An Organocatalytic Asymmetric Double Michael Cascade Reaction of

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spectra were recorded on Brucker 300 MHz spectrometer in CDCl3 unless otherwise noted. Data are presented as follows: chemical shift, integration, multiplicity ...
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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

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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

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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

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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

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

(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

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

[]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

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

13

C NMR (75 MHz, CDCl3): δ = 209.53, 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

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% Area

Time

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Height

16.00

Int type

18.00

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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

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18.00

20.00

22.00

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??

Retention

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% 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

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% Area

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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

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10.00

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18.00

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Area

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Height

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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

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30.00 ??

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40.00

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% Area

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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

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25.00 ??

30.00

35.00

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% 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

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23.049

AU

0.40

0.00 15.00

20.00

Retention

25.00

30.00

35.00 ??

40.00

45.00

Area

% Area

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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

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20.00

30.00

40.00

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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

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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

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8.00

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% 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

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18.00

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% Area

Height

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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

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11.981

0.80

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4.00

Retention

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12.00

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% Area

Height

Int type

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18.00

Time 11.981

34566769

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863376

bb

2

14.698

31026367

47.30

376161

Vb

11.959

1

AU

0.40

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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%.

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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11.981

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2.00

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6.00

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14.00

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% Area

Height

Int type

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Time 11.981

34566769

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863376

bb

2

14.698

31026367

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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

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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

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8.00

10.00

12.00

14.00

16.00

18.00

20.00

22.00

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??

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

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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

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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

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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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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2013

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