tert-butyl 2-formylpiperidine-1-carboxylate

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

実験手順: To a stirred solution of 2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.737 g, 3.4 mmol) in dry CH2Cl2 (10 mL) was added 3 Å molecular sieves (1.03 g), N-methylmorpholine N-oxide (0.644 g, 5.5 mmol), and tetrapropylammonium perruthenate (72 mg, 0.21 mmol) and the mixture stirred at room temperature for 3 h. The reaction mixture was purified through a silica gel plug (Hexanes/EtOAc, 70:30 followed by 100:0) to afford the title aldehyde (0.500 g, 70%) as a pale yellow oil. The reaction mixture was purified through a silica gel plug (Hexanes/EtOAc, 70:30 followed by 100:0)

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

実験手順: To a stirred solution of 2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.737 g, 3.4 mmol) in dry CH2Cl2 (10 mL) was added 3 A molecular sieves (1.03 g), N-methylmorpholine N-oxide (0.644 g, 5.5 mmol), and tetrapropylammonium perruthenate (72 mg, 0.21 mmol) and the mixture stirred at room temperature for 3 h. The reaction mixture was purified through a silica gel plug (Hexanes/EtOAc, 70:30 followed by 100:0) to afford the title aldehyde (0.500 g, 70%) as a pale yellow oil. The reaction mixture was purified through a silica gel plug (Hexanes/EtOAc, 70:30 followed by 100:0)

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of ethyltriphenylphosphonium bromide (7.31 g, 19.68 mmol) in 40 mL of THF was cooled to −30° C. and treated with n-BuLi (10.9 mL, 19.68 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of N-Boc-piperidine-2-carboxaldehyde (3.53 g, 17.89 mmol) in 10 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 1.6 g (41%) of the product which was homogenous by TLC analysis. 1H NMR (250 MHz) δ5.73-5.51 (m, 2 H), 5.05-5.01 (m, 1 H), 3.98-3.93 (br d, 1 H), 2.90-2.81 (m, 1 H), 1.7-1.39 (m, 18 H); 13C NMR (62.7 MHz) 154.8 (s), 128.0 (s), 125.8 (s), 79.0 (s), 47.7 (s), 39.6 (s), 30.3 (s), 28.5 (s), 25.6 (s), 19.5 (s), 13.2 (s) ppm. The deep red solution was slowly warmed to 0° C. cooled to −78° C the mixture was slowly warmed to room temperature the organic layer was separated The aqueous layer was extracted with ether the combined extracts were dried over K2CO3 concentrated to give a crude product as an oil

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-Boc-Piperidine (6.0 g, 32.4 mmol) in ether (65 mL) was cooled to −60° C. and treated with TMEDA (4.9 mL, 32.4 mmol) followed by sec-BuLi (54.8 mL, 71.2 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 10 min and then cooled to −78° C. The mixture was treated with a solution of DMF (3.8 mL, 48.6 mmol) in 6 mL of ether via syringe, stirred for 10 min, and then quenched with 60 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted three times with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an orange oil. Purification by column chomatography on silica gel with hexanes:EtOAc (4: 1) afforded 4.2 g (67%) of the product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ9.58 (s, 1 H), 4.69-4.51 (br. m, 1 H), 4.12-3.85 (br. m, 1 H), 2.85 (br. s, 1 H), 2.19-2.13 (d, 1 H), 1.72-1.23 (m, 15 H); 13C NMR (75 MHz) 201.4 (s), 80.4 (s), 43.0 (br. s), 28.3 (s), 24.7 (s), 23.6 (s), 20.9 (s) ppm. cooled to −78° C stirred for 10 min quenched with 60 mL saturated ammonium chloride solution The mixture was warmed to room temperature the organic layer was separated The aqueous layer was extracted three times with ether the combined extracts were dried over K2CO3 The organic layer was concentrated to give a crude product as an orange oil Purification by column chomatography on silica gel with hexanes:EtOAc (4: 1)

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-Boc-Piperidine (6.0 g, 32.4 mmol) in ether (65 mL) was cooled to −60° C. and treated with TMEDA (4.9 mL, 32.4 mmol) followed by sec-BuLi (54.8 mL, 71.2 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 10 min and then cooled to −78° C. The mixture was treated with a solution of DMF (3.8 mL, 48.6 mmol) in 6 mL of ether via syringe, stirred for 10 min, and then quenched with 60 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted three times with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an orange oil. Purification by column chomatography on silica gel with hexanes:EtOAc (4: 1) afforded 4.2 g (67%) of the product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ9.58 (s, 1 H), 4.69-4.51 (br. m, 1 H), 4.12-3.85 (br. m, 1 H), 2.85 (br. s, 1 H), 2.19-2.13 (d, 1 H), 1.72-1.23 (m, 15 H); 13C NMR (75 MHz) 201.4 (s), 80.4 (s), 43.0 (br. s), 28.3 (s), 24.7 (s), 23.6 (s), 20.9 (s) ppm. cooled to −78° C stirred for 10 min quenched with 60 mL saturated ammonium chloride solution The mixture was warmed to room temperature the organic layer was separated The aqueous layer was extracted three times with ether the combined extracts were dried over K2CO3 The organic layer was concentrated to give a crude product as an orange oil Purification by column chomatography on silica gel with hexanes:EtOAc (4: 1)

