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Supporting Information
An Organocatalytic Asymmetric Double Michael Cascade Reaction of Unsaturated Ketones and Unsaturated Pyrazolones: Highly Efficient Synthesis of Spiropyrazolones Derivatives Jinyan Liang, a Qiao Chen, a Luping Liu, a Xianxing Jiang, a and Rui Wang*a,b a
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Life Sciences, School of Basic Medical Sciences, School of Pharmacy, State Key Laboratory of Applied Organic Chemistry and Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou, 730000, China, and bState Key Laboratory of Chiroscience and Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong E-mail:
[email protected]
Contents
S1
1 Supplementary Methods for Procedure of the Synthesis
S2
2 General Procedures for Synthesis of chiral Spiropyrazolones 5 and 5’
S2
3 Characterization of Products
S3
4 References
S22
5 X-Ray Structure of 5s
S22
6 Copies of HPLC spectra of racemic /chiral products
S23
7 Copies of NMR spectra of products
S56
S1
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1 Supplementary Methods for Procedure of the Synthesis: All reactions were carried out under an air atmosphere condition unless otherwise noted and solvents were dried according to established procedures. Reactions were monitored by thin layer chromatography (TLC), column chromatography purifications were carried out using silica gel GF254. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on Brucker 300 MHz spectrometer in CDCl3 unless otherwise noted and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on Brucker 300 MHz spectrometer in CDCl3 unless otherwise noted. Data are presented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, cm = complex multiplet) and coupling constant in Hertz (Hz). Infrared (IR) spectra were recorded on a FT-IR spectrometer. HR-MS was measured with an APEX II 47e mass spectrometer. The ee values determination was carried out using chiral high-performance liquid chromatography (HPLC) with Daicel Chirapak column on Waters with a 2996 UV-detector. 2 General Procedures for Synthesis of chiral Spiropyrazolones 5 and 5’
To a stirred solution of catalyst 1a (0.02 mmol, 0.2 equiv) and ,-unsaturated ketones 3 (0.2 mmol, 2.0 equiv) in Toluene (1.0 ml) at 40 oC was added unsaturated pyrazolones 2[1], [2] (0.1 mmol, 1.0 equiv) and BzOH (0.04 mmol, 0.4 equiv). The mixture was stirred for 3-24h until unsaturated pyrazolones 2 was consumed monitoring by TLC. The solvent was evaporated and the crude product was directly charged on a flash chromatography (ethyl acetate/petroleum ether 5:1 -3:1) to afford the desired products 5 as white solid. The enantiomeric purity of the product was determined by using HPLC. The enantiomers 5’ of compound 5 was obtained using the same steps while catalyst 1a’s pseudoenantiomer 1b was employed during the reaction process. S2
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3 Characterization of Products
(6S,10S)-4-methyl-2,6,10-triphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
white solid. m.p.79 – 80 oC, ee was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/ Hexane = 30/70, 1.0 mL/min.) Retention time: tmajor =4.98 min, tminor =7.21 min, 1
H NMR (300 MHz, CDCl3): δ = 7.48 – 7.45 (m, 2H), 7.34 – 7.29 (m, 5H), 7.21 – 7.11 (m, 8H),
3.94 – 3.83 (m, 2H), 3.66 (dd, J = 14.3, 3.0 Hz, 1H), 3.37 (dd, J = 16.4, 5.1 Hz, 1H), 2.98 (dd, J = 16.4, 9.5 Hz, 1H), 2.66 (dd, J = 16.1, 2.9 Hz, 1H), 1.67 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.37, 174.81, 160.60, 138.50, 137.11, 136.53, 128.96, 128.75,
128.62, 128.12, 128.09, 127.72, 127.67, 125.65, 119.82, 61.82, 44.16, 42.42, 41.27, 40.56, 15.70; IR: 3425, 2956, 2924, 2854, 1699, 1457, 1262, 1099, 1026, 803cm -1; HRMS ( ESI): [C27H24N2O2+H]+, Calc: 409.1911, Found: 409.1916; []D25 = - 49 (c = 1.0, CHCl3). (6S,10S)-4-methyl-2-phenyl-6,10-di-p-tolyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N Me
O
O
5b
white solid. m.p.90 –92 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.53 – 7.50 (m, 2H), 7.34 (dd, J = 10.7, 5.1 Hz, 2H), 7.22 – 7.09
(m, 3H), 7.04 – 6.97 (m, 6H), 3.90 – 3.80 (m, 2H), 3.63 (dd, J = 14.3, 3.1 Hz, 1H), 3.39 (dd, J = 16.3, 5.3 Hz, 1H), 2.91 (dd, J = 16.3, 8.8 Hz, 1H), 2.62 (dd, J = 16.0, 3.0 Hz, 1H), 2.32 (s, 3H), 2.20 (s, 3H), 1.63 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.69, 174.98, 161.00, 137.80, 137.78, 137.25, 135.64, 133.74,
129.58, 129.29, 128.73, 127.63, 127.53, 125.55, 119.81, 61.78, 44.11, 42.12, 41.62, 40.77, 21.06, 20.95, 15.77. S3
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IR: 2924, 2854, 1700, 1597, 1499, 1460, 1368, 818, 740cm -1; HRMS ( ESI): [C29H28N2O2+H]+, Calc: 437.2224, Found: 437.2226; []D25 = - 62 (c = 1.0, CHCl3). (6S,10S)-6,10-bis(4-fluorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
white solid. m.p.125 –126 oC; 1
H NMR (300 MHz, CDCl3): δ =7.45 (dt, J = 8.8, 1.8 Hz, 2H), 7.35 – 7.30 (m, 2H), 7.20 –
7.05(m, 5H), 7.01 (dt, J = 8.7, 2.4 Hz, 2H), 6.93 – 6.87 (m, 2H), 3.96 – 3.76 (m, 2H), 3.61 (dd, J = 14.4, 2.9 Hz, 1H), 3.28 (dd, J = 16.5, 4.8 Hz, 1H), 2.98 (dd, J = 16.5, 10.4 Hz, 1H), 2.62 (dd, J = 16.1, 2.9 Hz, 1H), 1.76 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.61, 174.56, 163.92, 160.64, 160.11, 136.87, 134.01, 133.96,
132.08, 132.03, 129.45, 129.34, 129.14, 129.03, 128.84, 125.84, 119.62, 116.08, 115.80, 115.72, 115.43, 61.99, 43.11, 41.58, 41.09, 40.51, 15.72; IR: 3379, 3048, 2925, 2854, 1700, 1600, 1510, 1461, 1371, 1232, 840, 741cm -1; HRMS ( ESI): [C27H22F2N2O2+H]+, Calc: 445.1722, Found: 445.1725; []D25 = - 47 (c = 1.0, CHCl3). (6S,10S)-6,10-bis(4-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
white solid. m.p.78 – 79 oC 1
H NMR (300 MHz, CDCl3): δ = 7.45 (dd, J = 8.6, 1.0 Hz, 2H), 7.34 – 7.27 (m, 4H), 7.21 – 7.17
(m, 3H), 7.06 (dd, J = 8.5, 6.8 Hz, 4H), 3.94 – 3.77 (m, 2H), 3.59 (dd, J = 14.3, 2.9 Hz, 1H), 3.29 (dd, J = 16.5, 4.8 Hz, 1H), 2.96 (dd, J = 16.5, 10.2 Hz, 1H), 2.62 (dd, J = 16.2, 2.9 Hz, 1H), 1.75 (s, 3H);
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13
C NMR (75 MHz, CDCl3): δ = 208.34, 174.40, 159.92, 136.79, 136.62, 134.70, 134.12, 129.16,
129.06, 128.87, 128.84, 128.82, 125.93, 119.68, 61.68, 43.30, 41.74, 40.91, 40.31, 15.78; IR: 3431, 2924, 2854, 1670, 1495, 1461, 1374, 1093, 821,756cm -1; HRMS ( ESI): [C27H22Cl2N2O2+H]+, Calc: 477.1131, Found: 477.1141; []D25 = - 87 (c = 1.0, CHCl3). (6S,10S)-6,10-bis(4-bromophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
white solid. m.p. 139 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 7.8, 4.5 Hz, 4H), 7.37 – 7.32 (m, 4H), 7.19 (t, J =
