General and Scalable Amide Bond Formation with Epimerization-Prone Substrates Using T3P and Pyridine
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1 General and Scalable Amide Bond ormation with Epimerization-Prone Substrates Using T3P and Pyridine Joshua R. Dunetz,*,a Yanqiao Xiang, b Aaron Baldwin, b Justin Ringling b a Chemical Research and Development b Analytical Research and Development Pharmaceutical Sciences, Pfizer Worldwide Research and Development Eastern Point Road, Groton, Connecticut joshua.r.dunetz@pfizer.com Table of Contents Materials, Instrumentation, Chiral Assays S1 S2 Procedures for synthesis of amides 1, 7a g, 8a b, 9a b, 10 S2 S10 Chiral PLC/SC chromatograms of amides 1, 7a g, 8a b, 9a b, 10 S11 S17 1, 13 C MR spectra of amides 1, 7a g, 8a b, 9a b, 10 S18 S43 Materials. Common substrates, reagents, and solvents were obtained from commercial suppliers and used without further purification. Commercial solutions of T3P (50% in EtAc) were purchased from Aldrich or Alfa Aesar. The preparation of acid 2 and amine 3 will be disclosed in a future publication. Instrumentation. 1 and 13 C MR spectra were obtained on a Varian MR 400 Mz spectrometer. 1 MR chemical shifts are expressed in parts per million (δ) downfield from tetramethylsilane (with the central peak of DMS referenced to 2.50 ppm). 13 C MR chemical shifts are expressed in parts per million (δ) downfield from tetramethylsilane (with the central peak of DMS referenced to ppm). igh-resolution positive electrospray ionization mass spectrometric data (RMS-ESI) were obtained using a Thermo LTQ-TICR ultra mass S-1
2 spectrometer. Melting points were acquired using a Thomas oover UniMelt Capillary Melting Point Apparatus. Chiral Assays. Analytical methods to determine the enantiomeric ratio of amide products were developed using racemic samples. Amides 1 and 7a were evaluated by chiral PLC via AD-R column at 40 C using 70% MeC/ 2 (flow rate = 0.8 ml/min). Amides 7b, 7c, and 7e were evaluated by chiral SC via IC column at 40 C using 5 50% gradient of Me/scC 2 at 6.5%/min with hold for 1 min at 50% Me (flow rate = 4 ml/min). 1 Amides 7d and 8b were evaluated by chiral SC via AD column at 40 C using 5 50% gradient of Me/scC 2 at 6.5%/min with hold for 1 min at 50% Me (flow rate = 4 ml/min). Amides 7f, 7g, 8a, and 9b were evaluated by chiral SC via D column at 40 C using 5 50% gradient of Me/scC 2 at 6.5%/min with hold for 1 min at 50% Me (flow rate = 4 ml/min). Amides 9a and 10 were evaluated by chiral SC via J column at 40 C using 5 50% gradient of Me/scC 2 at 6.5%/min with hold for 1 min at 50% Me (flow rate = 4 ml/min). General Procedure for Amide Coupling. Synthesis of (S)-benzyl 6-(3-cyclopentyl-2- (4-(trifluoromethyl)-1-imidazol-1-yl)propanamido)nicotinate (1). Gram scale: A 250-mL, jacketed reaction vessel equipped with overhead stirrer and internal temperature probe was