Supplementary Information

Transcript

1 Supplementary Information Dieter Enders, Matthias R. M. Hüttl, Christoph Grondal & Gerhard Raabe Asymmetric rganocatalytic Domino Reactions. Control of Four Stereogenic Centres in a Triple Cascade Content: General.. SI 02 Materials SI 02 General procedure... SI 02 Analytical data.. SI 03 GC measurements SI 09 X-ray data.. SI 10 SI 1

2 General Toluene was freshly distilled from sodium-lead alloy under Ar. Preparative column chromatography: Merck silica gel 60, particle size mm ( mesh, flash). Analytical TLC: silica gel 60 F 254 plates from Merck, Darmstadt. Visualization of the developed chromatograms was performed by ultraviolet irradiation (254 nm) or stained using Mostain ((NH 4 ) 6 Mo 7 24, CeS 4, H 2 S 4, H 2 ). ptical rotation values were measured on a Perkin-Elmer P241 polarimeter. Microanalyses were obtained with a Vario EL element analyser. Mass spectra were acquired on a Finnigan SSQ7000 (EI 70 ev) spectrometer and high resolution mass spectra on a Finnigan MAT 95. IR spectra were taken on a Perkin-Elmer FT-IR H- and 13 C- NMR spectra were recorded on Varian Mercury 300 or Inova 400 with tetramethylsilane as an internal standard and at ambient temperature. Analytical HPLC was performed on Hewlett- Packard 1100 Series chromatographs using chiral stationary phases (Daicel D, Daicel J, Daicel AD, Daicel AS). All racemic samples were obtained according to general procedure by mixing equal amounts of 2 and ent-2 independently obtained by using (S)- and (R)-1. Materials Starting materials A and C were purchased from commercial suppliers and destilled before use. Nitroalkenes B and catalyst 1 were prepared according to standard literature procedures. General procedure R 1 R 2 N 2 ent-2 R 3 Ph N H Ph TMS (R)-1, 20 mol% toluene, 0 C - rt R 1 A R 2 R 3 C + N 2 B Ph N H Ph TMS (S)-1, 20 mol% toluene, 0 C - rt R 1 R 2 N 2 2 R 3 Figure 1 Asymmetric, organocatalytic three component multistep reaction cascade. To a solution of catalyst (S)-1 (65 mg, 0.20 mmol) and nitroolefin B (1.00 mmol, 1.00 eq.) in toluene (0.8 ml) was added subsequently under stirring aldehyde A (1.20 mmol, 1.20 eq.) and α,β-unsaturated aldehyde C (1.05 mmol, 1.05 eq.) at 0 C. After 1 hour the solution was allowed to reach room temperature and stirred until complete conversion of the starting materials (16-24 hours, monitored by GC). The reaction mixture was directly purified by flash column chromatography (Si 2, ethyl acetate/pentane, 1:8 1:6) to afford the product 2 as the pure major diastereomer. All new compounds were fully characterised. SI 2

3 Analytical data N 2 (3S,4S,5R,6R)-3-methyl-5-nitro-4,6-diphenylcyclohex-1-ene carbaldehyde (2a). The title compound was prepared according to the general procedure. The product was obtained as a colourless solid. The e.e. was measured by HPLC using a chiral stationary phase (Daicel D, n-heptane/iso-propanol 95:05) relative to the racemic sample: major isomer 13.6 min., minor isomer 17.3 min. Mp. = 126 C (recrystallised from diethyl ether). [α] 22 D = 52.0 (1.01, CHCl 3 ). IR (KBr) ν 3057, 2815, 2720, 2361, 1693, 1650, 1548, 1494, 1450, 1365, 1163, 761, 702 cm 1. 1 H-NMR (300 MHz, CDCl 3 ) δ 1.23 (d, J = 7.2 Hz, 3H), 2.91 (dd, J = 10.4, 3.5 Hz, 1H), 3.45 (ddq, J = 10.4, 7.2, 1.4 Hz, 1H), 4.48 (s, 1H), 4.86 (s, 1H), 7.0 (m, 2H), (m, 9H), 9.59 (s, 1H) ppm. 13 C-NMR (75 MHz, CDCl 3 ) δ 18.7, 32.2, 43.2, 45.3, 92.4, (2C), (3C), 128.1, (2C), (2C), 136.8, 137.2, 138.8, 156.1, ppm. MS (EI, 70 ev) m/z (%) = 321 (13) [M + ], 274 (75), 259 (20), 245 (35), 231 (45), 215 (20), 183 (17), 167 (30), 115 (34), 105 (48), 91 (100), 77 (17). Anal. calcd. for C 20 H 19 N 3 (321.37) C, 74.75; H, 5.96; N, 4.36 found: C, 74.62; H, 6.22; N, (3S,4S,5R,6R)-4-(2-chlorophenyl)-3-methyl-5-nitro-6- phenylcyclohex-1-ene carbaldehyde (2b). The title compound was prepared according to the general procedure. The product was obtained as a colourless solid and recrystallised from diethyl ether. The e.e. was N Cl 2 measured by HPLC using a chiral stationary phase (Daicel D, n- heptane/iso-propanol 90:10) relative to the racemic sample: major isomer 11.8 min., minor isomer 16.8 min. Mp. = 170 C (recrystallised from diethyl ether). [α] 23 D = (1.03, CHCl 3 ). IR (KBr) ν 3747, 3356, 3063, 3027, 3003, 2974, 2926, 2897, 2852, 2748, 2361, 2336, 1953, 1651, 1547, 1473, 1447, 1413, 1366, 1328, 1279, 1248, 1167, 1120, 1071, 1026, 900, 849, 821, 762, 729, 700 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ = 1.22 (d, J = 7.2 Hz, 3H), 3.45 (m, 1H), 3.59 (dd, J = 10.7, 3.0 Hz, 1H), 4.56 (s, 1H), 4.92 (d, J = 3.0 Hz, 1H), (m, 10H), 9.61 (s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3 ) δ = 18.4, 31.3, 40.7, 43.2, 89.5, 127.2, 127.7, (2C), (3C), 128.9, 129.9, 134.0, 134.4, 136.6, 137.9, 155.4, ppm. MS (EI, 70 ev) m/z (%) = 355 (4, M + ), 311 (21), 310 (43), 309 (82), 308 (100), 307 (27), 279 (24), 230 (21), 229 (19), 228 (19), 183 (23), 165 (23), 125 (37), 115 (26), 114 (11), 105 (13), 91 (59), 77 (11). Anal. calcd. for C 20 H 18 ClN 3 (355.81) C, 67.51; H, 5.10; N, 3.94 found: C, 67.10; H, 5.32; N, SI 3