7.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 4H), 3.91 – 3.76 (m, 2H), 3.58 (dd, J = 14.3, 2.6 Hz, 1H), 3.28 (dd, J = 16.5, 4.7 Hz, 1H), 2.95 (dd, J = 16.5, 10.2 Hz, 1H), 2.60 (dd, J = 16.1, 2.6 Hz, 1H), 1.74 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.24, 174.38, 159.89, 137.16, 136.80, 135.25, 132.12, 131.80,
129.39, 129.17, 128.89, 125.96, 122.28, 122.23, 119.72, 61.54, 43.37, 41.82, 40.85, 40.25, 15.81; IR: 3381, 3049, 2925, 2854, 1721, 1700, 1493, 1461, 1370, 1009, 821, 740cm -1; HRMS ( ESI): [C27H22Br2N2O2+H]+, Calc: 565.0121, Found: 565.0120; []D25 = - 90 (c = 1.0, CHCl3). (6S,10S)-6,10-bis(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dion e
white solid. m.p.98 –100 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.52 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.17 (t, J = 7.4
Hz, 1H), 7.05 (dd, J = 8.6, 7.2 Hz, 4H), 6.83 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 3.89 –
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3.82 (m, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.61 (dd, J = 14.3, 3.0 Hz, 1H), 3.37 (dd, J = 16.3, 5.2 Hz, 1H), 2.91 (dd, J = 16.3, 9.1 Hz, 1H), 2.61 (dd, J = 16.0, 2.9 Hz, 1H), 1.67 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.70, 175.00, 161.03, 159.15, 159.13, 137.21, 130.62, 128.76,
128.71, 125.56, 119.74, 114.19, 113.95, 62.02, 55.27, 55.18, 43.61, 41.70, 40.88, 15.77; IR: 2954, 2925, 2854, 1718, 1700, 1513, 1462, 1257, 1182, 1032, 738cm -1; HRMS ( ESI): [C29H28N2O4+H]+, Calc: 469.2122, Found: 469.2127; []D25 = - 82 (c = 1.0, CHCl3). (6S,10S)-6,10-bis(3-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N Me
O
Cl Cl O
5g
white solid. m.p.65 –66 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.46 (dd, J = 8.5, 0.9 Hz, 2H), 7.36 – 7.27 (m, 3H), 7.24 – 7.11
(m, 6H), 7.05 – 6.98 (m, 2H), 3.94 – 3.77 (m, 2H), 3.59 (dd, J = 14.3, 2.9 Hz, 1H), 3.29 (dd, J = 16.5, 4.8 Hz, 1H), 2.97 (dd, J = 16.5, 10.3 Hz, 1H), 2.63 (dd, J = 16.2, 2.8 Hz, 1H), 1.76 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.01, 174.32, 159.77, 140.16, 138.18, 136.75, 134.94, 134.45,
130.31, 129.95, 128.85, 128.49, 128.42, 128.02, 127.66, 126.00, 125.89, 125.66, 120.00, 61.53, 43.43, 42.05, 40.72, 40.13, 15.75; IR: 3314, 3062, 2955, 2925, 2855, 1721, 1699, 1596, 1499, 740, 693cm -1; HRMS ( ESI): [C27H22Cl2N2O2+H]+, Calc: 477.1131, Found: 477.1133; []D25 = - 65 (c = 1.0, CHCl3). (6S,10S)-6,10-bis(3-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dion e Ph N
N Me
O
OMe MeO O
5h
white solid. m.p.121 –123 oC;
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1
H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.23 – 7.08 (m,
3H), 6.82 (dd, J = 8.2, 2.1 Hz, 1H), 6.70 (dd, J = 8.6, 6.1 Hz, 4H), 6.63 (d, J = 1.8 Hz, 1H), 3.89 – 3.79 (m, 2H), 3.68 – 3.62 (m, 7H), 3.39 (dd, J = 16.3, 5.2 Hz, 1H), 2.92 (dd, J = 16.3, 9.0 Hz, 1H), 2.64 (dd, J = 16.0, 2.9 Hz, 1H), 1.67 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.22, 174.95, 160.79, 159.85, 159.60, 140.13, 138.18, 137.26,
129.97, 129.62, 128.75, 125.54, 120.04, 119.84, 119.56, 113.64, 113.35, 113.24, 61.58, 55.17, 55.12, 44.43, 42.62, 41.42, 40.61, 15.72; IR: 2954, 2925, 2855, 1698, 1598, 1460, 1265, 740, 699cm -1; HRMS ( ESI): [C29H28N2O4+H]+, Calc: 469.2122, Found: 469.2128; []D25 = - 58 (c = 1.0, CHCl3). (6S,10S)-4-methyl-6,10-di(naphthalen-2-yl)-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
white solid. m.p.128 –131 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.84 – 7.77 (m, 3H), 7.69 (t, J = 7.8 Hz, 3H), 7.63 (s, 1H), 7.59
(s, 1H), 7.64 – 7.48 (m, 2H), 7.44 – 7.39 (m, 4H), 7.32 – 7.21 (m, 4H), 7.12 (t, J = 7.4 Hz, 1H), 4.12 – 4.06 (m, 2H), 3.92 (dd, J = 14.3, 2.6 Hz, 1H), 3.58 (dd, J = 16.3, 5.3 Hz, 1H), 3.10 (dd, J = 16.3, 8.7 Hz, 1H), 2.78 (dd, J = 15.7, 2.5 Hz, 1H), 1.60 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.28, 175.00, 160.79, 137.03, 136.17, 134.18, 133.16, 133.05,
132.82, 132.73, 128.80, 128.71, 128.54, 127.94, 127.79, 127.68, 127.52, 127.05, 126.72, 126.57, 126.51, 126.34, 126.24, 125.84, 125.67, 125.10, 119.85, 61.62, 44.72, 42.81, 41.68, 40.83, 15.89; IR: 3325, 3053, 2925, 2856, 1699, 1461, 1370, 1265, 742cm -1; HRMS ( ESI): [C35H28N2O2+H]+, Calc: 509.2224, Found: 509.2233; []D25 = - 139 (c = 1.0, CHCl3). (6R,10R)-6,10-di(furan-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
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white solid. m.p.114 –116 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.50 (dd, J = 8.6, 1.0 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.23 –
7.14 (m, 3H), 6.20 (dd, J = 3.3, 1.9 Hz, 2H), 6.12 (d, J = 3.3 Hz, 2H), 3.84 (t, J = 14.3 Hz, 2H), 3.66 (dd, J = 14.0, 3.8 Hz, 2H), 2.61 (dd, J = 14.6, 3.8 Hz, 2H), 2.23 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 206.38, 171.84, 160.58, 151.18, 142.15, 137.22, 128.75, 125.61,
120.02, 110.45, 106.76, 59.11, 40.43, 40.05, 13.64; IR: 3372, 2954, 2924, 2854, 1703, 1499, 1460, 1371, 741cm -1; HRMS ( ESI): [C23H20N2O4+H]+, Calc: 389.1496, Found: 389.1500; []D25 = - 6 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne
white solid. m.p.165 –166 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.73 (dd, J = 8.6, 1.0 Hz, 2H), 7.44 – 7.40 (m, 3H), 7.37 (d, J =
1.6 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 7.19 – 7.11 (m, 5H), 4.42 (dd, J = 7.7, 2.6 Hz, 1H), 3.97 – 3.86 (m, 2H), 3.72 (dd, J = 14.0, 3.9 Hz, 1H), 2.71 – 2.65 (m, 1H), 2.59 (dd, J = 15.7, 2.3 Hz, 1H), 1.29 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.48, 174.28, 160.35, 137.68, 137.44, 134.88, 130.23, 129.61,
129.39, 128.89, 128.86, 128.23, 127.69, 127.44, 125.65, 119.78, 59.17, 42.90, 42.59, 41.38, 40.88, 15.16; HRMS ( ESI): [C27H23ClN2O2+Na]+, Calc: 465.1340, Found: 465.1338; IR: 3439, 2906, 2359, 1714, 1691, 1499, 1369, 1276, 760cm -1; []D25 = + 81 (c = 1.0, CHCl3). S8
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(5S,6R,10S)-6-(2-chlorophenyl)-4-methyl-2-phenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene1,8-dione
white solid. m.p.235 –236 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 14.1, 6.6 Hz, 4H), 7.33
(dd, J = 6.3, 3.9 Hz, 2H), 7.25 – 7.20 (m, 1H), 6.99 (q, J = 8.2 Hz, 4H), 4.40 (d, J = 5.5 Hz, 1H), 3.96 – 3.84 (m, 2H), 3.68 (dd, J = 13.9, 3.8 Hz, 1H), 2.69 – 2.53 (m, 2H), 2.22 (s, 3H), 1.28 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.53, 174.37, 160.45, 137.93, 137.79, 137.55, 134.89, 134.48,
130.20, 129.62, 129.54, 129.31, 128.82, 127.64, 127.27, 125.58, 119.78, 59.21, 42.82, 42.55, 41.36, 40.92, 20.92, 15.11; HRMS ( ESI): [C28H25ClN2O2+Na]+, Calc: 479.1497, Found: 479.1500; IR: 3059, 2959, 2922, 2859, 1711, 1686, 1369, 1263, 1039, 803, 739cm -1; []D25 = + 96 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-10-(4-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]de c-3-ene-1,8-dione Ph N
