% ee by Mosher ester analysis). LC/MS 209.0 (M-H2O+3), 211.0 (M-H2O+3). After the addition The solution was then stirred at −78° C. an additional 4 h (reaction time varies from 4-24 h) until TLC the resultant mixture was extracted with three 100-mL portions of diethyl ether washed with two 100-mL portions of 1 N NaOH aqueous solution, two 100 mL portions of 5% hydrochloric acid solution, 100-mL portions of saturated aqueous brine dried over magnesium sulfate filtered evaporated in vacuo to yield the crude waxy solid The crude material was then purified by flash chromatography on a Biotage® system (silica gel, 0 to 20% ethyl acetate/hexanes gradient)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 5.55 g (24.7 mmol) of the ketone from Step A dissolved in 100 mL of toluene was added 3.7 mL (3.7 mmol, 1M in toluene) of (R)-2-methyl-CBS-oxazaborolidine catalyst and the resultant mixture was stirred at ambient temperature for 15 min. The mixture was cooled to −78° C. and 4.0 mL (37.1 mmol) of catecholborane in 30 mL of toluene was added dropwise over 30 min. After the addition, the slurry was stirred at −78° C. for 60 min while slowly turning homogeneous. The solution was then stirred at −78° C. an additional 4 h (reaction time varies from 4-24 h) until TLC revealed complete disappearance of starting material. Next, the reaction mixture was diluted with 100 mL of water and the resultant mixture was extracted with three 100-mL portions of diethyl ether. The organic phases were then combined and washed with two 100-mL portions of 1 N NaOH aqueous solution, two 100 mL portions of 5% hydrochloric acid solution, 100-mL portions of saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude waxy solid. The crude material was then purified by flash chromatography on a Biotage® system (silica gel, 0 to 20% ethyl acetate/hexanes gradient) to give the alcohol as a colorless crystalline solid. This compound was recrystallized in hexanes to yield the alcohol as colorless crystals (96% ee by Mosher ester analysis). LC/MS 209.0 (M-H2O+3), 211.0 (M-H2O+3). After the addition The solution was then stirred at −78° C. an additional 4 h (reaction time varies from 4-24 h) until TLC the resultant mixture was extracted with three 100-mL portions of diethyl ether washed with two 100-mL portions of 1 N NaOH aqueous solution, two 100 mL portions of 5% hydrochloric acid solution, 100-mL portions of saturated aqueous brine dried over magnesium sulfate filtered evaporated in vacuo to yield the crude waxy solid The crude material was then purified by flash chromatography on a Biotage® system (silica gel, 0 to 20% ethyl acetate/hexanes gradient)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl 2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (16.3 g, 40 mmol) in toluene (250 mL) cooled to an internal temperature of −40° C. was treated with (R)-(+)-2-methyl-CBS-oxazaborolidine (5.6 g, 20.1 mmol). Freshly distilled catecholborane (4.7 mL, 44.2 mmol) was diluted with toluene (20 mL) and the solution added dropwise to the reaction over 30 minutes to produce a clear yellow solution. After an additional 15 minutes, saturated Na2CO3 (300 mL) was added and the reaction allowed to warm to room temperature over 2.5 hours. The aqueous layer is extracted with EtOAc and the combined organics are washed with saturated Na2CO3 (3×300 mL), saturated NH4Cl (300 mL) and brine. Following drying over anhydrous MgSO4 and concentration in vacuo, the residue was purified using Isco silica gel column chromatography (10-75% EtOAc/hex) to produce (S)-ethyl 2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate that was determined to be 66% enantiomeric excess by HPLC analysis on a Chiralpak AS-H column with a 80:20 heptane/EtOH isocratic method. LCMS-ESI+ (m/z): [M+Na]+ calcd for C17H17F3O6SNa: 429.3. found: 429.3. the solution added dropwise to the reaction over 30 minutes to produce a clear yellow solution The aqueous layer is extracted with EtOAc the combined organics are washed with saturated Na2CO3 (3×300 mL), saturated NH4Cl (300 mL) and brine Following drying over anhydrous MgSO4 and concentration in vacuo the residue was purified

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.31 g, 3.3 mmol) was dissolved in toluene (20 mL) and cooled to −40° C. After stirring for 20 minutes, (R)-(+)-2-Methyl-CBS-oxazaborolidine (219 mg, 7.5 mmol) and catecholborane (750 μL, 7.04 mmol) were added and the mixture stirred at −40° C. After 2 hrs at −40° C. the reaction was quenched by the addition of 15% Na2CO3 (12 mL) and the mixture was allowed to warm to room temperature. The mixture was washed with 15% Na2CO3 (8×12 mL) and saturated NH4Cl (24 mL), organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Chromatography using silica gel using EtOAc in hexanes produced the desired (S)-ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDCl3): δ 8.08-8.06 (m, 1H); 7.81-7.79 (m, 1H); 7.69 (s, 1H); 7.60-7.57 (m, 2H); 5.81-5.80 (m, 1H); 4.35-4.19 (m, 2H); 3.42 (d, J=2.4 Hz, 1H); 2.50 (s, 3H); 1.21 (t, J=7.0 Hz, 3H). the mixture stirred at −40° C After 2 hrs at −40° C. the reaction was quenched by the addition of 15% Na2CO3 (12 mL) to warm to room temperature The mixture was washed with 15% Na2CO3 (8×12 mL) and saturated NH4Cl (24 mL), organic layer was dried with sodium sulfate filtered concentrated in vacuo