charged with acid 2 (10.10 g, mmol; 99.7 : 0.3 er), amine 3 (9.20 g, 40.3 mmol, 1.1 equiv), pyridine (10 ml, 120 mmol, 1 volume), and EtAc (20 ml, 2 volumes). The heterogeneous mixture was cooled between 20 C and 10 C as 44 ml of T3P solution (50 wt% in EtAc, 74 mmol, 2.0 equiv) were added via addition funnel at a rate to maintain an internal temperature below 0 C. The resulting homogeneous, golden-yellow solution was stirred at 0 C for 20 h, at which time the coupling was complete and amide 1 was formed with 99.0 : 1.0 er. Cooled between 20 C and 10 C as 30 ml (3 volumes) of 0.5 M aq Cl solution were added (exothermic) via addition funnel at a rate to maintain an internal temperature below 5 C. The quenched mixture was stirred at 20 C for 2 h, and the thick solids were collected on a Buchner funnel and rinsed with three 100-mL portions of water. The solids were transferred to a clean vessel with 100 ml of water and granulated for 1 h. The slurry was 1 scc 2 = supercritical carbon dioxide S-2
3 filtered through a Buchner funnel, and the filter cake was rinsed with 50 ml of water and dried (vacuum oven at 50 C) to obtain g of amide 1 (83% yield, 99.4 : 0.6 er) as a white solid. Kilogram scale: A 200-L, jacketed reactor was charged with acid 2 (15.00 kg, mol; 99.6 : 0.4 er), amine 3 (13.60 kg, mol, 1.1 equiv), pyridine (15.1 L, 187 mol, 1 volume), and EtAc (29.7 L, 2 volumes). The heterogeneous mixture was held at 10 C (jacket) as 64.9 L of T3P solution (50 wt% in EtAc, 108 mol, 2.0 equiv) were added (exothermic) over 1.5 h while maintaining an internal temperature below 0 C. The resulting homogeneous, goldenyellow solution was held at 0 C for 20 h, at which time the coupling was complete and amide 1 was formed with 98.5 : 1.5 er. The solution was held at 10 C (jacket) as 46 L (3 volumes) of 0.5 M aq Cl solution were added (exothermic) at a rate to maintain an internal temperature below 5 C. The quenched mixture was mixed at 20 C for 4 h, and the thick solids were collected on a utsche filter and rinsed with 50 L of water. The filter cake was dried under 2 for 1 h, returned to the 200-L reactor, and reslurried in 150 L of water for 2 h. The fine solids were collected on a utsche filter, rinsed with 50 L of water, and dried under 2 for 1 h. The filter cake was dried in a vacuum oven with 2 sweep at 50 C to obtain kg of amide 1 (85% yield, 99.1 : 0.9 er) as a white solid: mp C; 1 MR (400 Mz, d 6 -DMS) δ (s, 1); 8.91 (dd, J = 0.8, 2.4 z, 1), 8.34 (dd, J = 2.4, 8.8 z, 1), 8.17 (d, J = 8.8 z, 1), (m, 2), (m, 5), 5.36 (s, 2), 5.27 (dd, J = 4.8, 10.0 z, 1), 2.20 (m, 1), 2.10 (m, 1), (m, 8), 1.07 (m, 1); 13 C MR (100 Mz, d 6 -DMS): δ 168.9, 164.1, 154.7, 149.6, 139.7, 138.9, 135.9, (q, J C = 38 z), 128.5, 128.2, 128.1, (q, J C = 265 z), 121.5, (q, J C = 4 z), 113.0, 66.3, 60.0, 37.5, 36.2, 32.0, 30.8, 24.6, 