N
O
Cl O
Cl
5m
white solid. m.p. 198 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 7.7 Hz, 2H), 7.33 (dd, J = 15.7, 7.8 Hz, 4H), 7.26 –
7.21 (m, 2H), 7.19 – 7.13 (m, 1H), 7.04 (dd, J = 25.6, 8.5 Hz, 4H), 4.34 (dd, J = 7.6, 2.4 Hz, 1H), 3.87 – 3.73 (m, 2H), 3.63 (dd, J = 14.0, 3.5 Hz, 1H), 2.66 – 2.42 (m, 2H), 1.21 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.98, 174.04, 160.14, 137.47, 137.32, 136.01, 134.88, 134.10,
130.30, 129.49, 129.11, 128.94, 128.82, 127.73, 125.80, 119.67, 59.05, 42.42, 42.24, 41.29, 40.81, 15.15; S9
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IR: 3317, 3058, 2925, 2854, 1693, 1461, 1368, 1264, 742cm -1; HRMS ( ESI): [C27H22Cl2N2O2+H]+, Calc: 477.1131, Found: 477.1130; []D25 = + 116 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-10-(3-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]de c-3-ene-1,8-dione
white solid. m.p.129 –130 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.75 – 7.72 (m, 2H), 7.45 – 7.37 (m, 4H), 7.33 (dd, J = 10.8, 4.7
Hz, 2H), 7.26 – 7.22 (m, 1H), 7.18 – 7.09 (m, 3H), 7.05 – 7.02 (m, 1H), 4.42 (dd, J = 7.6, 2.5 Hz, 1H), 3.96 – 3.82 (m, 2H), 3.69 (dd, J = 14.0, 3.8 Hz, 1H), δ 2.70 – 2.64 (m, 1H), 2.58 (dd, J = 15.7, 2.0 Hz, 1H), 1.30 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.74, 174.86, 160.96, 140.33, 138.34, 138.08, 135.75, 135.53,
131.17, 131.12, 130.36, 129.78, 129.37, 128.76, 128.64, 126.76, 126.28, 120.83, 59.80, 43.39, 43.12, 42.15, 41.65, 16.02; IR: 2924, 2854, 1697, 1596, 1462, 1372, 1265, 742cm -1; HRMS ( ESI): [C27H22Cl2N2O2+H]+, Calc: 477.1131, Found: 477.1137; []D25 = + 81 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-10-(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione
white solid. m.p. 199 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.76 – 7.32 (m, 2H), 7.44 – 7.31 (m, 6H), 7.22 (t, J = 7.4 Hz,
1H), 7.04 (dd, J = 9.3, 2.5 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 4.39 (dd, J = 7.7, 2.5 Hz, 1H), 3.95 –
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3.82 (m, 2H), 3.70 – 3.64 (m, 4H), δ 2.68 – 2.62 (m, 1H), 2.57 (dd, J = 15.6, 2.0 Hz, 1H), 1.29 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.71, 174.34, 160.53, 159.21, 137.73, 137.48, 134.86, 130.21,
129.59, 129.42, 129.35, 128.85, 128.52, 127.67, 125.62, 119.76, 114.15, 59.31, 55.16, 42.89, 42.10, 41.37, 40.77, 15.13; IR: 3335, 2924, 2854, 1698, 1461, 1373, 1261, 1035, 760cm -1; HRMS ( ESI): [C28H25ClN2O3+H]+, Calc: 473.1626, Found: 473.1632; []D25 = + 88 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-10-(3-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione
white solid. m.p.89 –90 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.77 (dd, J = 8.6, 1.1 Hz, 2H), 7.44 – 7.32 (m, 6H), 7.22 (t, J =
7.4 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.73 – 6.66 (m, 3H), 4.42 (dd, J = 7.7, 2.3 Hz, 1H), 3.98 – 3.83 (m, 2H), 3.68 (dd, J = 14.1, 4.0 Hz, 1H), 3.54 (s, 3H), δ 2.71 – 2.65 (m, 1H), 2.57 (dd, J = 15.8, 1.9 Hz, 1H), 1.28 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.47, 174.40, 160.50, 159.85, 139.00, 137.65, 137.52, 134.89,
130.22, 129.87, 129.61, 129.40, 128.86, 127.72, 125.62, 119.76, 119.62, 114.08, 112.44, 59.05, 55.00, 42.90, 42.66, 41.34, 40.91, 15.15; IR: 2924, 2854, 1696, 1496, 1461, 1372, 1267, 1042, 759cm -1; HRMS ( ESI): [C28H25ClN2O3+H]+, Calc: 473.1626, Found: 473.1634; []D25 = + 67 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-10-(3,4-dimethylphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4. 5]dec-3-ene-1,8-dione
S11
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
white solid. m.p.174 –176 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.69 – 7.66 (m, 2H), 7.36 – 7.29 (m, 4H), 7.26 – 7.18 (m, 2H),
7.15 (t, J = 7.4 Hz, 1H), 6.85 – 6.81 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 4.32 (dd, J = 7.7, 2.3 Hz, 1H), 3.91 – 3.75 (m, 2H), 3.57 (dd, J = 13.9, 4.0 Hz, 1H), 2.61 – 2.54 (m, 1H), 2.47 (d, J = 15.7 Hz, 1H), 2.04 (s, 3H), 1.97 (s, 3H), 1.19 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.76, 174.48, 160.62, 137.83, 137.49, 137.14, 136.57, 134.89,
134.86, 130.17, 130.02, 129.65, 129.32, 128.82, 128.46, 127.69, 125.61, 124.80, 119.83, 59.13, 42.89, 42.60, 41.39, 40.85, 19.64, 19.32, 15.14; HRMS ( ESI): [C29H27ClN2O2+H]+, Calc: 471.1834, Found: 471.1839; IR: 3060, 2960, 2924, 2857, 1696, 1597, 1499, 1366, 1121, 1041, 758cm -1; []D25 = + 75 (c = 1.0, CHCl3). (5S,6R,10S)-6-(2-chlorophenyl)-4-methyl-10-(naphthalen-2-yl)-2-phenyl-2,3-diazaspiro[4.5]d ec-3-ene-1,8-dione Ph N
N
O
Cl O
5r
white solid. m.p.122 –124 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.73 – 7.70 (m, 3H), 7.66 (d, J = 8.6 Hz, 1H), 7.63 – 7.60 (m,
1H), 7.56 (s, 1H), 7.45 – 7.38 (m, 7H), 7.35 – 7.28 (m, 2H), 7.21 (t, J = 7.4 Hz, 1H), 4.46 (dd, J = 7.8, 2.3 Hz, 1H), 4.01 (dt, J = 7.7, 4.7 Hz, 2H), 3.90 (dd, J = 14.0, 3.3 Hz, 1H), 2.77 – 2.71 (m, 1H), 2.60 (dd, J = 15.8, 1.8 Hz, 1H), 1.29 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.28, 174.46, 160.43, 137.81, 137.49, 135.04, 135.00, 133.27,
132.96, 130.28, 129.69, 129.42, 128.88, 128.85, 127.76, 127.73, 127.58, 126.82, 126.45, 126.31, 125.70, 124.76, 119.87, 59.13, 43.16, 42.85, 41.43, 41.10, 15.17; HRMS ( ESI): [C31H25ClN2O2+Na]+, Calc: 515.1497, Found: 515.1494; S12
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IR: 3059, 2961, 2925, 2857, 1695, 1498, 1367, 1265, 1041, 739cm -1; []D25 = + 102 (c = 1.0, CHCl3). (5R,6S,10R)-6-(4-bromophenyl)-10-(2-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]d ec-3-ene-1,8-dione
white solid. m.p. 226 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.76 – 7.74 (m, 2H), 7.45 – 7.36 (m, 4H), 7.34 – 7.21 (m, 5H),
7.01 (d, J = 8.5 Hz, 2H), 4.41 (dd, J = 7.6, 2.5 Hz, 1H), 3.95 – 3.80 (m, 2H), 3.69 (dd, J = 14.0, 3.7 Hz, 1H), 2.62 (ddd, J = 18.3, 9.6, 2.3 Hz, 2H), 1.28 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.98, 174.02, 160.15, 137.45, 137.30, 136.54, 134.88, 132.07,
130.30, 129.50, 129.14, 128.95, 127.74, 125.82, 122.26, 119.67, 58.96, 42.38, 42.29, 41.28, 40.83, 15.15; IR: 3422, 2924, 2854, 1712, 1692, 1462, 1369, 756cm -1; HRMS ( ESI): [C27H22BrClN2O2+H]+, Calc: 521.0626, Found: 521.0627; []D25 = + 105 (c = 1.0, CHCl3). (5R,6R,10S)-6-(2-chlorophenyl)-10-(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5 ]dec-3-ene-1,8-dione Ph N
N
O
Cl
MeO
O
5t
white solid. m.p.206 –208 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.76 (dd, J = 8.7, 1.2 Hz, 2H), 7.46 – 7.30 (m, 6H), 7.23 (t, J =
7.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.40 (dd, J = 7.7, 2.6 Hz, 1H), 3.95 – 3.85 (m, 2H), 3.72 – 3.64 (m, 4H), 2.68 – 2.54 (m, 2H), 1.30 (s, 3H);