4 (3S,4S,5R,6R)-4-(4-methoxyphenyl)-3-methyl-5-nitro-6- phenylcyclohex-1-ene carbaldehyde (2c). The title compound was prepared according to the general procedure. The product was obtained as a colourless, waxen solid. The e.e. was N H 2 3 C measured by HPLC using a chiral stationary phase (Daicel AS, n- heptane/iso-propanol 90:10) relative to the racemic sample: major isomer 38.9 min., minor isomer 33.9 min. [α] 23 D = 60.3 (1.07, CHCl 3 ). IR (KBr) ν 3028, 2802, 2707, 1694, 1645, 1547, 1492, 1449, 1364, 1154, 779, 753, 701 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.22 (d, J = 7.1 Hz, 3H), 2.85 (dd, J = 10.2, 3.3 Hz, 1H), 3.45 (ddq, J = 10.2, 7.1, 1.4 Hz, 1H), 3.76 (s, 3H), 4.46 (s, 1H), 4.83 (dd, J = 3.3, 1.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.20 (m, 3H), 7.32 (m, 1H), 7.37 (m, 2H), 9.58 (s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3 ) δ 19.0, 32.7, 43.3, 44.8, 55.4, 92.6, (2C), (3C), (2C), 129.1, (2C), 136.8, 138.8, 156.1, 159.2, ppm. MS (EI, 70 ev) m/z (%) = 352 (23) [M+1], 351 (100) [M + ], 304 (10), 275 (12), 135 (21), 121 (56), 115 (10), 105 (7), 91 (18), 77 (5). Anal. calcd. for C 21 H 21 N 3 (351.40) C, 71.78; H, 6.02; N, 3.99 found: C, 71.40; H, 6.09; N, (3S,4S,5R,6R)-4-(benzo[d][1,3]dioxol-5-yl)-3-methyl-5-nitro-6- phenylcyclohex-1-ene carbaldehyde (2d). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid. The e.e. was measured by HPLC using a N 2 chiral stationary phase (Daicel AD, n-heptane/iso-propanol 95:05) relative to the racemic sample: major isomer 26.4 min., minor isomer 20.3 min. Mp. = 121 C. [α] 22 D = 62.1 (1.00, CHCl 3 ). IR (KBr) ν 3442, 2969, 2900, 1736, 1687, 1651, 1549, 1490, 1446, 1370, 1253, 1167, 1038, 932, 763, 704, 617 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23 (d, J = 7.4 Hz, 3H), 2.82 (dd, J = 10.4, 3.3 Hz, 1H), 3.34 (ddq, J = 10.4, 7.4, 1.4 Hz, 1H), 4.45 (s, 1H), 4.83 (dd, J = 3.3, 1.6 Hz, 1H), 5.92 (s, 2H), 6.44 (dd, J = 8.0, 1.7 Hz, 1H), 6.49 (d, J = 1.7 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 2.8 Hz, 2H), 7.20 (d, J = 1.4 Hz, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 9.58 (s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3 ) δ 18.9, 32.7, 43.4, 45.3, 92.6, 101.3, 107.9, 108.7, 121.3, (2C), 128.1, (2C), 130.9, 136.8, 138.7, 147.3, 148.3, 156.0, ppm. MS (EI, 70 ev) m/z (%) = 366 (22) [M+1], 365 (100) [M + ], 318 (4), 135 (37), 115 (6), 105 (5), 91 (14), 77 (5). Anal. calcd. for C 21 H 19 N 5 (365.38) C, 69.03; H, 5.24; N, 3.83 found: C, 68.95; H, 5.25; N, SI 4

