Supporting Information Wiley-VCH 2007 69451 Weinheim, Germany
Diphenylprolinol Silyl Ether in Enantioselective, Catalytic Tandem Michael-Henry Reaction for the Control of Four Stereocenters Yujiro Hayashi*, Tsubasa Okano, Seiji Aratake, Damien Hazerard Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan Typical procedure for the synthesis of (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (S)-2-Diphenyltrimethylsiloxymethylpyrrolidine (8.8 mg, 0.027 mmol) was added to a mixture of 1-phenyl-2-nitroethylene (40.3 mg, 0.27 mmol) and glutaraldehyde solution (50% in water, 147 μl, 0.81 mmol) in THF (0.54 ml) at room temperature. The reaction mixture was stirred for 17 h at this temperature, the reaction was quenched by addition of 1 N hydrochloric acid for 3 min. Organic materials were extracted with ethyl acetate two times. The combined organic extracts were washed with brine five times, dried over anhydrous Na 2 SO 4 and concentrated in vacuo after filtration. Purification by neutral silica gel column chromatography (hexane : AcOEt = 2 : 1) gave (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (50.6 g, 0.20 mmol) in 88% yield as the diastereomeric mixture (5a:5b:5c:5d=75:8:8:9). Typical procedure for the synthesis of (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (large scale) (S)-2-Diphenyltrimethylsiloxymethylpyrrolidine (239 mg, 0.73 mmol) was added to a mixture of 1-phenyl-2-nitroethylene (5.5 g, 36.7 mmol) and glutaraldehyde solution (50% in water, 13.3 ml, 73.3 mmol) in THF (36.7 ml) at room temperature. The reaction mixture was stirred for 22 h at this temperature, the reaction was quenched by addition of 1 N hydrochloric acid for 3 min. Organic materials were extracted with ethyl acetate two times. The combined organic extracts were washed with brine five times, dried over anhydrous Na 2 SO 4 and concentrated in vacuo after filtration. Purification by neutral silica gel column chromatography (hexane : AcOEt = 2 : 1) gave (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (6.5 g, 26.0 mmol) in 92% yield as the diastereomeric mixture (5a:5b:5c:5d=73:8:7:12). Synthesis of (1S, 2S, 3S,4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5a to 5b) (1R, 2S, 3S, 4R)-4-Hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (33.4 mg, 0.134 mmol) was charged on preparative thin layer chromatography plate and it left for 5 h. After that, the TLC was developed by hexane and AcOEt (2:1) for 1 h, which afforded (1S, 2S, 3S,4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (31.3 mg, 0.126 mmol) in 94% yield. Synthesis of (1S, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5b to 5c) A solution of 1, 8-diazabicyclo[5.4.0]-undec-7-ene in methanol (0.05 M, 0.25 ml) was added to (1S, 2S, 3S,4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (31.3 mg, 0.126 mmol) at room temperature. The reaction mixture was stirred for 20 h at this temperature, the reaction was quenched