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

実験手順: A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N—BOC-piperidine-2-carboxaldehyde (0.15 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (144 mg, 70%) as a white foam. NMR (D2O) δ 3.85-4.05 (m, 3 H), 3.60-3.80 (m, 3 H), 3.40 (m, 1 H), 3.30 (m, 2 H), 2.55-2.70 (m, 1 H), 2.20-2.35 (m, 1 H), 1.85-2.10 (m, 2 H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.1; MS (m−H2O+1): 282.1. cooled to room temperature stirred for 18 h the mixture stirred for a few minutes extracted with ethyl acetate (30 mL The combined organic solution was washed with water and brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

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

実験手順: In a manner similar to that described in Preparation CD, 2-formyl-piperidine-1-carboxylic acid tert-butyl ester (360 mg, 1.69 mmol) was treated with 2,6-diaminopyridine (184 mg, 1.69 mmol) and stirred at RT to give a light brown oil. MS m/z: 307.3(M+H). Calc'd. for C16H26N4O2-306.21. to give a light brown oil

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

実験手順: In a manner similar to that described in Preparation CD, 2-formyl-piperidine-1-carboxylic acid tert-butyl ester (360 mg, 1.69 mmol) was treated with 2,6-diaminopyridine (184 mg, 1.69 mmol) and stirred at RT to give a light brown oil. MS m/z: 307.3(M+H). Calc'd. for C16H26N4O2-306.21. to give a light brown oil

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

実験手順: A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-BOC-piperidine-2-carboxaldehyde (0.15 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (144 mg, 70%) as a white foam. NMR (D2O) δ 3.85-4.05 (m, 3 H), 3.60-3.80 (m, 3 H), 3.40 (m, 1 H), 3.30 (m, 2 H), 2.55-2.70 (m, 1 H), 2.20-2.35 (m, 1 H), 1.85-2.10 (m, 2 H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.1; MS (m−H2O+1): 282.1. cooled to room temperature stirred for 18 h the mixture stirred for a few minutes extracted with ethyl acetate (30 mL The combined organic solution was washed with water and brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

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

実験手順: A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-BOC-piperidine-2-carboxaldehyde (0.15 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyrrolidin-2-ylmethyl)pyrrolidine-3-carboxylic acid (144 mg, 70%) as a white foam. NMR (D2O) δ 3.85-4.05 (m, 3 H), 3.60-3.80 (m, 3 H), 3.40 (m, 1 H), 3.30 (m, 2 H), 2.55-2.70 (m, 1 H), 2.20-2.35 (m, 1 H), 1.85-2.10 (m, 2 H), 1.75 (m, 1 H), 1.60 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.1; MS (m−H2O+1): 282.1. cooled to room temperature stirred for 18 h the mixture stirred for a few minutes extracted with ethyl acetate (30 mL The combined organic solution was washed with water and brine (20 mL each) dried (MgSO4) concentrated in vacuo isolated

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of heptyltriphenylphosphonium bromide (13.0 g, 30.41 mmol) in 60 mL of THF was cooled to −30° C. and treated with n-BuLi (12.2 mL, 30.41 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of N-Boc-piperidine-2-carboxaldehyde (4.0 g, 20.27 mmol) in 7 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 5.7 g (70%) of the product that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 5.72-5.49 (pair of m, 2H), 5.02-4.96 (br s, 1H), 3.97-3.89 (br d, 1H), 2.89-2.76 (dt, 1H), 2.14-1.99 (m, 2H), 1.61-1.24 (m, 21H), 0.88-0.83 (t, 3H); 13C NMR (62.7 MHz) 154.6 (s), 133.3 (s), 127.8 (s), 78.9 (s), 48.8 (s), 39.5 (s), 32.3 (s), 30.9 (s), 30.6 (s), 27.6 (s), 25.9 (s), 23.9 (s), 22.5 (s), 21.1 (s), 19.4 (s), 16.9 (s), 14.8 (s), 13.2 (s) ppm. The deep red solution was slowly warmed to 0° C. cooled to −78° C the mixture was slowly warmed to room temperature the organic layer was separated The aqueous layer was extracted with ether the combined extracts were dried over K2CO3 concentrated to give a crude product as an oil

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of ethyltriphenylphosphonium bromide (7.31 g, 19.68 mmol) in 40 mL of THF was cooled to −30° C. and treated with n-BuLi (10.9 mL, 19.68 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of N-Boc-piperidine-2-carboxaldehyde (3.53 g, 17.89 mmol) in 10 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 1.6 g (41%) of the product which was homogenous by TLC analysis. 1H NMR (250 MHz) δ 5.73-5.51 (m, 2H), 5.05-5.01 (m, 1H), 3.98-3.93 (br d, 1H), 2.90-2.81 (m, 1H), 1.7-1.39 (m, 18H); 13C NMR (62.7 MHz) 154.8 (s), 128.0 (s), 125.8 (s), 79.0 (s), 47.7 (s), 39.6 (s), 30.3 (s), 28.5 (s), 25.6 (s), 19.5 (s), 13.2 (s) ppm. The deep red solution was slowly warmed to 0° C. cooled to −78° C the mixture was slowly warmed to room temperature the organic layer was separated The aqueous layer was extracted with ether the combined extracts were dried over K2CO3 concentrated to give a crude product as an oil