5 (3S,4S,5R,6R)-3-ethyl-5-nitro-4,6-diphenylcyclohex-1-ene carbaldehyde (2e, major diastereomer). The title compound was prepared according to the general procedure. The product was obtained as a colourless oil. The e.e. was measured by HPLC using a chiral N 2 stationary phase (Daicel D, n-heptane/iso-propanol 85:15) relative to the racemic sample: major isomer 6.8 min., minor isomer 8.2 min. [α] 23 D = 53.2 (1.03, CHCl 3 ). IR (CHCl 3 ) ν 3028, 2965, 2933, 1688, 1649, 1549, 1454, 1369, 1166, 1370, 758, 702, 617 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.05 (t, J = 7.4 Hz, 3H), 1.46 (m, 1H), 1.75 (m, 1H), 3.05 (dd, J = 10.4, 3.3 Hz, 1H), 3.34 (m, 1H), 4.46 (s, 1H), 4.87 (dd, J = 3.3, 1.7 Hz, 1H), 7.00 (m, 2H), 7.20 (d, J = 6.9 Hz, 2H), (m, 7H), 9.60 (s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3 ) δ 10.7, 25.0, 38.1, 42.7, 42.9, 92.4, (2C), (3C), 127.9, (2C), (2C), 137.1, 137.5, 138.6, 154.2, ppm. MS (EI, 70 ev) m/z (%) = 336 (10) [M+1], 335 (41) [M + ], 288 (18), 259 (34), 231 (20), 167 (16), 115 (24), 105 (15), 91 (100), 77 (10). HRMS (C 21 H 21 N 3 ): calc.: , found: (3S,4S,5S,6R)-3-ethyl-5-nitro-4,6-diphenylcyclohex-1-ene carbaldehyde (2e, minor diastereomer). The title compound was prepared according to the general procedure. The product was obtained as a colourless oil. [α] 21 D = (0.44, CHCl 3 ). IR (CHCl 3 ) ν 3028, N , 2932, 2361, 1689, 1648, 1552, 1456, 1370, 757, 702, 664 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.07 (t, J = 7.4 Hz, 3H), 1.49 (m, 1H), 1.76 (m, 1H), 3.34 (m, 1H), 3.25 (dd, J = 12.4, 10.2 Hz, 1H), 4.65 (d, J = 5.8 Hz, 1H), 5.28 (dd, J = 12.4, 5.8 Hz, 1H), 7.08 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 7.16 (m, 2H), (m, 6H), 9.52 (s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3 ) δ 10.8, 24.5, 42.5, 42.7, 45.6, 90.0, 127.5, 127.9, 128.2, (2C), (2C), (3C), 135.0, 138.6, 139.1, 151.8, ppm. MS (EI, 70 ev) m/z (%) = 336 (3) [M+1], 335 (11) [M + ], 288 (44), 259 (52), 231 (79), 167 (23), 115 (28), 105 (22), 91 (100), 77 (15). HRMS (C 21 H 21 N 3 ): calc.: , found: CH 3 (3S,4S,5R,6R)-3-isopropyl-5-nitro-4,6-diphenylcyclohex-1-ene carbaldehyde (2f). The title compound was prepared according to the general procedure. The product was obtained as a colourless solid. The e.e. was measured by HPLC using a chiral stationary phase (Daicel D, N 2 SI 5

6 n-heptane/iso-propanol 85:15) relative to the racemic sample: major isomer 6.3 min., minor isomer 8.5 min. Mp. = 143 C. [α] 23 D = 40.4 (1.03, CHCl 3 ). IR (KBr) ν 3065, 3032, 2961, 2814, 1683, 1648, 1547, 1494, 1454, 1365, 1236, 1157, 886, 769, 698 cm 1. 1 H-NMR (300 MHz, CDCl 3 ) δ 0.91 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.85 (dh, J = 6.9, 3.2 Hz, 1H), 3.15 (dd, J = 10.9, 3.5 Hz, 1H) 3.31 (ddd, J = 10.9, 3.2, 2.5 Hz, 1H), 4.45 (s, 1H), 4.90 (dd, J = 3.5, 1.7 Hz, 1H), 6.99 (m, 2H), 7.20 (m, 2H), (m, 6H), 9.62 (s, 1H) ppm. 13 C-NMR (75 MHz, CDCl 3 ) δ 17.3, 21.3, 28.1, 41.5, 42.8, 92.9, (2C), (3C), 128.0, (2C), (3C), 137.4, 138.9, 139.0, 152.2, ppm. MS (EI, 70 ev) m/z (%) = 350 (11) [M+1], 349 (49) [M + ], 302 (23), 259 (43), 231 (52), 167 (33), 115 (31), 105 (21), 91 (100), 77 (13). Anal. calcd. for C 22 H 22 N 3 (349.42) C, 75.62; H, 6.63; N, 4.01 found: C, 75.95; H, 6.74; N, (3S,4S,5R,6R)-3-benzyl-5-nitro-4,6-diphenylcyclohex-1-ene carbaldehyde (2g). The title compound was prepared according to the general procedure. The product was obtained as a colourless solid. The e.e. was measured by HPLC using a chiral stationary phase (Daicel J, n-heptane/iso-propanol 80:20) relative to the racemic sample: major N 2 isomer 14.0 min., minor isomer 24.5 min. Mp. = 175 C (recrystallised from diethyl ether ). [α] 23 D = 13.4 (1.02, CHCl 3 ). IR (KBr) ν 3029, 2802, 2707, 1694, 1645, 1547, 1492, 1449, 1364, 1153, 779, 752, 701 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.68 (dd, J = 13.5, 7.1 Hz, 1H), 3.08 (dd, J = 10.7, 3.3 Hz, 1H), 3.13 (dd, J = 13.7, 4.1 Hz, 1H), 3.76 (m, 1H), 4.37 (s, 1H), 4.79 (dd, J = 3.3, 1.1 Hz, 1H), 6.74 (d, J = 7.1, 2H), (m, 7H), (m, 7H), 9.53 (s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3 ) δ 37.5, 38.3, 41.6, 42.8, 92.5, 126.9, 127.6, (2C), (2C), 128.1, (2C), (2C), (2C), (2C), 136.7, 136.9, 137.7, 138.4, 153.5, ppm. MS (EI, 70 ev) m/z (%) = 397 (5) [M + ], 350 (6), 259 (11), 231 (26), 115 (6), 105 (3), 91 (100), 77 (3). Anal. calcd. for C 26 H 23 N 3 (397.47) C, 78.57; H, 5.83; N, 3.52 found: C, H, 5.92; N, TBS (3S,4S,5R,6R)-3-((tert-butyldimethylsilyloxy)methyl)-5-nitro-4,6- diphenylcyclohex-1-ene carbaldehyde (2h). The title compound was prepared according to the general procedure. The product was obtained N 2 as a colourless oil. The e.e. was measured by HPLC using a chiral stationary phase (Daicel IA, n-heptane/iso-propanol 95:05) relative to the racemic sample: major isomer 10.8 min., minor isomer 14.9 min. [α] 22 D = 25.5 (1.48, CHCl 3 ). IR SI 6