24.4; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--phenyl-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)propanamide (7a). A mixture of acid 2 (2.6 g, 9.4 mmol; 98.1 : 1.9 er), aniline (0.94 ml, 0.96 g, 10 mmol), and pyridine (2.6 ml, 32 mmol) in 5.2 ml of EtAc at 10 C was treated with T3P (11 ml, 50 wt% in EtAc, 18 mmol) according to the general procedure. The coupling proceeded to completion within 16 h at 0 C, and amide 7a was formed in 97.7 : 2.3 er. The solution was quenched at 10 C with 7 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 30 ml of EtAc and the phases were separated. The S-3
4 organic layer was washed with 20 ml of 0.5 M aq Cl, 20 ml of satd acl solution, and concentrated to 3.42 g of an off-white solid. Column chromatography on 130 grams of silica gel (gradient elution with 35 40% EtAc/hexanes) provided 3.15 g of amide 7a (95% yield) as an off-white solid: 1 MR (400 Mz, d 6 -DMS) δ (s, 1); 7.98 (s, 1), 7.95 (s, 1), 7.58 (d, J = 7.6 z, 2), 7.33 (dd, J = 7.6 z, 2), 7.09 (t, J = 7.6 z, 1), 5.06 (dd, J = 6.0, 9.6 z, 1), (m, 2), (m, 7), 1.25 (m, 1), 1.09 (m, 1); 13 C MR (100 Mz, d 6 -DMS): δ 167.4, 138.7, 138.3, (q, J C = 38 z), 128.9, 124.0, (q, J C = 265 z), (q, J C = 4 z), 119.6, 60.3, 38.1, 36.3, 32.0, 31.2, 24.7, 24.5; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--methyl--phenyl-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)- propanamide (7b). A mixture of acid 2 (3.23 g, 11.7 mmol; 98.1 : 1.9 er), -methylaniline (1.4 ml, 1.4 g, 13 mmol), and pyridine (3.3 ml, 41 mmol) in 6.5 ml of EtAc at 20 C was treated with T3P (14 ml, 50 wt% in EtAc, 24 mmol) according to the general procedure. The coupling proceeded to completion within 19 h at 0 C, and amide 7b was formed in 97.0 : 3.0 er. The solution was quenched at 20 C with 10 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 100 ml of EtAc, washed with three 50-mL portions of 1 M aq Cl, and concentrated to 4.57 g of a viscous, golden-yellow oil. Column chromatography on 100 grams of silica gel (gradient elution with 15 20% EtAc/hexanes) provided 3.80 g of amide 7b (89% yield) as a colorless oil: 1 MR (400 Mz, d 6 -DMS) δ 7.88 (s, 1), 7.81 (s, 1), (m, 5), 4.85 (dd, J = 3.6, 10.4 z, 1), 3.18 (s, 3), 2.05 (m, 1), 1.70 (m, 1), (m, 7), 0.88 (m, 1), 0.38 (m, 1); 13 C MR (100 Mz, d 6 -DMS): δ 168.1, 142.3, 138.9, 130.1, (q, J C = 38 z), 128.4, 127.7, (q, J C = 265 z), (q, J C = 4 z), 56.6, 37.8, 37.6, 35.5, 31.9, 30.2, 24.3, 24.1; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--(4-methoxyphenyl)-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)- propanamide (7c). A mixture of acid 2 (1.78 g, 6.44 mmol; 98.1 : 1.9 er), p-anisidine (0.87 g, 7.1 mmol), and pyridine (1.8 ml, 22 mmol) in 3.6 ml of EtAc at 15 C was treated with T3P (8.0 ml, 50 wt% in EtAc, 13 mmol) according to the general procedure. The coupling proceeded to completion within 22 h at 0 C, and amide 7c was formed in 95.7 : 4.3 er. The S-4