S13
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
13
C NMR (75 MHz, CDCl3): δ = 209.69, 174.35, 160.52, 159.21, 137.73, 137.48, 134.86, 130.21,
129.59, 129.42, 129.34, 128.85, 128.52, 127.67, 125.62, 119.76, 114.15, 59.31, 55.16, 42.89, 42.11, 41.37, 40.77, 15.13; IR: 3376, 3062, 2960, 2922, 2840, 1697, 1598, 1513, 1262, 1036, 761, 737cm -1; HRMS ( ESI): [C28H25ClN2O3+H]+, Calc: 473.1626, Found: 473.1635; []D25 = + 65 (c = 1.0, CHCl3). (5R,6R,10S)-6-(2-chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne
white solid. m.p.153 –155 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.73 (dd, J = 8.6, 1.1 Hz, 2H), 7.44 – 7.40 (m, 3H), 7.37 (d, J =
1.7 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.25 – 7.22 (m, 1H), 7.19 – 7.11 (m, 5H), 4.42 (dd, J = 7.7, 2.6 Hz, 1H), 3.97 – 3.86 (m, 2H), 3.72 (dd, J = 13.9, 3.9 Hz, 1H), 2.71 – 2.65 (m, 1H), 2.62 – 2.55 (m, 1H), 1.29 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.46, 173.26, 159.33, 136.66, 136.41, 133.86, 129.21, 128.58,
128.36, 127.86, 127.83, 127.21, 126.66, 126.41, 124.63, 118.76, 58.14, 41.87, 41.57, 40.35, 39.86, 14.13; HRMS ( ESI): [C27H23ClN2O2+Na]+, Calc: 465.1340, Found: 465.1342; IR: 3063, 2962, 2924, 2856, 1696, 1597, 1498, 1367, 1264, 1040, 737cm -1; []D25 = + 82 (c = 1.0, CHCl3). (5S,6R,10R)-6-(2-chlorophenyl)-10-(furan-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3ene-1,8-dione
white solid. m.p.91 –93 oC; S14
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1
H NMR (300 MHz, CDCl3): δ = 7.79 – 7.76 (m, 2H), 7.45 – 7.37 (m, 4H), 7.35 – 7.28 (m, 1.5H),
7.24 – 7.19 (m, 1.5H), 7.16 (d, J = 1.2 Hz, 1H), 6.18 (dd, J = 3.2, 1.9 Hz, 1H), 6.07 (d, J = 3.2 Hz, 1H), 4.39 (dd, J = 7.6, 2.4 Hz, 1H), 3.96 – 3.81 (m, 3H), 2.74 (d, J = 13.6 Hz, 1H), 2.54 (d, J = 15.9 Hz, 1H), 1.36 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.66, 173.75, 160.45, 151.41, 142.07, 137.59, 137.47, 134.85,
130.27, 129.43, 129.33, 128.86, 127.77, 125.54, 119.68, 110.50, 106.98, 57.85, 41.16, 40.80, 40.28, 36.26, 14.85; HRMS ( ESI): [C25H21ClN2O3+Na]+, Calc: 455.1133, Found: 445.1132; IR: 3009, 2959, 2925, 2854, 1742, 1262, 1098, 1019, 801, 740cm -1; []D25 = + 44 (c = 1.0, CHCl3). (5R,6R,10R)-6-(2-chlorophenyl)-10-isobutyl-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene1,8-dione Ph N
N
O
Cl
O
5w
white solid. m.p.174 –176 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.7 Hz,1.5H), 7.55 (d, J = 7.7 Hz, 0.5H), 7.46 –
7.39 (m, 2.5H), 7.33 – 7.19 (m, 3.5H), 7.18 – 7.05 (m, 1H), 4.32 (dd, J = 7.3, 3.2 Hz, 0.78H), 4.20 (dd, J = 14.1, 3.3 Hz, 0.22H), 3.67 (dd, J = 15.7, 7.4 Hz, 0.78H), 3.53 (dd, J = 16.1, 14.2 Hz, 0.22H), 3.16 (dd, J = 15.7, 13.0 Hz, 0.78H), 2.94 (dd, J = 16.8, 3.6 Hz, 0.22H), 2.77 – 2.66 (m, 1H), 2.58 – 2.47 (m, 1.83H), 2.44 – 2.39 (m, 0.27H), 2.34 (s, 0.64H), 1.71 – 1.51 (m, 1H), 1.35 (s, 2.32H), 1.29 – 1.20 (m, 1H), 1.06 – 0.97 (m, 0.37H), 0.90 (d, J = 6.6 Hz, 0.70H), 0.83 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.5 Hz, 2.3H), 0.74 – 0.65 (m, 0.87H); 13
C NMR (75 MHz, CDCl3): δ = 209.97, 174.25, 160.92, 137.77, 137.66, 134.67, 130.20, 129.34,
129.21, 128.91, 127.52, 125.38, 119.17, 58.86, 41.32, 40.63, 40.26, 39.82, 33.32, 24.21, 24.02, 20.87, 14.73; HRMS ( ESI): [C25H27ClN2O2+Na]+, Calc: 445.1653, Found: 445.1654; IR: 3062, 2959, 2926, 2870, 1700, 1596, 1266, 1116, 761, 696cm -1; []D25 = +8 (c = 1.0, CHCl3). S15
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(5S,6S,10S)-4-methyl-2,6-diphenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N
O
O
5x
white solid. m.p. 99 –100oC; 1
H NMR (300 MHz, CDCl3): δ = 7.42 (t, J = 8.6 Hz, 2H), 7.29 – 7.23 (m, 4H), 7.12 – 7.04 (m,
4H), 6.97 – 6.91 (m, 4H), 3.84 – 3.74 (m, 2H), 3.57 (dd, J = 14.3, 3.0 Hz, 1H), 3.34 (dd, J = 16.4, 5.2 Hz, 1H), 2.87 (dd, J = 16.3, 8.9 Hz, 1H), 2.56 (dd, J = 16.0, 2.9 Hz, 1H), 2.25 (s, 0.3H), 2.13 (s, 2.7H), 1.60 (s, 0.3H), 1.55 (s, 2.7H); 13
C NMR (75 MHz, CDCl3): δ = 209.56, 174.91, 160.81, 138.69, 137.83, 137.20, 133.62, 129.31,
128.95, 128.74, 128.07, 127.76, 127.54, 125.60, 119.82, 61.75, 44.41, 42.12, 41.57, 40.63, 20.96, 15.70; IR: 3054, 2926, 2855, 1701, 1499, 1265, 740, 705cm -1; HRMS ( ESI): [C28H26N2O2+H]+, Calc: 423.2067, Found: 423.2076; []D25 = + 40 (c = 1.0, CHCl3). (6R,10R)-6,10-bis(3-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N O
Cl O
Cl
5g'
white solid. m.p.65 –66 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.46 (dd, J = 8.5, 0.9 Hz, 2H), 7.36 – 7.27 (m, 3H), 7.24 – 7.11
(m, 6H), 7.05 – 6.98 (m, 2H), 3.94 – 3.77 (m, 2H), 3.59 (dd, J = 14.3, 2.9 Hz, 1H), 3.29 (dd, J = 16.5, 4.8 Hz, 1H), 2.97 (dd, J = 16.5, 10.3 Hz, 1H), 2.63 (dd, J = 16.2, 2.8 Hz, 1H), 1.76 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.01, 174.32, 159.77, 140.16, 138.18, 136.75, 134.94, 134.45,
130.31, 129.95, 128.85, 128.49, 128.42, 128.02, 127.66, 126.00, 125.89, 125.66, 120.00, 61.53, 43.43, 42.05, 40.72, 40.13, 15.75; IR: 3314, 3062, 2955, 2925, 2855, 1721, 1699, 1596, 1499, 740, 693cm -1; HRMS ( ESI): [C27H22Cl2N2O2+H]+, Calc: 477.1131, Found: 477.1133; S16
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[]D25 = + 65 (c = 1.0, CHCl3). (6R,10R)-6,10-bis(3-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne Ph N
N O
MeO O
OMe
5h'
white solid. m.p.121 –123 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.23 – 7.08 (m,
3H), 6.82 (dd, J = 8.2, 2.1 Hz, 1H), 6.70 (dd, J = 8.6, 6.1 Hz, 4H), 6.63 (d, J = 1.8 Hz, 1H), 3.89 – 3.79 (m, 2H), 3.68 – 3.62 (m, 7H), 3.39 (dd, J = 16.3, 5.2 Hz, 1H), 2.92 (dd, J = 16.3, 9.0 Hz, 1H), 2.64 (dd, J = 16.0, 2.9 Hz, 1H), 1.67 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.22, 174.95, 160.79, 159.85, 159.60, 140.13, 138.18, 137.26,
129.97, 129.62, 128.75, 125.54, 120.04, 119.84, 119.56, 113.64, 113.35, 113.24, 61.58, 55.17, 55.12, 44.43, 42.62, 41.42, 40.61, 15.72; IR: 2954, 2925, 2855, 1698, 1598, 1460, 1265, 740, 699cm -1; HRMS ( ESI): [C29H28N2O4+H]+, Calc: 469.2122, Found: 469.2128; []D25 = + 58 (c = 1.0, CHCl3). (5R,6S,10R)-6-(2-chlorophenyl)-4-methyl-2-phenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene-1,8-d ione
white solid. m.p.235 –236 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 14.1, 6.6 Hz, 4H), 7.33
(dd, J = 6.3, 3.9 Hz, 2H), 7.25 – 7.20 (m, 1H), 6.99 (q, J = 8.2 Hz, 4H), 4.40 (d, J = 5.5 Hz, 1H), 3.96 – 3.84 (m, 2H), 3.68 (dd, J = 13.9, 3.8 Hz, 1H), 2.69 – 2.53 (m, 2H), 2.22 (s, 3H), 1.28 (s, 3H);
S17
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13
C NMR (75 MHz, CDCl3): δ = 209.53, 174.37, 160.45, 137.93, 137.79, 137.55, 134.89, 134.48,