7 (CHCl 3 ) ν 3062, 3031, 2953, 2930, 2857, 2818, 2739, 1682, 1626, 1549, 1453, 1368, 1254, 1122, 972, 838, 777, 751, 701 cm 1. 1 H-NMR (300 MHz, CDCl 3 ) δ 0.07 (s, 3H), 0.12 (s, 3H), 1.02 (s, 9H), 3.55 (m, 1H), 3.65 (dd, J = 6.7, 3.2 Hz, 1H), 3.70 (dd, J = 9.9, 3.7 Hz, 1H), 4.08 (dd, J = 9.9, 2.7 Hz, 1H), 4.55 (s br, 1H), 5.01 (dd, J = 3.2, 1.2 Hz, 1H), 7.11 (m, 2H), (m, 9H), 9.70 (s, 1H) ppm. 13 C-NMR (75 MHz, CDCl 3 ) δ -5.7, -5.6, 18.4, 25.9 (3C), 38.8, 40.5, 43.2, 63.2, 92.5, (2C), 128.2, (2C), (3C), (2C), 136.9, (2C), 154.0, ppm. MS (EI, 70 ev) m/z (%) = 394 (74) [M + C 4 H 9 ], 364 (100), 347 (43), 334 (25), 243 (36), 232 (44), 167 (38), 115 (22), 91 (43), 77 (19). HRMS (C 26 H 33 N 4 Si C 4 H 9 ): calc.: , found: (3S,4S,5S)-3-methyl-5-nitro-4-phenylcyclohex-1-ene carbaldehyde (2i). The title compound was prepared according to the general procedure. The product was obtained as a colourless solid. The e.e. was measured by HPLC using a chiral stationary phase (Daicel AS, n-heptane/iso-propanol 80:20) N 2 relative to the racemic sample: major isomer 25.4 min., minor isomer 21.8 min. Mp. = 94 C. [α] 22 D = (1.02, CHCl 3 ). IR (CHCl 3 ) ν 3026, 2970, 2361, 1685, 1550, 1455, 1375, 1218, 1171, 758, 703, 668 cm 1. 1 H-NMR (300 MHz, CDCl 3 ) δ 1.23 (d, J = 7.0 Hz, 3H), 2.81 (m, 2H), 3.15 (dd, J = 7.2, 3.7 Hz, 1H), 3.23 (m, 1H), 4.93 (ddd, J = 10.9, 5.4, 4.0 Hz, 1H), 6.91 (m, 1H), 7.09 (m, 2H), 7.31 (m, 3H), 9.57 (s, 1H) ppm. 13 C-NMR (75 MHz, CDCl 3 ) δ 19.6, 24.6, 33.9, 49.4, 83.7, (2C), 128.2, (2C), 135.8, 137.5, 154.0, ppm. MS (EI, 70 ev) m/z (%) = 245 (6) [M + ], 198 (15), 197 (19), 169 (56), 155 (30), 115 (22), 105 (29), 91 (100), 77 (21). HRMS (C 14 H 15 N 3 ): calc.: , found: (3S,4S,5S,6R)-3,6-dimethyl-5-nitro-4-phenylcyclohex-1-ene carbaldehyde (2j). The title compound was prepared according to the general procedure. The product was obtained as a light yellow oil. The e.e. CH 3 was measured by HPLC using a chiral stationary phase (Daicel J, n- N 2 heptane/iso-propanol 90:10) relative to the racemic sample: major isomer 20.7 min., minor isomer 26.7 min. [α] 22 D = (1.50, CHCl 3 ). IR (CHCl 3 ) ν 3025, 2972, 1686, 1549, 1454, 1372, 1171, 757, 701 cm 1. 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33 (d, J = 7.1 Hz, 3H), 1.53 (d, J = 7.2 Hz, 3H), 3.13 (dd, J = 10.4, 3.3 Hz, 1H) 3.45 (m, 1H), 3.54 (m, 1H), 4.92 (dd, J = 3.3, 1.1 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.36 (m, 2H), 7.54 (m, 3H), 9.72 (s, 1H) ppm. 13 C-NMR SI 7