5 solution was quenched at 15 C with 6 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 20 ml of EtAc, washed with three 20-mL portions of 0.5 M aq Cl, and concentrated to 2.55 g of a purple solid. Column chromatography on 100 grams of silica gel (elution with 40% EtAc/hexanes) provided 2.41 g of amide 7c (98% yield) as a pale green solid: 1 MR (400 Mz, d 6 -DMS) δ (s, 1), 7.97 (s, 1), 7.94 (s, 1), 7.49 (d, J = 8.8 z, 2), 6.90 (d, J = 8.8 z, 2), 5.02 (dd, J = 6.0, 9.6 z, 1), 3.72 (s, 3), (m, 2), (m, 7), 1.25 (m, 1), 1.08 (m, 1); 13 C MR (100 Mz, d 6 -DMS): δ 166.8, 155.7, 138.7, 131.3, (q, J C = 37 z), (q, J C = 265 z), 121.1, (q, J C = 4 z), 113.9, 60.2, 55.1, 38.2, 36.3, 32.0, 31.2, 24.6, 24.5; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--(2,6-dimethylphenyl)-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)- propanamide (7d). A mixture of acid 2 (2.91 g, 10.5 mmol; 98.1 : 1.9 er), 2,6-dimethylaniline (1.4 ml, 1.4 g, 11 mmol), and pyridine (2.9 ml, 36 mmol) in 5.8 ml of EtAc at 20 C was treated with T3P (13 ml, 50 wt% in EtAc, 21 mmol) according to the general procedure. The coupling proceeded to completion within 18 h at 0 C, and amide 7d was formed in 97.3 : 2.7 er. The solution was quenched at 20 C with 9 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 100 ml of EtAc and washed with four 50-mL portions of 0.5 M aq Cl. Concentration of the organic layer to an oil and reconcentration three times from 20-mL portions of EtAc (to remove water) provided 3.98 g of amide 7d (99% yield) as a white solid: 1 MR (400 Mz, d 6 -DMS) δ 9.79 (s, 1), 8.01 (s, 1), 7.96 (app t, J = 1.2 z, 1), (m, 3), 5.14 (dd, J = 6.8, 8.8 z, 1), (m, 2), 2.05 (s, 6), (m, 7), 1.28 (m, 1), 1.14 (m, 1); 13 C MR (100 Mz, d 6 -DMS): δ 167.2, 138.7, 135.0, 134.0, (q, J C = 38 z), 127.8, 126.9, (q, J C = 265 z), (q, J C = 4 z), 59.7, 37.8, 36.4, 31.9, 31.5, 24.7, 24.4, 17.8; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--benzyl-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)propanamide (7e). A mixture of acid 2 (1.87 g, 6.77 mmol; 98.1 : 1.9 er), benzylamine (0.81 ml, 0.79 g, 7.4 mmol), and pyridine (1.9 ml, 23 mmol) in 3.8 ml of EtAc at 20 C was treated with T3P (8.1 ml, 50 wt% in EtAc, 14 mmol) according to the general procedure. The coupling S-5
6 proceeded to completion within 22 h at 0 C, and amide 7e was formed in 96.0 : 4.0 er. The solution was quenched at 20 C with 6 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 20 ml of EtAc and washed with two 20-mL portions of 0.5 M aq Cl. Concentration of the organic layer to an oil and reconcentration from 20 ml of EtAc (to remove water) provided 2.43 g of amide 7e (98% yield) as a white solid: 1 MR (400 Mz, d 6 -DMS) δ 8.89 (t, J = 6.0 z, 1), 7.93 (s, 1), 7.89 (app t, J = 1.2 z, 1), (m, 2), (m, 3), 4.94 (dd, J = 6.8, 9.2 z, 1), 4.33 (dd, J = 6.0, 15.2 z, 1), 4.27 (dd, J = 6.0, 15.2 