130.20, 129.62, 129.54, 129.31, 128.82, 127.64, 127.27, 125.58, 119.78, 59.21, 42.82, 42.55, 41.36, 40.92, 20.92, 15.11; HRMS ( ESI): [C28H25ClN2O2+Na]+, Calc: 479.1497, Found: 479.1500; IR: 3059, 2959, 2922, 2859, 1711, 1686, 1369, 1263, 1039, 803, 739cm -1; []D25 = - 96 (c = 1.0, CHCl3). (5R,6S,10R)-6-(2-chlorophenyl)-4-methyl-10-(naphthalen-2-yl)-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione Ph N
N O
Cl
O
5r'
white solid. m.p.122 –124 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.73 – 7.70 (m, 3H), 7.66 (d, J = 8.6 Hz, 1H), 7.63 – 7.60 (m,
1H), 7.56 (s, 1H), 7.45 – 7.38 (m, 7H), 7.35 – 7.28 (m, 2H), 7.21 (t, J = 7.4 Hz, 1H), 4.46 (dd, J = 7.8, 2.3 Hz, 1H), 4.01 (dt, J = 7.7, 4.7 Hz, 2H), 3.90 (dd, J = 14.0, 3.3 Hz, 1H), 2.77 – 2.71 (m, 1H), 2.60 (dd, J = 15.8, 1.8 Hz, 1H), 1.29 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.28, 174.46, 160.43, 137.81, 137.49, 135.04, 135.00, 133.27,
132.96, 130.28, 129.69, 129.42, 128.88, 128.85, 127.76, 127.73, 127.58, 126.82, 126.45, 126.31, 125.70, 124.76, 119.87, 59.13, 43.16, 42.85, 41.43, 41.10, 15.17; HRMS ( ESI): [C31H25ClN2O2+Na]+, Calc: 515.1497, Found: 515.1494; IR: 3059, 2961, 2925, 2857, 1695, 1498, 1367, 1265, 1041, 739cm -1; []D25 = - 102 (c = 1.0, CHCl3). (5S,6R,10S)-6-(4-bromophenyl)-10-(2-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]d ec-3-ene-1,8-dione
white solid. m.p. 226 oC; S18
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1
H NMR (300 MHz, CDCl3): δ = 7.76 – 7.74 (m, 2H), 7.45 – 7.36 (m, 4H), 7.34 – 7.21 (m, 5H),
7.01 (d, J = 8.5 Hz, 2H), 4.41 (dd, J = 7.6, 2.5 Hz, 1H), 3.95 – 3.80 (m, 2H), 3.69 (dd, J = 14.0, 3.7 Hz, 1H), 2.62 (ddd, J = 18.3, 9.6, 2.3 Hz, 2H), 1.28 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.98, 174.02, 160.15, 137.45, 137.30, 136.54, 134.88, 132.07,
130.30, 129.50, 129.14, 128.95, 127.74, 125.82, 122.26, 119.67, 58.96, 42.38, 42.29, 41.28, 40.83, 15.15; IR: 3422, 2924, 2854, 1712, 1692, 1462, 1369, 756cm -1; HRMS ( ESI): [C27H22BrClN2O2+H]+, Calc: 521.0626, Found: 521.0627; []D25 = - 105 (c = 1.0, CHCl3). (5S,6S,10R)-6-(2-chlorophenyl)-10-(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione
white solid. m.p.206 –208 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.76 (dd, J = 8.7, 1.2 Hz, 2H), 7.46 – 7.30 (m, 6H), 7.23 (t, J =
7.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.40 (dd, J = 7.7, 2.6 Hz, 1H), 3.95 – 3.85 (m, 2H), 3.72 – 3.64 (m, 4H), 2.68 – 2.54 (m, 2H), 1.30 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 209.69, 174.35, 160.52, 159.21, 137.73, 137.48, 134.86, 130.21,
129.59, 129.42, 129.34, 128.85, 128.52, 127.67, 125.62, 119.76, 114.15, 59.31, 55.16, 42.89, 42.11, 41.37, 40.77, 15.13; IR: 3376, 3062, 2960, 2922, 2840, 1697, 1598, 1513, 1262, 1036, 761, 737cm -1; HRMS ( ESI): [C28H25ClN2O3+H]+, Calc: 473.1626, Found: 473.1635; []D25 = - 65 (c = 1.0, CHCl3). (5S,6S,10R)-6-(2-chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne
S19
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
white solid. m.p.153 –155 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.73 (dd, J = 8.6, 1.1 Hz, 2H), 7.44 – 7.40 (m, 3H), 7.37 (d, J =
1.7 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.25 – 7.22 (m, 1H), 7.19 – 7.11 (m, 5H), 4.42 (dd, J = 7.7, 2.6 Hz, 1H), 3.97 – 3.86 (m, 2H), 3.72 (dd, J = 13.9, 3.9 Hz, 1H), 2.71 – 2.65 (m, 1H), 2.62 – 2.55 (m, 1H), 1.29 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.46, 173.26, 159.33, 136.66, 136.41, 133.86, 129.21, 128.58,
128.36, 127.86, 127.83, 127.21, 126.66, 126.41, 124.63, 118.76, 58.14, 41.87, 41.57, 40.35, 39.86, 14.13; HRMS ( ESI): [C27H23ClN2O2+Na]+, Calc: 465.1340, Found: 465.1342; IR: 3063, 2962, 2924, 2856, 1696, 1597, 1498, 1367, 1264, 1040, 737cm -1; []D25 = - 82 (c = 1.0, CHCl3). (5R,6S,10S)-6-(2-chlorophenyl)-10-(furan-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-e ne-1,8-dione Ph N
N O
O
Cl O
5v'
white solid. m.p.91 –93 oC; 1
H NMR (300 MHz, CDCl3): δ =7.79 – 7.76 (m, 2H), 7.45 – 7.37 (m, 4H), 7.35 – 7.28 (m, 1.5H),
7.24 – 7.19 (m, 1.5H), 7.16 (d, J = 1.2 Hz, 1H), 6.18 (dd, J = 3.2, 1.9 Hz, 1H), 6.07 (d, J = 3.2 Hz, 1H), 4.39 (dd, J = 7.6, 2.4 Hz, 1H), 3.96 – 3.81 (m, 3H), 2.74 (d, J = 13.6 Hz, 1H), 2.54 (d, J = 15.9 Hz, 1H), 1.36 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ = 208.66, 173.75, 160.45, 151.41, 142.07, 137.59, 137.47, 134.85,
130.27, 129.43, 129.33, 128.86, 127.77, 125.54, 119.68, 110.50, 106.98, 57.85, 41.16, 40.80, 40.28, 36.26, 14.85; HRMS ( ESI): [C25H21ClN2O3+Na]+, Calc: 455.1133, Found: 445.1132; S20
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
IR: 3009, 2959, 2925, 2854, 1742, 1262, 1098, 1019, 801, 740cm -1; []D25 = - 44 (c = 1.0, CHCl3). (5S,6S,10S)-6-(2-chlorophenyl)-10-isobutyl-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1 ,8-dione Ph N
N O
Cl O
5w'
white solid. m.p.174 –176 oC; 1
H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.7 Hz,1.5H), 7.55 (d, J = 7.7 Hz, 0.5H), 7.46 –
7.39 (m, 2.5H), 7.33 – 7.19 (m, 3.5H), 7.18 – 7.05 (m, 1H), 4.32 (dd, J = 7.3, 3.2 Hz, 0.78H), 4.20 (dd, J = 14.1, 3.3 Hz, 0.22H), 3.67 (dd, J = 15.7, 7.4 Hz, 0.78H), 3.53 (dd, J = 16.1, 14.2 Hz, 0.22H), 3.16 (dd, J = 15.7, 13.0 Hz, 0.78H), 2.94 (dd, J = 16.8, 3.6 Hz, 0.22H), 2.77 – 2.66 (m, 1H), 2.58 – 2.47 (m, 1.83H), 2.44 – 2.39 (m, 0.27H), 2.34 (s, 0.64H), 1.71 – 1.51 (m, 1H), 1.35 (s, 2.32H), 1.29 – 1.20 (m, 1H), 1.06 – 0.97 (m, 0.37H), 0.90 (d, J = 6.6 Hz, 0.70H), 0.83 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.5 Hz, 2.3H), 0.74 – 0.65 (m, 0.87H); 13
C NMR (75 MHz, CDCl3): δ = 209.97, 174.25, 160.92, 137.77, 137.66, 134.67, 130.20, 129.34,
129.21, 128.91, 127.52, 125.38, 119.17, 58.86, 41.32, 40.63, 40.26, 39.82, 33.32, 24.21, 24.02, 20.87, 14.73; HRMS ( ESI): [C25H27ClN2O2+Na]+, Calc: 445.1653, Found: 445.1654; IR: 3062, 2959, 2926, 2870, 1700, 1596, 1266, 1116, 761, 696cm -1; []D25 = -8 (c = 1.0, CHCl3). (5R,6R,10R)-4-methyl-2,6-diphenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
white solid. m.p. 99 –100oC; 1
H NMR (300 MHz, CDCl3): δ = 7.42 (t, J = 8.6 Hz, 2H), 7.29 – 7.23 (m, 4H), 7.12 – 7.04 (m,
4H), 6.97 – 6.91 (m, 4H), 3.84 – 3.74 (m, 2H), 3.57 (dd, J = 14.3, 3.0 Hz, 1H), 3.34 (dd, J = 16.4, S21
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
5.2 Hz, 1H), 2.87 (dd, J = 16.3, 8.9 Hz, 1H), 2.56 (dd, J = 16.0, 2.9 Hz, 1H), 2.25 (s, 0.3H), 2.13 (s, 2.7H), 1.60 (s, 0.3H), 1.55 (s, 2.7H); 13
C NMR (75 MHz, CDCl3): δ = 209.56, 174.91, 160.81, 138.69, 137.83, 137.20, 133.62, 129.31,
128.95, 128.74, 128.07, 127.76, 127.54, 125.60, 119.82, 61.75, 44.41, 42.12, 41.57, 40.63, 20.96, 15.70; IR: 3054, 2926, 2855, 1701, 1499, 1265, 740, 705cm -1; HRMS ( ESI): [C28H26N2O2+H]+, Calc: 423.2067, Found: 423.2076; []D25 = - 40 (c = 1.0, CHCl3).