8 (100 MHz, CDCl 3 ) δ 18.7, 19.8, 32.2, 32.3, 46.2, 91.6, (2C), 128.0, (2C), 137.3, 140.1, 154.5, ppm. MS (EI, 70 ev) m/z (%) = 259 (9) [M + ], 211 (27), 197 (26), 183 (72), 169 (92), 115 (20), 105 (64), 91 (100), 77 (20). HRMS (C 15 H 17 N 3 ): calc.: , found: (3S,4S,5S,6R)-6-butyl-3-methyl-5-nitro-4-phenylcyclohex-1-ene carbaldehyde (2k). The title compound was prepared according to CH the general procedure. The product was obtained as a light yellow 3 oil. The e.e. was measured by HPLC using a chiral stationary N 2 phase (Daicel J, n-heptane/iso-propanol 99:01) relative to the racemic sample: major isomer 23.3 min., minor isomer 28.4 min. [α] 22 D = (1.60, CHCl 3 ). IR (film) ν 3062, 3031, 2959, 2871, 2725, 1687, 1648, 1549, 1455, 1372, 1255, 1169, 1072, 877, 753, 702 cm 1. 1 H-NMR (300 MHz, CDCl 3 ) δ 1.14 (t, J = 7.1 Hz, 3H), 1.32 (d, J = 7.1 Hz, 3H), (m, 5H), 2.00 (m, 1H), 3.08 (dd, J = 10.4, 3.0 Hz, 1H), 3.28 (d, J = 7.7 Hz, 1H), 3.58 (m, 1H), 5.05 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 7.7 Hz, 2H), 7.55 (m, 3H), 9.71 (s, 1H) ppm. 13 C-NMR (75 MHz, CDCl 3 ) δ 13.9, 18.7, 22.3, 29.7, 32.1, 33.4, 37.6, 46.4, 88.9, (2C), 128.1, (2C), 137.6, 139.7, 155.0, ppm. MS (EI, 70 ev) m/z (%) = 301 (3) [M + ], 271 (4), 253 (19), 211 (29), 197 (33), 169 (100), 115 (14), 105 (43), 91 (75), 77 (14). HRMS (C 18 H 23 N 3 ): calc.: , found: (3S,4R,5S,6R)-3-methyl-4-(5-methylfuran-2-yl)-5-nitro-6- phenylcyclohex-1-ene carbaldehyde (2l). The title compound was prepared according to the general procedure. The product was obtained as a light yellow oil. The e.e. was measured by HPLC using a N 2 H chiral stationary phase (Daicel AD, n-heptane/iso-propanol 95:05) 3 C relative to the racemic sample: major isomer 8.7 min., minor isomer 11.5 min. [α] 22 D = (2.04, CHCl 3 ). IR (CHCl 3 ) ν 2969, 2926, 1689, 1653, 1551, 1453, 1368, 1219, 1166, 1071, 1025, 758, 703 cm 1. 1 H-NMR (300 MHz, CDCl 3 ) δ 1.37 (d, J = 7.2 Hz, 3H), 2.16 (d, J = 1.0 Hz, 3H), 3.01 (dd, J = 10.1, 3.5 Hz, 1H), 3.28 (m, 1H), 4.51 (s br, 1H), 5.03 (dd, J = 3.5, 1.7 Hz, 1H), 5.87 (m, 1H), 6.00 (d, J = 3.0 Hz, 1H), 7.12 (d, J = 3.0 Hz, 1H), 7.20 (m, 2H), 7.35 (m, 3H), 9.55 (s, 1H) ppm. 13 C-NMR (75 MHz, CDCl 3 ) δ 13.4, 19.0, 32.2, 39.3, 42.5, 89.5, 106.4, 108.2, (2C), 129.2, 136.6, 138.3, 149.2, 151.9, 155.2, ppm. MS (EI, 70 ev) SI 8

9 m/z (%) = 325 (11) [M + ], 199 (14), 197 (28), 179 (16), 169 (62), 115 (11), 97 (100), 95 (23), 91 (21), 77 (8). HRMS (C 19 H 19 N 4 ): calc.: , found: GC measurements of the reaction course conversion [%] adduct 3a product 2a time [h] Figure 2 Formation of 2a and 3a as a mixture of diastereomers (s. d. ±2%). The graphic shows the time dependend formation of 2a and 3a monitored by GC, indicating the trend of the reaction. SI 9

10 X-ray data of compound 2b Figure 3 Crystal structure of compound 2b (left: SCHAKAL, right: RTEP plot). Chemical formula : C 20 H 18 ClN 3 formula weight : Crystal system : monoclinic Space group (No.) : P21 (4) Z : 2 a (Å) : 8.070(2) b (Å) : 8.323(2) c (Å) : (4) α ( ) : 90.0 β ( ) : 99.51(1) γ ( ) : 90.0 cell volume : 922.4(4)Å 3 Density calc. : 1.281g/cm 3 Radiation : CuK α ( Å) Range for lattice parameters : 8.70 <Θ <20.89 Absorption coefficient : 1.981mm -1 Temperature : 298K Crystal source : recrystallized from dichloromethane Crystal colour : colourless Crystal shape : rod-like Crystal size : ca.0.2x0.2x0.5mm Data Collection SI 10