z, 1), (m, 2), (m, 7), (m, 1), (m, 1); 13 C MR (100 Mz, d 6 -DMS): δ 168.6, 138.7, 138.6, (q, J C = 38 z), 128.3, 127.3, 127.0, (q, J C = 265 z), (q, J C = 4 z), 59.6, 42.4, 38.1, 36.2, 31.9, 31.3, 24.6, 24.4; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--benzyl--methyl-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)- propanamide (7f). A mixture of acid 2 (2.34 g, 8.47 mmol; 98.1 : 1.9 er), -benzylmethylamine (1.2 ml, 1.1 g, 9.3 mmol), and pyridine (2.3 ml, 28 mmol) in 4.7 ml of EtAc at 20 C was treated with T3P (10 ml, 50 wt% in EtAc, 17 mmol) according to the general procedure. The coupling proceeded to completion within 19 h at 0 C, and amide 7f was formed in 97.3 : 2.7 er. The solution was quenched at 20 C with 15 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 100 ml of EtAc and washed with four 50-mL portions of 0.5 M aq Cl. Concentration of the organic layer to an oil and reconcentration three times from 50-mL portions of EtAc (to remove water) provided 3.16 g of amide 7f (98% yield) as a colorless oil: 1 MR (400 Mz, d 6 -DMS) major rotamer: δ 8.03 (s, 1), 7.97 (app t, J = 1.2 z, 1), (m, 5), 5.54 (dd, J = 4.4, 10.8 z, 1), 4.55 (d, J = 14.8 z, 1), 4.48 (d, J = 14.8 z, 1), 3.06 (s, 3), 2.16 (m, 1), (m, 10); minor rotamer: δ 7.91 (s, 1), 7.86 (app t, J = 1.2 z, 1), (m, 5), 5.45 (dd, J = 4.8, 9.6 z, 1), 4.83 (d, J = 16.8 z, 1), 4.73 (d, J = 16.8 z, 1), 2.86 (s, 3), 2.05 (m, 1), (m, 10); 13 C MR (100 Mz, d 6 -DMS): major rotamer: δ 169.0, 139.1, 137.1, (q, J C = 38 z), 128.5, 127.6, 126.6, (q, J C = 265 z), (q, J C = 4 z), 56.1, 50.7, 38.0, 36.4, 34.8, 31.9, 31.4, 24.54, 24.4; minor rotamer: δ 169.2, 138.7, 137.0, (q, J C = 38 z), 128.7, 127.5, 127.2, (q, J C = 265 z), (q, J C = 4 z), 55.4, 52.6, S-6
7 38.0, 36.1, 34.4, 31.9, 31.4, 24.46, 24.3; RMS-ESI m/z: [M+] + calcd for C , ; found, (S)--isopropyl-3-cyclopentyl-2-(4-(trifluoromethyl)-1-imidazol-1-yl)propanamide (7g). A mixture of acid 2 (2.61 g, 9.45 mmol; 98.1 : 1.9 er), isopropylamine (0.93 ml, 0.64 g, 11 mmol), and pyridine (2.6 ml, 32 mmol) in 5.2 ml of EtAc at 10 C was treated with T3P (11 ml, 50 wt% in EtAc, 18 mmol) according to the general procedure. After 21 h at 0 C, the coupling proceeded to 90% conversion and amide 7g was formed in 93.8 : 6.2 er. The solution was quenched at 20 C with 8 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 50 ml of EtAc, washed with three 30-mL portions of 0.5 M aq Cl, and washed with three 30-mL portions of satd aq ac 3 solution. Concentration of the organic layer and reconcentration from 50 ml of EtAc (to remove water) provided 2.46 g of amide 7g (82% yield) as a white solid: 1 MR (400 Mz, d 6 -DMS) δ 8.27 (d, J = 7.6 z, 1), 7.88 (s, 1), 7.84 (app t, J = 1.2 z, 1), 4.79 (dd, J = 6.4, 9.2 z, 1), 3.80 (d of sept, J = 6.4, 7.6 z, 1), (m, 2), (m, 7), 1.19 (m, 1), 1.07 (d, J = 6.4 z, 3), 1.05 (m, 1), 1.04 (d, J = 6.4 z, 3); 13 C MR (100 Mz, d 6 -DMS): δ 167.5, 138.5, (q, J C = 37 z), (q, J C = 265 z), (q, J C = 4 z), 59.6, 40.9, 38.4, 36.2, 31.9, 31.3, 24.7, 24.4, 22.1, 22.0; RMS-ESI m/z: [M+] + calcd for C , ; found, (R)--phenyl-2-phenylpropanamide (8a). A mixture of (R)-2-phenylpropionic acid (0.20 ml, 0.22 g, 1.5 mmol; >99.9 : 0.1 er), aniline (0.15 ml, 0.15 g, 1.6 mmol), and pyridine (0.22 ml, 2.7 mmol) in 0.5 ml of EtAc at 15 C was treated with T3P (1.7 ml, 50 wt% in EtAc, 2.9 mmol) according to the general procedure. After 20 h at 0 C, the coupling proceeded to 93% conversion and amide 8a was formed without detection of the minor enantiomer. The solution was quenched at 20 C with 2 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 25 ml of EtAc and washed with three 30-mL portions of 0.5 M aq Cl. The organic layer was washed with two 10-mL portions of satd aq ac 3 solution and then 20 ml of water. Concentration of the organic layer and reconcentration three times from 30-mL portions of EtAc (to remove water) provided g of amide 8a (81% yield) as an off-white solid: 1 MR (400 Mz, d 6 -DMS) S-7
8 δ (s, 1), (m, 2), (m, 2), (m, 5), 7.01 (m, 1), 3.82 (q, J = 7.2 z, 1), 1.41 (d, J = 7.2 z, 3); 13 C MR (100 Mz, d 6 -DMS): δ 172.2, 141.9, 139.2, 128.6, 128.4, 127.2, 126.7, 123.1, 119.1, 45.9, 18.6; RMS-ESI m/z: [M+] + calcd for C 15 15, ; found, (R)--benzyl-2-phenylpropanamide (8b). A mixture of (R)-2-phenylpropionic acid (0.20 ml, 0.22 g, 1.5 mmol; >99.9 : 0.1 er), benzylamine (0.18 ml, 0.18 g, 1.7 mmol), and pyridine (0.22 ml, 2.7 mmol) in 0.5 ml of EtAc at 20 C was treated with T3P (1.7 ml, 50 wt% in EtAc, 2.9 mmol) according to the general procedure. After 20 h at 0 C, the coupling proceeded to 96% conversion and amide 8b was formed without detection of the minor enantiomer. The solution was quenched at 20 C with 2 ml of 0.5 M aq Cl solution and warmed to 20 C (amide did not precipitate). The mixture was diluted with 30 ml of EtAc and washed with three 30-mL portions of 0.5 M aq Cl. The organic layer was washed with two 10-mL portions of satd aq ac 3 solution and then 20 ml of water. Concentration of the organic layer and reconcentration three times from 30-mL portions of EtAc (to remove water) provided g of amide 8b (82% yield) as an off-white solid: 1 MR (400 Mz, d 6 -DMS) δ 8.46 (t, J = 6.0 z, 1), (m, 10 ), 4.24 (app d, J = 6.0 z, 2), 3.66 (q, J = 7.2 z, 1), 1.35 (d, J = 7.2 z, 3); 13 C MR (100 Mz, d 6 -DMS): δ 173.3, 142.3, 139.5, (2C), 127.3, 127.0, 126.7, 126.5, 45.1, 42.0, 18.6; RMS-ESI m/z: [M+] + calcd for C 16 17, ; found, Phenyl-( -benzyloxycarbonyl-l-alaninyl)amide (9a). A mixture of -(benzyloxycarbonyl)-l-alanine (5.18 g, 23.2 mmol; >99.9 : 0.1 er), aniline (2.3 ml, 2.4 g, 25 mmol), and pyridine (5.2 ml, 64 mmol) in 10 ml of EtAc at 20 C was treated with T3P (27 ml, 50 wt% in EtAc, 45 mmol) according to the general procedure. The coupling proceeded to