4 References [1] For synthetic method of substrate 2 ,see : C. K. Patel, C. S. Rmi, B. Panigrahi, C.N. Patel, J. Chem.Pharm. Res. 2010, 2 (1): 73-78. [2] For asymetric synthesis using substrate 2, see : a) A. N. R. Alba, A. Zea, G. Valero, T. Calbet, M. Font-Bardia, A. Mazzanti, A. Moyano and R. Rios, Eur. J. Org. Chem., 2011, 1318–1325 ; b) A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano and R. Rios, Org. Biomol. Chem., 2011, 9, 6519 .
5 X-Ray Structure of 5s
S22
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
6.0 Copies of HPLC Spectra of Racemic /Chiral Products (6S,10S)-4-methyl-2,6,10-triphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow rate
AU
0.40
17.930
13.773
= 1.0 mL/min ): tR1 = 13.8 min, tR2 = 17.9 min, ee = >99%.
0.20
0.00 0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
??
Retention
Area
% Area
Height
Int type
Time 13.773
26061696
53.93
524753
bb
2
17.930
22265380
46.07
265364
Bb
18.369
1
0.50
13.758
AU
1.00
0.00 0.00
2.00
4.00
6.00
Retention
8.00
10.00
Area
12.00 ??
% Area
Time
S23
14.00
Height
16.00
Int type
18.00
20.00
22.00
26.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1
13.758
56617
0.07
2407
bb
2
18.369
78755877
99.93
1124260
Bb
(6S,10S)-4-methyl-2-phenyl-6,10-di-p-tolyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N Me
O
O
5b
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow
22.621
rate = 1.0 mL/min ): tR1 = 14.5 min, tR2 = 22.6 min, ee = >99%.
14.468
AU
0.60
0.40
0.20
0.00 8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
??
Retention
Area
% Area
Height
Int type
Time 1
14.468
28163481
48.69
606427
bb
2
22.621
29678953
51.31
413765
Vb
15.236
1.00 0.80
AU
0.60 0.40 0.20 0.00 0.00
5.00
10.00
15.00 ??
20.00
Retention
Area
% Area
Height
Int type
47623364
100.00
987701
bb
25.00
Time 1
15.236
(6S,10S)-6,10-bis(4-fluorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
S24
30.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 70/30, flow rate = 1.0 mL/min ): tR1 = 15.6 min, tR2 = 22.0 min, ee = >99%.
0.20
21.959
AU
15.584
0.40
0.00 8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
? ?
Retention
Area
% Area
Height
Int type
Time 1
15.584
6731799
50.35
185367
bb
2
21.959
6637786
49.65
115724
bb
15.020
1.00
21.679
AU
2.00
0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
22.00
Area
% Area
Height
Int type
24.00
26.00
28.00
Time 2
21.679
17431
0.06
1021
bb
1
15.020
31250885
99.94
813455
bb
(6S,10S)-6,10-bis(4-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
S25
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow rate = 1.0 mL/min ): tR1 = 25.0 min, tR2 = 46.7 min, ee = >99%.
AU
0.20
46.726
25.009
0.30
0.10
0.00 10.00
15.00
20.00
Retention
25.00
30.00 ??
35.00
40.00
Area
% Area
Height
Int type
45.00
50.00
55.00
Time 25.009
22722014
50.37
247062
Bb
2
46.726
22383737
49.63
113137
bb
27.213
1
AU
1.00
0.50
0.00 10.00
15.00
20.00
Retention
25.00
30.00 ??
35.00
40.00
Area
% Area
Height
Int type
141968716
100.00
1264806
bb
45.00
50.00
Time 1
27.213
(6S,10S)-6,10-bis(4-bromophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 60/40, S26
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
16.424
flow rate = 1.0 mL/min ): tR1 = 16.4 min, tR2 = 33.5 min, ee = >99% . 0.60
AU
33.491
0.40
0.20
0.00 10.00
15.00
Retention
20.00
25.00 ??
30.00
35.00
Area
% Area
Height
Int type
40.00
Time 16.424
33198770
50.91
484012
bb
2
33.491
32011167
49.09
201287
bb
16.312
1
AU
0.60
0.40
0.20
0.00 0.00
5.00
10.00
15.00
Retention
20.00
25.00 ??
30.00
35.00
Area
% Area
Height
Int type
38566852
100.00
695120
bb
40.00
45.00
Time 1
16.312
(6S,10S)-6,10-bis(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dion e
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow rate = 1.0 mL/min ): tR1 = 23.0 min, tR2 = 40.5 min, ee = >99%.
S27
50.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.20
40.527
23.049
AU
0.40
0.00 15.00
20.00
Retention
25.00
30.00
35.00 ??
40.00
45.00
Area
% Area
Height
Int type
50.00
55.00
Time 23.049
13331882
54.53
171968
bb
2
40.527
11116524
45.47
72997
bb
22.064
1
0.80
AU
0.60 0.40 0.20 0.00 0.00
10.00
20.00
30.00
40.00
50.00
60.00
??
Retention
Area
% Area
Height
Int type
70131020
100.00
900637
bb
Time 1
22.064
(6S,10S)-6,10-bis(3-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N Me
O
Cl Cl O
5g
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 70/30, flow
rate = 1.0 mL/min ): tR1 = 7.8 min, tR2 = 9.0 min, ee = >99%.
S28
7.776
0.80 0.60
AU
8.967
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.40 0.20 0.00 0.00
2.00
4.00
Retention
6.00 ??
8.00
10.00
Area
% Area
Height
Int type
12.00
Time 7.776
23182760
50.50
833966
BV
2
8.967
22723032
49.50
548563
VB
7.740
1
AU
1.00
0.50
0.00 0.00
2.00
4.00
Retention
6.00
8.00 ??
10.00
12.00
Area
% Area
Height
Int type
35143652
100.00
1239474
bb
14.00
Time 1
7.740
(6R,10R)-6,10-bis(3-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N O
Cl O
5g'
Cl
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 70/30, flow
rate = 1.0 mL/min ): tR1 = 7.8 min, tR2 = 9.0 min, ee = >99%.
S29
7.776
0.80
AU
0.60
8.967
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.40 0.20 0.00 0.00
2.00
4.00
Retention
6.00 ??
8.00
Area
% Area
Height
Int type
10.00
12 .00
Time 1
7.776
23182760
50.50
833966
BV
2
8.967
22723032
49.50
548563
VB
8.929
0.60
AU
0.40
7.836
0.20
0.00 0.00
2.00
4.00
6.00
Retention
8.00
10.00
12.00 14.00 ??
16.00
18.00
Area
% Area
Height
Int type
20.00
22.00
24.00
Time 1
7.836
83268
0.37
5646
bb
2
8.929
22665943
99.63
586108
bb
(6S,10S)-6,10-bis(3-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dion e Ph N
N Me
O
OMe MeO O
5h
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 70/30,
flow rate = 1.0 mL/min ): tR1 = 12.0 min, tR2 = 14.7 min, ee = >99%.
S30
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
0.60
14.698
11.981
0.80
0.40 0.20 0.00 0.00
2.00
4.00
Retention
6.00
8.00
10.00 ??
12.00
14.00
Area
% Area
Height
Int type
16.00
18.00
Time 11.981
34566769
52.70
863376
bb
2
14.698
31026367
47.30
376161
Vb
11.959
1
AU
0.40
0.20
0.00 6.00
8.00
Retention
10.00
12.00 ??
14.00
16.0 0
Area
% Area
Height
Int type
23220255
100.00
563771
bb
18.00
Time 1
11.959
(6R,10R)-6,10-bis(3-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne Ph N
N O
MeO O
OMe
5h'
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 70/30, flow rate = 1.0 mL/min ): tR1 = 12.0 min, tR2 = 14.7 min, ee = >99%.
S31
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
0.60
14.698
11.981
0.80
0.40 0.20 0.00 0.00
2.00
4.00
6.00
Retention
8.00
10.00 ??