with ph 7.0 phosphate buffer solution. Organic materials were extracted with ethyl acetate two times. The combined organic extracts were washed with brine three times, dried over anhydrous Na 2 SO 4 and concentrated in vacuo after filtration. Purification by preparative thin layer chromatography (hexane : AcOEt = 1 : 1) gave (1S, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (25.9 mg, 0.104 mmol) in 83% yield. Synthesis of (1S, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5a to 5c) A solution of 1, 8-diazabicyclo[5.4.0]-undec-7-ene in methanol (0.05 M, 0.20 ml) was added to (1R, 2S, 3S, 4R)-4-Hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (24.8 mg, 0.0995 mmol) at room temperature. The reaction mixture was stirred for 20 h at this temperature, the reaction was quenched with ph 7.0 phosphate buffer solution. Organic materials were extracted with ethyl acetate two times. The combined organic extracts were washed with brine three times, dried over anhydrous Na 2 SO 4 and concentrated in vacuo after filtration. Purification by preparative thin layer chromatography (hexane : AcOEt = 1 : 1) gave (1S, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (19.8 mg, 0.0794 mmol) in 80% yield. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5a) 1 H NMR (CDCl 3, 400 MHz): δ 1.69-1.81 (1H, m), 1.83-1.92 (1H, m), 1.94-2.02 (1H, m), 2.20-2.32 (1H, m), 2.43 (1H, br-s), 3.19 (1H, t, J = 4.8 Hz), 4.04 (1H, dd, J = 12.2, 4.8 Hz), S1
4.60 (1H, br-s), 5.63 (1H, dd, J = 12.2, 2.4 Hz), 7.18-7.32 (5H, m), 9.49 (1H, s); 13 C NMR (CDCl 3, 100 MHz): δ 18.4, 27.6, 40.7, 52.4, 67.9, 87.4, 127.6, 127.9, 128.9, 137.5, 202.4; IR (neat): ν 3420.1, 2924.5, 2852.2, 1717.3, 1549.5, 1456.0, 1374.0, 1069.3, 1032.7, 756.9, 702.0 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: 272.0893, found: 272.0893; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (25:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 46.9 min, minor enantiomer tr = 57.8 min. (1S, 2S, 3S,4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5b) 1 H NMR (CDCl 3, 400 MHz): δ 1.71-1.83 (2H, m), 1.97-2.11 (1H, m), 2.20-2.30 (1H, m), 2.66-2.76 (2H, m), 3.92 (1H, t, J = 12.0 Hz), 4.58 (1H, br-s), 4.82 (1H, dd, J = 12.0, 2.4 Hz), NO 7.21-7.35 (5H, m), 9.40 (1H, d, 2.4 Hz); 2 13 C NMR (CDCl 3, 100 MHz): δ 19.4, 30.2, 41.3, 54.0, 67.1, 92.7, 128.1, 128.3, 129.2, 136.6, 200.7; IR (neat): ν 3436.5, 2927.4, 1719.2, 1549.5, 1496.5, 1454.1, 1373.1, 1101.2, 1069.3, 1018.2, 758.9, 702.0 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: 272.0893, found: 272.0884; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (20:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 22.4 min, minor enantiomer tr = 30.7 min. (1S, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5c) 1 H NMR (CDCl 3, 400 MHz): δ 1.52-1.72 (2H, m), 2.01-2.10 (1H, m), 2.25-2.33 (1H, m), 2.72-2.83 (1H, m), 3.39 (1H, t, J = 11.6 Hz), 4.21 (1H, td, J = 10.8, 4.4 Hz), 