11 Diffractometer type : Enraf Nonius CAD4 collection method : w/2θ Absorption correction : none No. of reflections measured : 3885 No. of independent reflections: 3474 No. of observed reflections : 2808 Θ max ( ) : h min h max : -9 9 k min k max : l min l max : Criterion for observed : I > 2σ (I) Rint : 0.029(34) Standard reflections : 1 2 2; 1 2 3; Variation : 10427(249) 1665(54) 6956(198) Refinement: n : F Treatment of hydrogens : Located in part. Rest calculated in idealized positions. Us fixed at 1.5 U of the corresponding heavy atom. No refinement of hydrogen parameters R : R w : Weighting scheme : w=1/[7.85 σ 2 (F)] No. of parameters refined : 226 No. of reflections in refmnt. : 2806 Residual electron density : -0.37/0.42e/Å 3 r* [1] : not refined XABS [2] : -0.02(6) a) Goodness of fit : Solution : XTAL3.7 [3] Remarks : a) From separate calculation SI 11

12 Definitions: U eq = 1/3Σ i Σ j U ij a i *a j *a i a j The anisotropic displacement factor in the structure factor expression is: t = exp[ 2π 2 (Σ i Σ j U ij h i h j a i *a j *)] Literature: [1] a) A.C. Larson; Crystallographic Computing. F.R. Ahmed, S.R. Hall, C.P. Huber, eds., Munksgaard, Copenhagen, , (1970); b) W.H. Zachariasen, Acta Cryst. 23, (1967). [2] H.D. Flack; Acta Cryst. A39, (1983). [3] S.R. Hall, D.J. du Boulay & R.lthof-Hazekamp, Eds. XTAL3.7 System, University of Western Australia, Perth (2000). SI 12

13 Atomic Positional and Isotropic Displacement Parameters Atom x/a y/b z/c U eq /Å Cl (2) 0.311(2) (1) * 0.096(1) (4) 0.772(2) (3) * 0.076(3) (5) 0.425(2) (3) * 0.113(4) (7) 0.544(2) (6) * 0.195(7) N (6) 0.480(2) (4) * 0.071(3) C (5) 0.477(2) (3) * 0.044(2) C (5) 0.595(2) (3) * 0.040(2) C (6) 0.523(2) (3) * 0.044(3) C (6) 0.364(2) (4) * 0.056(3) C (6) 0.238(2) (4) * 0.057(3) C (5) 0.305(2) (3) * 0.041(2) C (5) 0.191(2) (3) * 0.044(3) C (6) 0.087(2) (4) * 0.064(3) C (7) (2) (5) * 0.081(4) C (8) (2) (6) * 0.084(5) C (8) 0.078(2) (4) * 0.078(4) C (6) 0.184(2) (4) * 0.058(3) C (6) 0.650(2) (3) * 0.044(3) C (7) 0.757(2) (4) * 0.067(4) C (1) 0.806(2) (5) * 0.091(5) C (1) 0.751(2) (4) * 0.092(5) C (8) 0.648(2) (4) * 0.079(4) C (6) 0.595(2) (4) * 0.059(3) C (6) 0.627(2) (4) * 0.059(3) C (1) 0.109(2) (7) * 0.118(7) H (-) (-) (-) 0.060(-) H (-) (-) (-) 0.065(-) H (-) (-) (-) 0.099(-) H (-) (-) (-) 0.138(-) H (-) (-) (-) 0.140(-) H (-) (-) (-) 0.119(-) H (-) (-) (-) 0.089(-) H (-) (-) (-) 0.095(-) H (-) (-) (-) 0.119(-) H (-) (-) (-) 0.125(-) H (-) (-) (-) 0.115(-) H (-) (-) (-) 0.060(-) H (-) (-) (-) 0.085(-) H (-) (-) (-) 0.085(-) H (-) (-) (-) 0.086(-) H20a (-) (-) (-) 0.174(-) H20b (-) (-) (-) 0.174(-) H20c (-) (-) (-) 0.174(-) SI 13