12.00
14.00
Area
% Area
Height
Int type
16.00
18.00
Time 11.981
34566769
52.70
863376
bb
2
14.698
31026367
47.30
376161
Vb
14.621
1
0.20
11.987
AU
0.40
0.00 0.00
2.00
4.00
Retention
6.00
8.00
10.00 ??
12.00
14.00
Area
% Area
Height
Int type
16.00
18.00
Time 1
11.987
367715
0.95
11195
bb
2
14.621
38175935
99.05
462563
BB
(6S,10S)-4-methyl-6,10-di(naphthalen-2-yl)-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow rate = 1.0 mL/min ): tR1 = 18.1 min, tR2 = 23.5 min, ee = >99%.
S32
20.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
0.60
23.477
18.089
0.80
0.40 0.20 0.00 0.00
5.00
10.00
15.00
20.00
25.00
30.00
??
Retention
Area
% Area
Height
Int type
Time 1
18.089
68135248
51.34
869036
bb
2
23.477
64581760
48.66
657563
VB
17.909
1.00 0.80
AU
0.60 0.40 0.20 0.00 0.00
5.00
Retention
10.00
15.00 ??
20.00
Area
% Area
Height
Int type
77973937
100.00
952274
bb
25.00
Time 1
17.909
(5S,6R,10S)-6-(2-chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 10.7 min, tR2 = 20.7 min, ee = >99%.
S33
30.00
AU
0.40
20.701
10.740
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.20
0.00 6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
??
Retention
Area
% Area
Height
Int type
Time 2
20.701
17969203
49.39
261515
bb
1
10.740
18410001
50.61
548936
bb
20.663
0.40
AU
0.30
0.20
0.10
0.00 8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
Area
% Area
Height
Int type
29099395
100.00
425944
bb
22.00
24.00
Time 1
20.663
(5S,6R,10S)-6-(2-chlorophenyl)-4-methyl-2-phenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 8.8 min, tR2 = 17.0 min, ee = >99%.
S34
0.15
16.955
8.779
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
0.10
0.05
0.00 8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
??
Retention
Area
% Area
Height
Int type
Time 8.779
4380937
49.54
173407
bb
2
16.955
4462533
50.46
88122
bb
17.986
1
AU
0.30
0.20
8.489
0.10
0.00 6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
??
Retention
Area
% Area
Height
Int type
Time 1
8.489
74610
0.38
4627
bb
2
17.986
19405338
99.62
338462
bb
(5R,6S,10R)-6-(2-chlorophenyl)-4-methyl-2-phenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene-1,8-d ione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 8.8 min, tR2 = 17.0 min, ee = >99%.
S35
0.15
16.955
8.779
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
0.10
0.05
0.00 8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
20.00
22.00
24.00
??
Retention
Area
% Area
Height
Int type
Time 1
8.779
4380937
49.54
173407
bb
2
16.955
4462533
50.46
88122
bb
9.213
0.40
AU
0.30
0.20
0.10
0.00 6.00
8.00
10.00
12.00
14.00
16.00
18.00
24.00
??
Retention
Area
% Area
Height
Int type
10020598
100.00
389674
bb
Time 1
9.213
(5S,6R,10S)-6-(2-chlorophenyl)-10-(4-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]de c-3-ene-1,8-dione Ph N
N
O
Cl O
5m
Cl
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 98/2, flow
rate = 1.0 mL/min ): tR1 = 48.0 min, tR2 = 62.9 min, ee = >99%.
S36
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.04
62.924
48.049
AU
0.06
0.02
0.00 10.00
20.00
30.00
Retention
40.00 ??
50.00
60.00
Area
% Area
Height
Int type
70.00
Time 1
48.049
9114555
50.87
57780
bb
2
62.924
8801840
49.13
56922
bb
AU
69.536
0.20
0.10
0.00 20.00
30.00
40.00
50.00
60.00
70.00
??
Retention
Area
% Area
Height
Int type
13782404
100.00
68129
bb
Time 1
69.536
(5S,6R,10S)-6-(2-chlorophenyl)-10-(3-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]de c-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 8.7 min, tR2 = 16.8 min, ee = >99%.
S37
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
0.30
16.790
8.698
0.40
0.20 0.10 0.00 6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
??
Retention
Area
% Area
Height
Int type
Time 2
16.790
8984886
47.26
155081
VV
1
8.698
10025669
52.74
391025
Bb
15.964
0.60
AU
0.40
0.20
0.00 6.00
8.00
10.00
Retention
12.00
14.00 ??
16.00
18.00
Area
% Area
Height
Int type
35654946
100.00
524029
bb
20.00
22.00
Time 1
15.964
(5S,6R,10S)-6-(2-chlorophenyl)-10-(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD/H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 14.0 min, tR2 = 21.7 min, ee = >99%.
S38
AU
0.10
21.698
13.975
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.05
0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
Area
% Area
Height
Int type
22.00
24.00
26.00
Time 1
13.975
2304688
50.74
55895
bb
2
21.698
2237397
49.26
35516
bb
0.80
21.223
AU
0.60 0.40 0.20 0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
Area
% Area
Height
Int type
23093671
100.00
319095
bb
22.00
24.00
26.00
Time 1
21.223
(5S,6R,10S)-6-(2-chlorophenyl)-10-(3-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 10.8 min, tR2 = 22.9 min, ee = >99%.
S39
AU
0.20
22.889
10.830
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.10
0.00 6.00
8.00
10.00
12.00
Retention
14.00
16.00
18.00 ??
20.00
22.00
Area
% Area
Height
Int type
24.00
26.00
28.00
Time 1
10.830
8858150
50.63
278749
bb
2
22.889
8637098
49.37
108051
bb
22.433
0.20
10.070
AU
0.40
0.00 8.00
10.00
12.00
Retention
14.00
16.00
18.00 ??
20.00
22.00
Area
% Area
Height
Int type
24.00
26.00
28.00
Time 1
10.070
102780
0.28
4921
bb
2
22.433
36740279
99.72
423142
bb
(5S,6R,10S)-6-(2-chlorophenyl)-10-(3,4-dimethylphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4. 5]dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 7.2 min, tR2 = 15.7 min, ee = >99%.
S40
7.163
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
15.738
0.20
0.10
0.00 8.00
10.00
12.00
14.00
Retention
16.00
18.00
20.00 ??
22.00
24.00
Area
% Area
Height
Int type
26.00
28 .00
30.00
32.00
Time 1
7.163
4943985
48.42
285447
bb
2
15.738
5267662
51.58
115921
bb
16.472
0.30
AU
0.20
7.137
0.10
0.00 6.00
8.00
10.00
Retention
12.00
14.00 ??
16.00
18.00
Area
% Area
Height
Int type
20.00
22.00
Time 1
7.137
22455
0.15
2241
bb
2
16.472
14955057
99.85
311153
Bb
(5S,6R,10S)-6-(2-chlorophenyl)-4-methyl-10-(naphthalen-2-yl)-2-phenyl-2,3-diazaspiro[4.5]d ec-3-ene-1,8-dione Ph N
N
O
Cl O
5r
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow
rate = 1.0 mL/min ): tR1 = 10.6 min, tR2 = 20.1 min, ee = >99%.
S41
1.00
AU
0.80
20.139
10.555
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.60 0.40 0.20 0.00 6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
28.00
??
Retention
Area
% Area
Height
Int type
Time 1
10.555
32925478
50.46
1091452
bb
2
20.139
32321462
49.54
525761
bb
20.921
1.00
AU
0.80 0.60 0.40 0.20 0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
Area
% Area
Height
Int type
70491319
100.00
1041106
bb
22.00
24.00
26.00
Time 1
20.921
(5R,6S,10R)-6-(2-chlorophenyl)-4-methyl-10-(naphthalen-2-yl)-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione Ph N
N O
Cl
O
5r'
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10,
flow rate = 1.0 mL/min ): tR1 = 10.6 min, tR2 = 20.1 min, ee = >99%.
S42
1.00
AU
0.80
20.139
10.555
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.60 0.40 0.20 0.00 6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
28.00
??
Retention
Area
% Area
Height
Int type
Time 10.555
32925478
50.46
1091452
bb
2
20.139
32321462
49.54
525761
bb
10.862
1
2.00
AU
1.50 1.00 0.50 0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
Area
% Area
Height
Int type
78012622
100.00
2347811
bb
22.00
24.00
26.00
Time 1
10.862
(5R,6S,10R)-6-(4-bromophenyl)-10-(2-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]d ec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 13.1 min, tR2 = 14.9 min, ee = >99%.
S43
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
14.860
13.133
0.10
0.05
0.00 0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
??
Retention
Area
% Area
Height
Int type
Time 13.133
5609528
50.49
104214
BV
2
14.860
5500382
49.51
98560
VB
15.290
1
0.10
13.713
AU
0.20
0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
Area
% Area
Height
Int type
22.00
24.00
Time 1
13.713
26607
0.21
1065
bb
2
15.290
12606605
99.79
224302
bb
(5S,6R,10S)-6-(4-bromophenyl)-10-(2-chlorophenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]d ec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 13.1 min, tR2 = 14.9 min, ee = >99%.
S44
26.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
14.860
13.133
0.10
0.05
0.00 0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
??