4.62 (1H, dd, J = 11.6, 10.8 Hz), 7.16-7.37 (5H, m), 9.35 (1H, d, 2.4 Hz); 13 C NMR (CDCl 3, 100 MHz): δ 23.9, 31.8, 47.5, 53.0, 71.7, 96.7, 127.8, 128.5, 129.3, 135.6, 200.6; IR (neat): ν 3398.9, 2924.5, 2848.4, 1718.3, 1555.3, 1456.0, 1375.0, 1064.5, 750.2, 701.0 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: 272.0893, found: 272.0885; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (20:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = 104.1 min, major enantiomer tr = 120.6 min. (1R, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5d) 1 H NMR (CDCl 3, 400 MHz): δ 1.63-1.67 (2H, m), 1.79-1.90 (1H, m), 2.05-2.13 (2H, m), 3.12 (1H, t, J = 3.6 Hz), 3.55 (1H, dd, J = 12.0, 3.6 Hz), 4.19 (1H, m), 5.42 (1H, dd, J = 12.0, 9.2 Hz), 7.27-7.31 (5H, m), 9.55 (1H, s); 13 C NMR (CDCl 3, 100 MHz): δ 22.9, 29.3, 47.2, 51.9, 73.0, 91.2, 128.0, 128.3, 128.9, 135.9, 201.6; IR (neat): ν 3420.1, 2919.7, 2850.3, 1716.3, 1652.7, 1557.2, 1507.1, 1457.0, 1384.7, 1062.6, 702.0 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: 272.0893, found: 272.0892; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (20:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 104.1 min, minor enantiomer tr = 120.6 min, after conversion to (1S,2S,3S,4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5c). (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(4-nitrophenyl)cyclohexanecarbaldehyde (Table 2, Entry 2) 1 H NMR (CDCl 3, 400 MHz): δ 1.49-1.60 (1H, m), 1.78-1.87 (1H, m), 1.87-1.95 (1H, m), 2.20-2.32 (1H, m), 2.41 (1H, br-s), 3.18 (1H, t, J = 4.8 Hz), 3.99 (1H, dd, J = 12.4, 4.8 Hz), 4.57 (1H, br-d, J = 2.8 Hz), 5.66 (1H, dd, J = 12.4, 2.8 Hz), 7.36 (2H, br-d, J = 8.0 Hz), 8.04 (2H, br-d, J = 8.0 Hz), 9.31 (1H, s); 13 C NMR (CDCl NO O 2 3, 100 MHz): δ 14.1, 27.6, 40.3, 52.7, 67.8, 86.5, 123.9, 129.0, 145.8, 2 N 147.1, 201.0; IR (neat): ν 3437.5, 2922.6, 2852.0, 1719.2, 1603.5, 1550.5, 1519.6, 1349.0, 1110.8, 1087.7, 878.4, 753.1, 697.1 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 14 N 2 NaO 6 ]: 317.0744, found: 317.0742; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (10:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = 65.0 min, major enantiomer tr = 72.4 min. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(4-bromophenyl)cyclohexanecarbaldehyde (Table 2, Entry 3) 1 H NMR (CDCl 3, 400 MHz): δ 1.63 (1H, tdd, J = 14.4, 4.8, 2.4 Hz), 1.82 (1H, ddt, J = 14.4, 3.6, 2.4 Hz), 1.88-1.99 (1H, m), 2.24 (1H, tdd, J = 14.4, 6.0, 3.6 Hz), 2.35 (1H, br-s), 3.14 (1H, t, J = 4.8 Hz), 3.91(1H, dd, J = 12.4, 4.8 Hz), 4.56 (1H, br-d, J = 3.2 Hz), 5.60 (1H, dd, 12.4, 2.4 Hz), 7.10 (2H, br-d, J = 8.4 Hz), 7.36 (2H, br-d, J = 8.4 Hz), 9.41 (1H, s); 13 NO C NMR (CDCl 2 3, 100 MHz): δ 16.1, 25.3, 38.1, 50.4, 65.7, 84.9, 119.41, 127.6, 129.8, Br 134.7, 199.7; IR (neat): ν 3447.1, 2927.4, 1717.3, 1714.4, 1549.5, 1491.7, 1376.0, 1073.2, 1008.6, 873.6 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 14 BrNNaO 4 ]: 349.9998, found: 349.9988; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (30:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = 90.4 min, major enantiomer tr = 99.4 min. S2