14 Atomic Displacement Parameters Atom U 11 U 22 U 33 U 12 U 13 U Cl 0.110(1) 0.123(1) (8) (1) (8) (1) (2) 0.060(3) 0.103(3) (2) 0.035(2) 0.012(2) (3) 0.180(6) 0.068(3) (4) (2) 0.010(3) (3) 0.229(9) 0.252(8) 0.075(4) (4) (7) N 0.044(2) 0.069(3) 0.093(4) (2) (3) 0.003(3) C (2) 0.039(3) 0.054(3) 0.001(2) 0.012(2) 0.003(2) C (2) 0.031(2) 0.047(2) 0.002(2) 0.016(2) 0.004(2) C (2) 0.037(3) 0.053(3) (2) 0.019(2) (2) C (3) 0.054(3) 0.065(3) (3) 0.029(2) (3) C (3) 0.038(3) 0.075(3) (2) 0.035(3) (2) C (2) 0.037(2) 0.044(2) (2) 0.011(2) (2) C (2) 0.044(3) 0.044(2) (2) 0.004(2) 0.004(2) C (3) 0.054(3) 0.076(4) (3) 0.012(3) 0.002(3) C (3) 0.063(4) 0.116(5) (3) 0.003(3) 0.002(4) C (4) 0.065(4) 0.122(6) (3) 0.025(4) 0.029(4) C (4) 0.085(5) 0.082(4) (4) 0.029(3) 0.022(4) C (3) 0.060(3) 0.060(3) (3) 0.013(2) 0.011(3) C (3) 0.031(2) 0.050(2) (2) 0.016(2) 0.003(2) C (3) 0.057(4) 0.073(4) (3) 0.031(3) (3) C (6) 0.080(4) 0.073(4) (5) 0.042(4) (4) C (6) 0.097(6) 0.056(4) (5) 0.005(4) (3) C (4) 0.077(4) 0.062(4) (4) (3) 0.014(3) C (3) 0.047(3) 0.066(3) (3) 0.004(3) 0.005(3) C (3) 0.055(4) 0.070(3) (3) 0.024(3) 0.006(3) C (6) 0.055(4) 0.204(8) 0.041(4) 0.106(6) 0.036(5) H (-) 0.060(-) 0.060(-) 0.000(-) 0.010(-) 0.000(-) H (-) 0.065(-) 0.065(-) 0.000(-) 0.011(-) 0.000(-) H (-) 0.099(-) 0.099(-) 0.000(-) 0.016(-) 0.000(-) H (-) 0.138(-) 0.138(-) 0.000(-) 0.023(-) 0.000(-) H (-) 0.140(-) 0.140(-) 0.000(-) 0.023(-) 0.000(-) H (-) 0.119(-) 0.119(-) 0.000(-) 0.020(-) 0.000(-) H (-) 0.089(-) 0.089(-) 0.000(-) 0.015(-) 0.000(-) H (-) 0.095(-) 0.095(-) 0.000(-) 0.016(-) 0.000(-) H (-) 0.119(-) 0.119(-) 0.000(-) 0.020(-) 0.000(-) H (-) 0.125(-) 0.125(-) 0.000(-) 0.021(-) 0.000(-) H (-) 0.115(-) 0.115(-) 0.000(-) 0.019(-) 0.000(-) H (-) 0.060(-) 0.060(-) 0.000(-) 0.010(-) 0.000(-) H (-) 0.085(-) 0.085(-) 0.000(-) 0.014(-) 0.000(-) H (-) 0.085(-) 0.085(-) 0.000(-) 0.014(-) 0.000(-) H (-) 0.086(-) 0.086(-) 0.000(-) 0.014(-) 0.000(-) H20a 0.174(-) 0.174(-) 0.174(-) 0.000(-) 0.029(-) 0.000(-) H20b 0.174(-) 0.174(-) 0.174(-) 0.000(-) 0.029(-) 0.000(-) H20c 0.174(-) 0.174(-) 0.174(-) 0.000(-) 0.029(-) 0.000(-) SI 14

15 Bond Distances (Angstroms) Cl-C (2) C6-H (4) C6-C7 1.51(2) C6-C5 1.53(1) C6-C1 1.55(2) 1-C (3) C7-C8 1.38(2) C7-C (7) C13-C (1) C13-C (2) C13-C (9) C4-H4.962(8) C4-C3 1.34(3) C4-C5 1.49(2) C20-H20b.94(2) C20-H20c.95(1) C20-H20a.98(1) C20-C5 1.53(2) C11-H11.972(6) C11-C (2) C11-C (2) C19-H19.965(9) C19-C3 1.45(2) C8-H8.959(6) C8-C9 1.39(2) C9-H9.99(1) C9-C (1) C10-H10.96(1) C5-H5.971(9) C3-C2 1.50(1) N (1) N (1) N-C (6) C18-H18.98(1) C18-C (1) C1-H (8) C1-C2 1.55(2) C15-H15.97(1) C15-C (1) C15-C (1) C17-H17.985(9) C17-C (2) C14-H14.982(8) C2-H2.96(1) C16-H16.982(8) SI 15

16 Bond Angles (degrees) H6-C6-C (7) H6-C6-C (5) H6-C6-C1 104(1) C7-C6-C5 114(1) C7-C6-C (7) C5-C6-C (9) C8-C7-C12 116(1) C8-C7-C (6) C12-C7-C6 121(1) C18-C13-C (7) C18-C13-C2 122(1) C14-C13-C (7) H4-C4-C3 117(1) H4-C4-C5 118(2) C3-C4-C (8) H20b-C20-H20c 111(2) H20b-C20-H20a 107.7(9) H20b-C20-C (8) H20c-C20-H20a 106.9(8) H20c-C20-C (9) H20a-C20-C5 109(2) H11-C11-C10 120(1) H11-C11-C12 122(1) C10-C11-C (7) H19-C (1) H19-C19-C3 118(2) 1-C19-C (9) H8-C8-C7 119(1) H8-C8-C9 119(1) C7-C8-C (7) H9-C9-C10 121(1) H9-C9-C (8) C10-C9-C8 119(1) H10-C10-C (9) H10-C10-C9 120(1) C11-C10-C9 121(1) C7-C12-C11 123(1) C7-C12-Cl 120(1) C11-C12-Cl 117.0(6) H5-C5-C (7) H5-C5-C (5) H5-C5-C20 109(2) C4-C5-C6 113(1) C4-C5-C (7) C6-C5-C (7) C4-C3-C (9) C4-C3-C2 123(1) C19-C3-C2 119(1) 3-N (7) 3-N-C (9) 2-N-C (8) H18-C18-C (7) H18-C18-C (7) C13-C18-C17 120(1) H1-C1-N 110.8(6) H1-C1-C (9) SI 16