Retention
Area
% Area
Height
Int type
Time 1
13.133
5609528
50.49
104214
BV
2
14.860
5500382
49.51
98560
VB
12.425
0.80
AU
0.60 0.40 0.20 0.00 6.00
8.00
10.00
Retention
12.00
14.00 ??
16.00
18.00
Area
% Area
Height
Int type
19554510
100.00
339339
bb
20.00
22.00
Time 1
12.425
(5R,6R,10S)-6-(2-chlorophenyl)-10-(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5 ]dec-3-ene-1,8-dione Ph N
N
O
Cl
MeO
O
5t
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10,
flow 1.0 mL/min ): tR1 = 14.7 min, tR2 = 22.8 min, ee = >99%.
S45
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1.00
0.60
22.797
14.665
AU
0.80
0.40 0.20 0.00 10.00
15.00
20.00
25.00
30.00
35.00
??
Retention
Area
% Area
Height
Int type
Time 1
14.665
17376545
50.82
344069
bb
2
22.797
16816708
49.18
178862
bb
AU
23.398
0.20
14.943
0.10
0.00 6.00
8.00
10.00
12.00
Retention
14.00
16.00
18.00 ??
20.00
22.00
24.00
Area
% Area
Height
Int type
26.00
28.00
30.00
Time 2
23.398
8028495
99.18
85771
bb
1
14.943
66317
0.82
2280
bb
(5S,6S,10R)-6-(2-chlorophenyl)-10-(4-methoxyphenyl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5] dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 14.7 min, tR2 = 22.8 min, ee = >99%.
S46
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1.00
0.60
22.797
14.665
AU
0.80
0.40 0.20 0.00 10.00
15.00
20.00
25.00
30.00
35.00
??
Retention
Area
% Area
Height
Int type
Time 1
14.665
17376545
50.82
344069
bb
2
22.797
16816708
49.18
178862
bb
14.572 0.50
22.992
AU
1.00
0.00 6.00
8.00
10.00
Retention
12.00
14.00
16.00 ??
18.00
20.00
22.00
Area
% Area
Height
Int type
24.00
26.00
Time 1
14.572
31622402
99.95
471962
bb
2
22.992
16523
0.05
689
bb
(5R,6R,10S)-6-(2-chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow rate = 1.0 mL/min ): tR1 = 7.0 min, tR2 = 11.2 min, ee = >99%.
S47
AU
2.00
11.233
6.988
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1.00
0.00 0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
??
Retention
Area
% Area
Height
Int type
Time 6.988
50364968
54.57
2250744
bb
2
11.233
41920951
45.43
1034896
Bb
11.472
1
AU
0.40
7.172
0.20
0.00 6.00
8. 00
10.00
12.00
14 .00
16.00
??
Retention
Area
% Area
Height
Int type
Time 1
7.172
71547
0.34
5935
Vb
2
11.472
20909881
99.66
544963
BB
(5S,6S,10R)-6-(2-chlorophenyl)-4-methyl-2,10-diphenyl-2,3-diazaspiro[4.5]dec-3-ene-1,8-dio ne
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min ): tR1 = 14.7 min, tR2 = 22.8 min, ee = >99%.
S48
AU
2.00
11.233
6.988
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
1.00
0.00 0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
??
Retention
Area
% Area
Height
Int type
Time 6.988
50364968
54.57
2250744
bb
2
11.233
41920951
45.43
1034896
Bb
7.028
1
AU
2.00
11.594
1.00
0.00 0.00
2.00
4.00
Retention
6.00
8.00 ??
10.00
12.00
Area
% Area
Height
Int type
14.00
16.00
Time 1
7.028
57092745
99.61
2320097
Vb
2
11.594
220989
0.39
11287
Bb
(5S,6R,10R)-6-(2-chlorophenyl)-10-(furan-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow rate = 1.0 mL/min ): tR1 = 7.3 min, tR2 = 12.1 min, ee = >99%.
S49
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
12.146
7.286
2.00
1.00
0.00 0.00
2.00
4.00
Retention
6.00
8.00 ??
10.00
12.00
Area
% Area
Height
Int type
14.00
Time 1
7.286
51294694
49.01
2167164
VV
2
12.146
53364497
50.99
1104034
bb 12.057
1.00 0.80
0.40
6.894
AU
0.60
0.20 0.00 0.00
2.00
4.00
Retention
6.00
8.00 ??
10.00
12.00
Area
% Area
Height
Int type
14.00
16.00
Time 1
6.894
74742
0.16
8183
Vb
2
12.057
47567309
99.84
953549
BB
(5R,6S,10S)-6-(2-chlorophenyl)-10-(furan-2-yl)-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-e ne-1,8-dione Ph N
N
O
O
Cl O
5v'
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 75/25, flow
rate = 1.0 mL/min ): tR1 = 7.3 min, tR2 = 12.1 min, ee = >99%.
AU
12.146
7.286
2.00
1.00
0.00 0.00
2.00
4.00
6.00
S50
8.00 ??
10.00
12.00
14.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
Retention
Area
% Area
Height
Int type
Time 1
7.286
51294694
49.01
2167164
VV
2
12.146
53364497
50.99
1104034
bb
7.333
0.60
12.483
AU
0.40
0.20
0.00 0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
??
Retention
Area
% Area
Height
Int type
Time 1
7.333
13606358
99.65
617856
VV
2
12.483
48154
0.35
3045
bb
(5R,6R,10R)-6-(2-chlorophenyl)-10-isobutyl-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene1,8-dione Ph N
N
O
Cl
O
5w
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow rate =
1.0 mL/min ): tR1 = 5.6 min, tR2 = 8.0 min, ee = >99%.
7.955
5.603
3.00
AU
2.00
1.00
0.00 0.00
2.00
4.00
6.00
8.00
10.00
??
Retention
Area
% Area
Height
Int type
Time 1
5.603
43790970
52.51
3091849
bb
2
7.955
39604409
47.49
1819766
bb
S51
12.00
14.00
8.071
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
1.50
1.00
5.717
0.50
0.00 0.00
1.00
2.00
3.00
4.00
Retention
5.00
6.00 ??
7.00
8.00
9.00
Area
% Area
Height
Int type
10.00
11.00
Time 1
5.717
186068
0.49
17676
bb
2
8.071
37681780
99.51
1723829
bb
(5S,6S,10S)-6-(2-chlorophenyl)-10-isobutyl-4-methyl-2-phenyl-2,3-diazaspiro[4.5]dec-3-ene-1 ,8-dione Ph N
N
O
Cl O
5w'
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 90/10, flow
rate = 1.0 mL/min ): tR1 = 5.6 min, tR2 = 8.0 min, ee = 98%.
7.955
5.603
3.00
AU
2.00
1.00
0.00 0.00
2.00
4.00
6.00
8.00
10.00
??
Retention
Area
% Area
Height
Int type
Time 1
5.603
43790970
52.51
3091849
bb
2
7.955
39604409
47.49
1819766
bb
S52
12.00
14.00
5.632
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
AU
2.00
8.038
1.00
0.00 0.00
1.00
2.00
3.00
4.00
Retention
5.00
6.00 ??
7.00
8.00
9.00
Area
% Area
Height
Int type
10.00
11.00
12.00
Time 1
5.632
41628896
99.45
2407902
bb
2
8.038
228656
0.55
23340
bb
(5S,6S,10S)-4-methyl-2,6-diphenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione Ph N
N
O
O
5x
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 95/5, flow
AU
0.20
0.10
40.678
36.691
rate = 1.0 mL/min ): tR1 = 36.7 min, tR2 = 40.7 min, ee = >99%.
0.00 0.00
5.00
10.00
Retention
15.00
20.00
25.00 ??
30.00
35.00
Area
% Area
Height
Int type
Time 1
36.691
24890716
48.36
228793
bb
2
40.678
26578921
51.64
174976
bb
S53
40.00
45.00
50.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
41.586
0.80
0.40
38.132
AU
0.60
0.20 0.00 10.00
15.00
20.00
Retention
25.00
30.00 ??
35.00
40.00
Area
% Area
Height
Int type
45.00
50.00
Time 1
38.132
219143
0.38
4316
bb
2
41.586
7190518
99.62
423965
bb
(5R,6R,10R)-4-methyl-2,6-diphenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-3-ene-1,8-dione
HPLC (Daicel Chiralpak AD-H column, n-Hexane/i-PrOH = 95/5, flow
AU
0.20
0.10
40.678
36.691
rate = 1.0 mL/min ): tR1 = 36.7 min, tR2 = 40.7 min, ee = >99%.
0.00 0.00
5.00
10.00
Retention
15.00
20.00
25.00 ??
30.00
35.00
Area
% Area
Height
Int type
Time 1
36.691
24890716
48.36
228793
bb
2
40.678
26578921
51.64
174976
bb
S54
40.00
45.00
50.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
0.80
37.519
AU
0.60 0.40 0.20 0.00 10.00
15.00
20.00
Retention
25.00
30.00 ??
35.00
40.00
Area
% Area
Height
Int type
76941701
100.00
614082
bb
Time 1
37.519
S55
45.00
50.00
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013
7 Copies of NMR Spectra of Products
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