(1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(2-bromophenyl)cyclohexanecarbaldehyde (Table 2, Entry 4) 1 H NMR (CDCl 3, 400 MHz): δ 1.70 (1H, tdd, J = 14.4, 4.4, 2.4 Hz), 1.91 (1H, m), 2.01 (1H, dq, J = 14.4, 2.4 Hz), 2.32 (1H, tdd, J = 14.4, 5.6, 4.4 Hz), 3.44 (1H, t, J = 4.4 Hz), 4.46 (1H,dd, J = 12.4, 4.4 Hz), 4.64 (1H, dd, J = 5.6, 2.4 Hz), 5.70 (1H, dd, J = 12.4, 2.4 Hz), 7.08 (1H, td, 7.6, 1.6 Hz), 7.22 (1H, td, J = 7.6, 1.6 Hz), 7.32 (1H, dd, J = 7.6, 1.6 Hz), 7.56 (1H, dd, J = 7.6, 1.6 Hz), 9.44 (1H, s); Br 13 C NMR (CDCl 3, 100 MHz): δ 18.0, 22.7, 39.6, 49.3, 68.1, 87.0, 127.6, 128.2, 129.0, 130.9, 133.7, 136.2, 201.8; IR (neat): ν 3446.7, 2934.2, 2736.5, 1716.3, 1552.4, 1472.4, 1441.1, 1373.6, 1022.6, 846.6, 749.7, 668.7 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 14 BrNNaO 4 ]: 349.9998, found: 349.9988; Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (10:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 22.6 min, minor enantiomer tr = 34.2 min, after conversion to (1S,2S,3S,4S)-4-hydroxy-3-nitro-2-(2-bromophenyl)cyclohexanecarbaldehyde. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(2-naphtyl)cyclohexanecarbaldehyde (Table 2, Entry 5) 1 H NMR (CDCl 3, 400 MHz): δ 1.73-1.86 (1H, m), 1.88-1.94 (1H, m), 1.96-2.07 (1H, m), 2.22-2.37 (1H, m), 2.44 (1H, br-s), 3.30 (1H, br-t, J = 4.8 Hz), 4.21 (1H, dd, J = 12.4, 4.8 Hz), 4.66 (1H, br-s), 5.77 (1H, dd, J = 12.4, 2.4 Hz), 7.34-7.48 (3H, m), 7.70 (1H, br-s), 7.71-7.82 (3H, m), 9.50 (1H, s); 13 C NMR (CDCl 3, 100 MHz): δ 18.4, 27.6, 40.8, 52.3, 68.0, 87.5, 126.0, 126.2, 126.4, 126.6, 127.6, 127.9, 128.7, 132.6, 133.2, 135.0, 202.5; IR (neat): ν 3442.3, 2927.4, 1717.3, 1549.5, 1505.2, 1371.1, 1092.5, 896.7, 864.9, 813.8, 751.1, 484.1 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 17 H 17 NNaO 4 ]: 322.1050, found: 322.1056; Enantiomeric excess was determined by HPLC with a Chiralpak AS-H column (10:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = 13.7 min, major enantiomer tr = 17.1 min. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(4-methoxyphenyl)cyclohexanecarbaldehyde (Table 2, Entry 6) 1 H NMR (CDCl 3, 400 MHz): δ 1.68-1.78 (1H, m), 1.84-1.90 (1H, m), 1.93-2.01 (1H, m), 2.18-2.30 (1H, m), 2.46 (1H, br-s), 3.16 (1H, t, J = 4.8 Hz), 3.75 (3H, s), 3.98 (1H, dd, J = 12.4, 4.8 Hz), 4.57 (1H, br-s), 5.57 (1H, dd, J = 12.4, 2.4 Hz), 6.81 (2H, br-d, J = 8.4 Hz), 7.17(2H, br-d, J = 8.4 Hz), 9.52 (1H, s); 13 MeO C NMR (CDCl 3, 100 MHz): δ 18.4, 27.5, 40.2, 52.5, 55.2, 67.9, 87.8, 114.2, 129.1, 129.3, 158.9, 202.6; IR (neat): ν 3442.3, 2922.6, 2848.4, 1714.4, 1617.0, 1549.5, 1515.8, 1458.9, 1366.3, 1249.7, 1185.0, 1031.7, 864.9, 753.1 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 14 H 17 NNaO 4 ]: 302.0999, found: 302.1000; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (10:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 26.7 min, minor enantiomer tr = 33.7 min. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(3, 4-methylendioxyphenyl)cyclohexanecarbaldehyde (Table 2, Entry 7) 1 H NMR (CDCl 3, 400 MHz): δ 1.63-1.74 (1H, m), 1.76-1.84 (1H, m), 1.86-1.97 (1H, m), 2.13-2.28 (1H, m), 2.34 (1H, br-s), 3.12 (1H, t, J = 5.6 Hz), 3.89 (1H, dd, J = 12.4, 4.8 Hz), 4.53 (1H, br-s), 5.51 (1H, dd, J = 12.8, 2.4 Hz), 5.86 (2H, br-s), 6.66 (2H, br-s), 6.71 (1H, O br-s), 9.49 (1H, s); O 13 C NMR (CDCl 3, 100 MHz): δ 18.4, 27.5, 40.6, 52.5, 67.9, 87.7, 101.2, 108.5, 121.2, 128.3, 131.1, 147.0, 148.0, 202.5; IR (neat): ν 3447.1, 2922.6, 1714.4, 1550.5, 1445.4, 1371.1, 1249.7, 1036.6, 934.3, 873.6 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 14 H 15 NNaO 6 ]: 316.0792, found: 316.0794; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (10:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 32.1 min, minor enantiomer tr = 36.7 min. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(2-furyl)cyclohexanecarbaldehyde (Table 2, Entry 8) 1 H NMR (CDCl 3, 400 MHz): δ 1.67-1.79 (1H, m), 1.85-2.06 (2H, m), 2.11-2.23 (1H, m), 2.43 (1H, br-d, J = 4.0 Hz), 3.21 (1H, br-s), 4.22 (1H, dd, J = 11.2, 5.6 Hz), 4.51 (1H, br-s), 5.27 (1H, dd, J = 11.2, 2.4 Hz), 6.14 (1H, d, J = 3.2), 6.20 (1H, dd, J = 3.2, 2.0 Hz), 7.25 (1H, d, J = 2.0 Hz), 9.58 (1H, s); 13 C NMR (CDCl O 3, 100 MHz): δ 17.9, 29.7, 35.0, 49.8, 67.5, 87.1, 107.6, 110.6, 142.0, 151.0, 201.8; IR (neat): ν 3445.2, 2916.8, 2849.3, 1717.3, 1550.5, 1505.2, 1375.0, 1078.0, 1014.4, 911.2, 739.6, 594.9 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 11 H 13 NNaO 5 ]: 262.0686, found: 262.0680; S3
Enantiomeric excess was determined by HPLC with a Chiralpak IA column (10:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 40.9 min, minor enantiomer tr = 51.9 min. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-(1-tert-butoxycarbonylindol-3-yl)cyclohexanecarbaldehyde (Table 2, Entry 9) 1 H NMR (CDCl 3, 400 MHz): δ 1.64 (9H, s), 1.67-1.78 (1H, m), 1.98-1.96 (1H, m), 1.97-2.05 (1H, m), 2.28-2.39 (1H, m), 2.49 (1H, br-q, J = 1.6 Hz), 3.31 (1H, br-s), 4.33 (1H, dd, J = 12.0, 4.8 Hz), 4.57 (1H, br-s), 5.57 (1H, dd, J = 12.0, 2.4 Hz), 7.25-7.35 (2H, m), 7.43 (1H, s), 7.58 (1H, br-d, 7.6 Hz), 8.19 (1H, d, 7.6 Hz), 9.54 (1H, s); 13 C NMR (CDCl 3, 100 MHz): δ 18.0, 27.5, 28.2, 31.7, 49.6, 67.6, 84.1, 87.9, 115.54, 116.5, 118.3, 122.8, 123.5, 124.9, 129.3, 135.2, 149.4, 202.3; IR (neat): ν 3902.3, 3856.0, 3735.4, 3646.7, 3576.7, 3447.1, 2931.3, 1728.9, 1556.3, 1505.2, 1458.9, 1376.0, 1259.3, 1157.1, 1022.1, 762.7cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 20 H 24 N 2 NaO 6 ]: 411.1527, found: 411.1540; N Boc Enantiomeric excess was determined by HPLC with a Chiralpak IA column (30:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 