17 H1-C1-C2 103(1) N-C1-C6 112(1) N-C1-C (9) C6-C1-C (7) H15-C15-C (8) H15-C15-C (9) C16-C15-C14 121(1) H17-C17-C (8) H17-C17-C18 118(1) C16-C17-C (8) H14-C14-C15 123(1) H14-C14-C (7) C15-C14-C (8) H2-C2-C (7) H2-C2-C13 106(1) H2-C2-C (6) C3-C2-C (4) C3-C2-C1 111(1) C13-C2-C (6) H16-C16-C (9) H16-C16-C15 124(1) C17-C16-C (8) Dihedral Angles (degrees) C5-C6-C7-C8-32(2) C5-C6-C7-C12 146(1) C1-C6-C7-C8 99(1) C1-C6-C7-C12-83(1) H6-C6-C7-C8-148(1) H6-C6-C7-C12 30(2) C7-C6-C5-C (6) C7-C6-C5-C20-74(1) C7-C6-C5-H5 44(2) C1-C6-C5-C4 33.9(7) C1-C6-C5-C (9) C1-C6-C5-H5-86(2) H6-C6-C5-C4-80(1) H6-C6-C5-C20 42(2) H6-C6-C5-H5 160(1) C7-C6-C1-N -62.1(6) C7-C6-C1-C (5) C7-C6-C1-H1 61.5(8) C5-C6-C1-N 68.6(8) C5-C6-C1-C2-54.0(8) C5-C6-C1-H (7) H6-C6-C1-N (4) H6-C6-C1-C2 61.3(5) H6-C6-C1-H1-52.5(7) C6-C7-C8-C9 179(1) C6-C7-C8-H8-2(2) C12-C7-C8-C9 0(2) C12-C7-C8-H8 179(1) C6-C7-C12-Cl 2(2) SI 17

18 C6-C7-C12-C11-178(1) C8-C7-C12-Cl -180(1) C8-C7-C12-C11 0(2) C14-C13-C18-C17 0(2) C14-C13-C18-H18-177(1) C2-C13-C18-C17-179(1) C2-C13-C18-H18 3(2) C18-C13-C14-C15 0(2) C18-C13-C14-H14 178(1) C2-C13-C14-C15 179(1) C2-C13-C14-H14-2(2) C18-C13-C2-C3-19(2) C18-C13-C2-C1 106(1) C18-C13-C2-H2-137(1) C14-C13-C2-C3 162(1) C14-C13-C2-C1-73(2) C14-C13-C2-H2 43(1) C3-C4-C5-C6-7.2(7) C3-C4-C5-C (9) C3-C4-C5-H5 113(1) H4-C4-C5-C (4) H4-C4-C5-C (9) H4-C4-C5-H5-68(1) C5-C4-C3-C (4) C5-C4-C3-C2.4(7) H4-C4-C3-C19 -.7(7) H4-C4-C3-C (4) H20a-C20-C5-C6-93(1) H20a-C20-C5-C4 31(1) H20a-C20-C5-H (8) H20b-C20-C5-C6 149(1) H20b-C20-C5-C4-87(1) H20b-C20-C5-H5 30(1) H20c-C20-C5-C6 25(2) H20c-C20-C5-C4 149(1) H20c-C20-C5-H5-93(1) C12-C11-C10-C9 0(2) C12-C11-C10-H10 179(1) H11-C11-C10-C9 179(1) H11-C11-C10-H10-3(2) C10-C11-C12-Cl 179(1) C10-C11-C12-C7 0(2) H11-C11-C12-Cl 0(2) H11-C11-C12-C7-179(1) 1-C19-C3-C (5) 1-C19-C3-C2 1.8(7) H19-C19-C3-C4 8.5(8) H19-C19-C3-C (5) C7-C8-C9-C10 0(2) C7-C8-C9-H9 179(1) H8-C8-C9-C10-179(1) H8-C8-C9-H9 0(2) C8-C9-C10-C11 0(2) C8-C9-C10-H10-178(1) H9-C9-C10-C11-180(1) H9-C9-C10-H10 3(2) C4-C3-C2-C13 104(1) C4-C3-C2-C1-20.1(8) SI 18

19 C4-C3-C2-H (9) C19-C3-C2-C13-75(1) C19-C3-C2-C (6) C19-C3-C2-H2 43.3(9) 3-N-C1-C6 129(2) 3-N-C1-C2-107(2) 3-N-C1-H1 6(2) 2-N-C1-C6-53(2) 2-N-C1-C2 71(2) 2-N-C1-H1-177(2) C13-C18-C17-C16 0(2) C13-C18-C17-H17 177(1) H18-C18-C17-C16 178(1) H18-C18-C17-H17-6(2) C6-C1-C2-C13-82(1) C6-C1-C2-C3 45.3(6) C6-C1-C2-H (6) N-C1-C2-C13 154(1) N-C1-C2-C3-79(1) N-C1-C2-H2 39(1) H1-C1-C2-C13 36(1) H1-C1-C2-C (8) H1-C1-C2-H2-78.9(8) C16-C15-C14-C13 0(2) C16-C15-C14-H14-178(1) H15-C15-C14-C13-178(1) H15-C15-C14-H14 3(3) C14-C15-C16-C17 0(2) C14-C15-C16-H16 179(2) H15-C15-C16-C17 179(2) H15-C15-C16-H16-3(3) C18-C17-C16-C15 0(2) C18-C17-C16-H16-179(1) H17-C17-C16-C15-177(1) H17-C17-C16-H16 4(2) SI 19