completion within 18 h at 0 C, and amide 9a was formed without detection of the minor enantiomer. The solution was quenched at 20 C with 10 ml of 0.5 M aq Cl solution and warmed to 20 C. The precipitated solids were collected on a Buchner funnel, transferred to a clean flask, and reslurried in 70 ml of water for 20 h. iltration of the solids and drying in the vacuum oven at 50 C provided 6.27 g of amide 9a (91% yield) as a white solid: 1 MR (400 Mz, d 6 -DMS) δ 9.99 (s, 1), (m, 3), (m, 6), 7.04 (app t, J = 7.2 z, 1), S-8
9 5.05 (d, J = 12.8 z, 1), 5.01 (d, J = 12.8 z, 1), 4.20 (dq, J = 7.2, 7.2 z, 1), 1.29 (d, J = 7.2 z, 3); 13 C MR (100 Mz, d 6 -DMS): δ 171.5, 155.8, 139.0, 137.0, 128.7, 128.3, 127.8, 127.7, 123.2, 119.1, 65.4, 50.8, 18.0; RMS-ESI m/z: [M+] + calcd for C , ; found, Benzyl-( -benzyloxycarbonyl-l-alaninyl)amide (9b). A mixture of -(benzyloxycarbonyl)-l-alanine (5.07 g, 22.7 mmol; >99.9 : 0.1 er), benzylamine (2.7 ml, 2.7 g, 25 mmol), and pyridine (5.2 ml, 64 mmol) in 10 ml of EtAc at 20 C was treated with T3P (15 ml, 50 wt% in EtAc, 25 mmol) according to the general procedure. The coupling proceeded to completion within 20 h at 0 C, and amide 9b was formed without detection of the minor enantiomer. The solution was quenched at 20 C with 15 ml of 0.5 M Cl solution and warmed to 20 C. The precipitated solids were collected on a Buchner funnel, transferred to a clean flask, and reslurried in 70 ml of water for 18 h. iltration of the solids and drying in the vacuum oven at 50 C provided 6.45 g of amide 9b (91% yield) as a white solid: 1 MR (400 Mz, d 6 -DMS) δ 8.40 (t, J = 6.0 z, 1), 7.48 (d, J = 7.6 z, 1), (m, 10), 5.05 (d, J = 12.4 z, 1), 5.01 (d, J = 12.4 z, 1), 4.29 (app d, J = 5.6 z, 2), 4.09 (dq, J = 7.2, 7.2 z, 1), 1.24 (d, J = 7.2 z, 3); 13 C MR (100 Mz, d 6 -DMS): δ 172.5, 155.7, 139.4, 137.0, 128.3, 128.2, , , 127.0, 126.7, 65.4, 50.2, 42.0, 18.2; RMS-ESI m/z: [M+] + calcd for C , ; found, Phenyl-( -benzyloxycarbonyl-l-alaninyl)amide (10). A mixture of -(benzyloxycarbonyl)-l-phenylglycine (2.26 g, 7.92 mmol; >99.9 : 0.1 er), aniline (0.80 ml, 0.82 g, 8.8 mmol), and pyridine (2.3 ml, 28 mmol) in 4.5 ml of EtAc at 20 C was treated with T3P (10 ml, 50 wt% in EtAc, 17 mmol) according to the general procedure. The coupling proceeded to completion within 18 h at 0 C, and amide 10 was formed without detection of the minor enantiomer. The solution was quenched at 20 C with 8 ml of 0.5 M aq Cl solution and warmed to 20 C. The precipitated solids were collected on a Buchner funnel, transferred to a clean flask, and reslurried in 30 ml of water for 24 h. iltration of the solids and drying in the vacuum oven at 50 C provided 2.91 g of white solid containing grains of insoluble material. The soluble material was dissolved in 250 ml of EtAc, passed through a Celite plug, washed with 200 ml of satd aq ac 3, and then washed with 200 ml of water. Concentration of the S-9
