Supporting Information

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1 Supporting Information Wiley-VCH Weinheim, Germany

2 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 , Japan Typical procedure for the synthesis of (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (S)-2-Diphenyltrimethylsiloxymethylpyrrolidine (8.8 mg, 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, 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, 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, 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, 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, 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, mmol) in 80% yield. (1R, 2S, 3S, 4R)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5a) 1 H NMR (CDCl 3, 400 MHz): δ (1H, m), (1H, m), (1H, m), (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

3 4.60 (1H, br-s), 5.63 (1H, dd, J = 12.2, 2.4 Hz), (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 , , , , , , , , , 756.9, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: , found: ; 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 (2H, m), (1H, m), (1H, m), (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 (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 , , , , , , , , , , 758.9, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: , found: ; 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 (2H, m), (1H, m), (1H, m), (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), (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 , , , , , , , , 750.2, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: , found: ; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (20:1 hexane:2-propanol), 1.0 ml/min; minor enantiomer tr = min, major enantiomer tr = min. (1R, 2S, 3S, 4S)-4-hydroxy-3-nitro-2-phenylcyclohexanecarbaldehyde (5d) 1 H NMR (CDCl 3, 400 MHz): δ (2H, m), (1H, m), (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), (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 , , , , , , , , , , cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 15 NNaO 4 ]: , found: ; Enantiomeric excess was determined by HPLC with a Chiralpak IA column (20:1 hexane:2-propanol), 1.0 ml/min; major enantiomer tr = min, minor enantiomer tr = 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 (1H, m), (1H, m), (1H, m), (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 , , , , , , , , , , 878.4, 753.1, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 14 N 2 NaO 6 ]: , found: ; 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), (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, , 127.6, 129.8, Br 134.7, 199.7; IR (neat): ν , , , , , , , , , cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 14 BrNNaO 4 ]: , found: ; 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

4 (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 , , , , , , , , , 846.6, 749.7, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 14 BrNNaO 4 ]: , found: ; 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 (1H, m), (1H, m), (1H, m), (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), (3H, m), 7.70 (1H, br-s), (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 , , , , , , , 896.7, 864.9, 813.8, 751.1, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 17 H 17 NNaO 4 ]: , found: ; 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 (1H, m), (1H, m), (1H, m), (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 , , , , , , , , , , , , 864.9, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 14 H 17 NNaO 4 ]: , found: ; 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 (1H, m), (1H, m), (1H, m), (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 , , , , , , , , 934.3, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 14 H 15 NNaO 6 ]: , found: ; 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 (1H, m), (2H, m), (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 , , , , , , , , , 911.2, 739.6, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 11 H 13 NNaO 5 ]: , found: ; S3

5 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), (1H, m), (1H, m), (1H, m), (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), (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, , 116.5, 118.3, 122.8, 123.5, 124.9, 129.3, 135.2, 149.4, 202.3; IR (neat): ν , , , , , , , , , , , , , , , 762.7cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 20 H 24 N 2 NaO 6 ]: , found: ; 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), (2H, m), (1H, m), 2.88 (1H, br-s), 3.01 (1H, br-s), (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), (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 , , , , , , , , , 971.0, 748.3, cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 15 H 17 NNaO 4 ]: , found: ; 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 (1H, m), (4H, m), (1H, m), (7H, m), (1H, m), (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 , , , , , , , , , , , , cm -1 ; HRMS (ESI) : [M+Na] calcd for [C 13 H 21 NNaO 4 ]: , found: ; 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

6 (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 (2H, m), (1H, m), 2.27 (1H, s br), (1H, m), (1H, m), 3.41 (1H, t, J=11.6 Hz), (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, 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]: , found: 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, mmol) was dissolved in dichloromethane (0,5 ml). Then Et 3 N (5 μl, mmol), DMAP (4.1 mg, 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 (2H, m), (1H, m), (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), (1H, m), 7.06 (2H, d, J=8,4 Hz), (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, mmol) in hexane (2.5 ml) was added DMF (4.5 mg, 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, mmol), dichloromethane (0.5 ml), Et 3 N (5 μl, mmol) and DMAP (4.4 mg, 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 (1H, m), (1H, m), (1H, m), (1H, m), (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), (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 H +0 H Br H H H H 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

7 References 1) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc. 1991, 113, ) D.E. Ward, C. K. Rhee, Tetrahedron Letters 1991, 32, S6

8 S7

9 S8

10 S9

11 S10

12 S11

13 S12

14 S13

15 S14

16 S15

17 S16

18 S17

19 O 2 N S18

20 O 2 N S19

21 O 2 N S20

22 Br S21

23 Br S22

24 Br S23

25 Br S24

26 Br S25

27 Br S26

28 S27

29 S28

30 S29

31 MeO S30

32 MeO S31

33 MeO S32

34 O O S33

35 O O S34

36 O O S35

37 O S36

38 O S37

39 O S38

40 N Boc S39

41 N Boc S40

42 N Boc S41

43 S42

44 S43

45 S44

46 S45

47 S46

48 S47

49 Br S48

50 Br S49

51 Br S50

52 S51 (R) and (S)- MPTA esters of 7c