25.2 min, minor enantiomer tr = 27.8 min. (1R, 2R, 3S, 4R)- 4-hydroxy-3-nitro-2-styrylcyclohexanecarbaldehyde (Table 2, Entry 10) 1 H NMR (CDCl 3, 400 MHz): δ 1.45 (1H, br-t, J = 14.0 Hz), 1.73-1.96 (2H, m), 2.12-2.26 (1H, m), 2.88 (1H, br-s), 3.01 (1H, br-s), 3.38-3.49 (1H, m), 4.39 (1H, br-s), 5.10 (1H, dd, J = 11.2, 2.4 Hz), 6.27 (1H, dd, J = 14.4, 8.4 Hz), 6.48 (1H, d, J = 14.4 Hz), 7.13-7.31 (5H, m), 9.61 (1H, s); 13 C NMR (CDCl 3, 100 MHz): δ 17.6, 27.4, 39.7, 51.8, 66.6, 88.4, 124.9, 126.5, 128.0, 128.6, 134.8, 136.2, 201.8; IR (neat): ν 3846.3, 3735.4, 3567.7, 3447.1, 2927.4, 1719.2, 1542.8, 1376.0, 1073.2, 971.0, 748.3, 669.2 cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 15 H 17 NNaO 4 ]: 298.1050, found: 298.1049; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (10:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = 12.2 min, major enantiomer tr = 14.9 min. (1R, 2R, 3S, 4R)-4-hydroxy-3-nitro-2-cyclohexylcyclohexanecarbaldehyde (Table 2, Entry 11) 1 H NMR (CDCl 3, 400 MHz): δ 0.77-0.90 (1H, m), 1.02-1.28 (4H, m), 1.37-1.49 (1H, m), 1.55-1.77 (7H, m), 1.84-1.93 (1H, m), 2.07-2.18 (1H, m), 2.69 (1H, quint, J = 4.8 Hz), 2.86 (1H, br-s), 2.97 (1H, br-d, J = 3.6 Hz), 4.32 (1H, q, J = 2.4 Hz), 5.28 (1H, dd, J = 10.8, 2.4 Hz), 9.84 (1H, br-s); NO 13 2 C NMR (CDCl 3, 100 MHz): δ 19.1, 26.2, 26.6, 26.8, 27.4, 31.4, 31.8, 38.4, 41.5, 47.3, 67.6, 88.1, 202.7; IR (neat): ν 3851.2, 3735.4, 3646.7, 3567.7, 3437.5, 2927.4, 2852.2, 1719.2, 1542.8, 1510.0, 1450.2, 1073.2, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 21 NNaO 4 ]: 278.1363, found: 278.1358; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (30:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = 27.2 min, major enantiomer tr = 31.0 min. Determination of absolute configuration. The absolute configuration was determined by Mosher s MPTA method 1 from 7c. Br 7c + + Ph OMe Cl CF 3 O (R) MeO Ph Cl CF 3 O (S) NEt 3, DMAP CH 2 Cl 2 quant. NEt 3, DMAP CH 2 Cl 2 70 % Br Br O O CF 3 MeO Ph (S)-MPTA ester O O CF 3 Ph OMe (R)-MPTA ester S4
(1S, 2S, 3S, 4S) 2-(4-Bromo-phenyl)-4-hydroxy-3-nitro-cyclohexanecarbaldehyde 7c According to typical procedure 7c was prepared in 52 % yield from glutaraldehyde and 1-Bromo-4-(2-nitro-vinyl)-benzene after racemization with DBU (5 % mol) in Me. 1 H (CDCl 3, 400 MHz) δ 1.51-1.78 (2H, m), 2.05-2.18 (1H, m), 2.27 (1H, s br), 2.30-2.39 (1H, m), 2.71-2.85 (1H, m), 3.41 (1H, t, J=11.6 Hz), 4.16-4.32 (1H, m), 4.57 (1H, dd, J=11.6 Hz, J=9.6), 7.09 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=8,6 Hz), 9.39 (1H, d, J=2Hz, 1H) 13 C (CDCl 3, 100 MHz) δ 23.9, 31.7, 46.7, 52.9, 71.5, 96.4, 122.4, 129.5, 132.4, 134.9, 200.3. IR (neat) 3421, 2934, 2867, 2731, 1724, 1661, 1591, 1555, 1489, 1455, 1412, 1376, 1272, 1212, 1108, 1073, 1011, 911, 817, 734, 664, 553, 420. HRMS (ESI) : [M+Na] calcd for [C 13 H 14 NO 4 Na]: 349.9998, found: 349.9995 Ee = 93 % (determined