10 organic layer and drying of the residue in the vacuum oven at 50 C provided 2.67 g of amide 10 (94% yield) as a white solid: 1 MR (400 Mz, d 6 -DMS) δ (s, 1), 8.13 (d, J = 8.4 z, 1), 7.58 (d, J = 7.6 z, 2), 7.52 (d, J = 6.8 z, 2), (m, 10), 7.05 (app t, J = 7.6 z, 1), 5.44 (d, J = 8.4 z, 1), 5.07 (s, 2); 13 C MR (100 Mz, d 6 -DMS): δ 168.9, 155.9, 138.8, 137.9, 136.9, 128.8, 128.4, 128.3, 127.9, 127.8, 127.7, 127.4, 123.5, 119.2, 65.7, 58.9; RMS-ESI m/z: [M+] + calcd for C , ; found, S-10
11 Chiral PLC/SC chromatograms of amides 1, 7a g, 8a b, 9a b, 10 (before workup, unless otherwise noted) Amide 1 (in solution before workup) C 3 1 C 2 Bn Amide 1 (isolated) S-11
12 C 3 7a Me C 3 7b S-12
13 Me C 3 7c C 3 7d S-13
14 C 3 7e Me C 3 7f S-14
15 C 3 7g mixture of 8a enantiomers Me Ph 8a S-15
16 Me Ph 8b mixture of 8b enantiomers mixture of 9a enantiomers Me Cbz 9a S-16
17 mixture of 9b enantiomers Me Cbz 9b Ph Cbz 10 mixture of 10 enantiomers S-17
18 C 3 1 (400 Mz, DMS) o_p-x_ _ _s2pul_
19 o_p _ _ _s2pul_ o_p _ _ _s2pul_
20 C 3 7a (400 Mz, DMS) o_p-x_ _ _s2pul_
21 o_p-x_ _ _s2pul_003.esp VerticalScaleactor = o_p-x_ _ _s2pul_003.esp
22 Me 7b C 3 (400 Mz, DMS) o_p-x_ _ _s2pul_
23 o_p-x_ _ _s2pul_002 VerticalScaleactor = 1 o_p-x_ _ _s2pul_ o_p-x_ _ _s2pul_ C
24 Me C 3 7c (400 Mz, DMS) o_p-x_ _ _s2pul_
25 Points Count Pulse Sequence s2pul Receiver Gain Solvent DMS-d6 o_p-x_ _ _s2pul_001 Spectrum ffset (z) Spectrum Type STADARD Sweep Width (z) Temperature (degree C) o_p-x_ _ _s2pul_001 VerticalScaleactor = o_p-x_ _ _s2pul_ C
26 C 3 7d (400 Mz, DMS) o_p-x_ _ _s2pul_
27 o_p-x_ _ _s2pul_002 VerticalScaleactor = 1 o_p-x_ _ _s2pul_002 o_p-x_ _ _s2pul_ C C
28 C 3 7e (400 Mz, DMS) o_p-x_ _ _s2pul_
29 o_p-x_ _ _s2pul_002 VerticalScaleactor = o_p-x_ _ _s2pul_ o_p-x_ _ _s2pul_
30 o_p-x_ _ _s2pul_001 Me C 3 7f (400 Mz, DMS)
31 o_p-x_ _ _s2pul_002.esp VerticalScaleactor o_p-x_ _ _s2pul_002.esp = 1 o_p-x_ _ _s2pul_002.esp o_p-x_ _ _s2pul_002.esp o_p-x_ _ _s2pul_002.esp Chem o_p-x_ _ _s2pul_002.esp o_p-x_ _ _s2pul_002.esp Chemic Chemical S o_p-x_ _ _s2pul_002.esp o_p-x_ _ _s2pul_002.esp o_p-x_ _ _s2pul_002.esp Chemi Chemic o_p-x_ _ _s2pul_002.esp o_p-x_ _ _s2pul_002.esp Chemic Chemical S C
32 o_p-x_ _ _s2pul_001 C 3 7g (400 Mz, DMS)
33 o_p-x_ _ _s2pul_002 VerticalScaleactor = o_p-x_ _ _s2pul_002 C 3 C o_p-x_ _ _s2pul_
34 3 C 8a (400 Mz, DMS) o_p-x_ _ _s2pul_
35 -x_ _ _s2pul_003 VerticalScaleactor = C
36 3 C 8b (400 Mz, DMS) o_p-x_ _ _s2pul_
37 -x_ _ _s2pul_002 VerticalScaleactor = o_p-x_ _ _s2pul_ C
38 3 C 9a (400 Mz, DMS) o_p-x_ _ _s2pul_
39 -x_ _ _s2pul_003 VerticalScaleactor = 1 o_p-x_ _ _s2pul_003 C
40 3 C 9b (400 Mz, DMS) o_p-x_ _ _s2pul_
41 x_ _ _s2pul_002 VerticalScaleactor = o_p-x_ _ _s2pul_ C
42 10 (400 Mz, DMS) o_p-x_ _ _s2pul_
43 -x_ _ _s2pul_002 VerticalScaleactor = 1 o_p-x_ _ _s2pul_
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