by HPLC with a Chiralpak IA column (10:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = 58.8 min, minor enantiomer tr = 68.1 min. Synthesis of (R)-MPTA ester : 7c (4.2 mg, 0.013 mmol) was dissolved in dichloromethane (0,5 ml). Then Et 3 N (5 μl, 0.035 mmol), DMAP (4.1 mg, 0.034 mmol) and 1 drop of (S) 3,3,3-Trifluoro-2-methoxy-2-phenyl-propionyl chloride were successively added. The mixture was stirred 3.5 h at room temperature. Then the mixture was concentrated and purified by preparative TLC to give 4.7 mg (70 % yield) of (R)-MPTA ester. 1 H (CDCl 3, 400 MHz) δ 1.64-1.84 (2H, m), 2.14-2.24 (1H, m), 2.52-2.61 (1H, m), 2.80 (1H, t, J=10.8 Hz), 3.44 (1H, t, J=11.6 Hz), 3.46 (3H, s), 4.75 (1H, t, J=11.2 Hz), 5.54-5.64 (1H, m), 7.06 (2H, d, J=8,4 Hz), 7.32-7.43 (5H, m), 7.45 (2H, d, J=8,4 Hz), 9.39 (1H, d, J=2Hz) Synthesis of (S)-MPTA ester (R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionyl chloride was prepared from (S)-3,3,3-Trifluoro-2-methoxy-2- phenyl-propionic acid according to literature 2 : To a solution of the acid (15 mg, 0.064 mmol) in hexane (2.5 ml) was added DMF (4.5 mg, 0.059 mmol) and oxalic chloride (25 μl, 0.29 mmol). The mixture was stirred 1.5 h at room temperature and concentrated in vaccuo. To the crude mixture was added 7c (4.4 mg, 0.013 mmol), dichloromethane (0.5 ml), Et 3 N (5 μl, 0.035 mmol) and DMAP (4.4 mg, 0.036 mmol). The mixture was stirred at room temperature 3,5 h, then it was concentrated in vaccuo to give after preparative TLC (S)-MPTA ester with quantitative yield. 1 H (CDCl 3, 400 MHz) δ 1.50-1.63(1H, m), 1.64-1.78 (1H, m), 2.10-2.20 (1H, m), 2.46-2.55 (1H, m), 2.71-2.82 (1H, m), 3.43 (3H, s), 3.46 (1H, t, J=10.4 Hz), 4.76 (1H, dd, J=11.6 Hz, 10,4 Hz), 5.55 (1H, td, J= 10.8 Hz, 4.8 Hz), 7.06 (2H, d, J=8,4 Hz), 7.35-7.43 (5H, m), 7.46 (2H, d, J=8,4 Hz), 9.38 (1H, d, J=2Hz) Representation of MPTA ester with Δδ and determination of absolute configuration according to Kakisawa model 1 Br S S S S OMPTA -0.04H -0.01H -0.04 H +0 H -0.16 Br H H +0.02 H -0.06 H +0.01 +0.01 OMPTA Δδ<0 OMPTA C Δδ>0 H Δδ = δ((s)-mpta) δ((r)-mpta) Represention of MPTA ester with Δδ (left)for some protons and Kakisawa model (rigth) The scheme above show clearly that all the protons in the right side of MPTA plan have positive values while these in the left have negative values. According to Kakisawa, 1 the absolute configuration of hydroxyl group in 7c is (S). The relative configuration is determined by coupling constants. S5
References 1) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc. 1991, 113, 4092. 2) D.E. Ward, C. K. Rhee, Tetrahedron Letters 1991, 32, 7165. S6
S7
S8
S9
S10
S11
S12
S13
S14
S15
S16
S17
O 2 N S18
O 2 N S19
O 2 N S20
Br S21
Br S22
Br S23
Br S24
Br S25
Br S26
S27
S28
S29
MeO S30
MeO S31
MeO S32
O O S33
O O S34
O O S35
O S36
O S37
O S38
N Boc S39
N Boc S40
N Boc S41
S42
S43
S44
S45
S46
S47
Br S48
Br S49
Br S50
S51 (R) and (S)- MPTA esters of 7c