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Supporting Information for

Asymmetric Synthesis of Indol ines through Int ramolecular Shi ft ing of

Aromatic Su lf inyl Groups. Role of the ,-Stacking Interactions in theseUnusual SNAr Processes.

Jos L. Garca Ruano,*[a] Alejandro Parra,[a] Vanesa Marcos,[a] Carlos del Pozo, [b]Silvia Cataln,[b] Silvia Monteagudo,[b] Santos Fustero,* [b], [c] Ana Poveda[d]

[a] Prof. Dr. Jos L. Garca Ruano, Mr Alejandro Parra, and Ms Vanesa Marcos. Departamento de

Qumica Orgnica (C-I). Universidad Autnoma de Madrid. Cantoblanco, 28049-Madrid (Spain)

Fax: (+) 3491497466.

[b] Prof. Dr. Santos Fustero, Dr. Carlos del Pozo, Dr. Silvia Cataln, and Ms Silvia Monteagudo.

Departamento de Qumica Orgnica.Universidad de Valencia (Spain). Burjassot, 46100 Valencia.

[c] Prof. Dr. Santos Fustero. Laboratorio de Molculas Orgnicas. Centro de Investigacin. Prncipe

Felipe. E-46013-Valencia (Spain)

[d] Dr. Ana Poveda. Servicio Interdepartamental de Investigacin (NMR). Universidad Autnoma

de Madrid. Cantoblanco, 28049-Madrid.

Synthesis of imines 2 .....page S2

Synthesis of amines anti-3...page S3

NMR studies.page S17

Molecular mechanics calculationspage S22

X-Ray structure ofanti-3apage S25

X-Ray structure ofanti-15page S38

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General procedure for the synthesis of the imines 2.1

O

H

NH2

YN

HY

4 MS

DCM or Toluene

Reflux or rtZ

Z

2

A dried Schlenk-tube was charged with the corresponding aromatic aldehyde

(1.0 mmol), the appropriate aniline (1.0 mmol), activated 4 molecular sieves (1g /1.0

mmol aldehyde), and 10mL of the solvent (as indicated for each case below). The

reaction mixture was stirred at the temperature indicated in each case below and

checked with the aid of TLC until the reaction was complete. The crude mixture was

then filtered and the solvent was removed under reduced pressure to afford the pure

imine with no additional purification.

(E)-N-(4-Chlorobenzylidene)-4-methoxybenzenamine (2d).2 CH2Cl2 at room

temperature was used in a sealed tube. A white solid was obtained. Yield: 95%; mp:

115-117 C;1H-NMR (300 MHz): 8.40 (s, 1H), 7.86 (d,J= 8.4 Hz, 2H), 7.46 (d,J=

8.4 Hz, 2H), 7.26 (d, J= 8.9 Hz, 2H), 6.98 (d, J= 8.9 Hz, 2H). 13C-NMR (75 MHz,

CDCl3): 158.5, 156.6, 144.5, 139.9, 134.9, 129.7, 128.9, 122.2, 114.4, 55.5.

(E)-N-(4-Chlorobenzylidene)benzenamine (2h).3 CH2Cl2 at room temperature was

used in a sealed tube. A white solid was obtained. Yield: 98%; mp: 75-77 C;1H-NMR

(300 MHz): 8.46 (s, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.50-7.43 (m, 4H), 7.32-7.24 (m,

1(a) Casey, C. P.; Johnson; J. B.J. Am. Chem. Soc.2005, 127, 1883. (b) Mangeney, P.; Tejero, T. A.;

Grosjean, J. N. Synthesis1988, 3, 255.2 Ille, S.; Abello, N.; Izirian, J.C.; Lexakis, A. Tetrahedron: Asymmetric2006, 17, 1045.3

Jia, X.; Han, B.; Zhang, W.; Jin, X.; Yang, L.; Liu, Z.L. Synthesis2006, 17, 2831.

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3H), 6.98 (d, J = 8.9 Hz, 2H). 13C-NMR (75 MHz, CDCl3): 158.7, 151.7, 137.3,

134.7, 129.9, 129.2, 128.0, 126.2, 120.8.

(E)-4-Chloro-N-(4-methoxybenzylidene)benzenamine (2j).4 CH2Cl2 at reflux

temperature was used in a sealed tube. A white solid was obtained. Yield: 97%; mp:


8.7 Hz, 2H), 7.12 (d,J= 8.7 Hz, 2H), 6.98 (d,J= 8.7 Hz, 2H), 3.87 (s, 3H). 13C-NMR

(75 MHz, CDCl3): 162.4, 159.9, 150.9 (2C), 131.0, 130.6, 129.2, 122.2, 114.2, 55.4.

(E)-4-Chloro-N-(4-chlorobenzylidene)benzenamine (2l).4 Toluene at reflux

temperature was used in a sealed tube. A brown solid was obtained. Yield: 90%; mp:


8.4 Hz, 2H), 7.35 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 8.5 Hz, 2H). 13C-NMR (75 MHz,

CDCl3): 159.1, 150.1, 137.6, 134.5, 131.7, 129.9, 129.3, 129.1, 122.2.

(E)-4-(4-Methoxybenzylideneamino)benzonitrile (2m).4 Toluene at reflux

temperature was used in a sealed tube. A brown solid was obtained. Yield: 97%; mp:


8.7 Hz, 2H), 7.20 (d,J= 8.7 Hz, 2H), 7.00 (d,J= 8.8 Hz, 2H), 3.89 (s, 3H). 13C-NMR

(75 MHz, CDCl3): 162.4, 161.5, 156.4, 133.2, 131.0, 128.5, 121.6, 119.1, 114.3,

108.6, 55.4.

(E)-4-((3,4-Dimethoxyphenylimino)methyl)benzonitrile (2p). CH2Cl2 at room

temperature was used in a sealed tube. A yellow solid was obtained. Yield: 98%; mp:


8.2 Hz, 2H), 6.90 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H). 13C-NMR (75 MHz, CDCl3):

155.4, 149.3, 148.4, 143.9, 140.0, 132.4, 128.8, 118.4, 113.9, 112.4, 111.2, 105.4, 55.9,

55.8.

4Neuvonen, H.; Neuvonen, K.; Fueloep, F. J. Org. Chem.2006, 71, 3141.

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General procedure for addition of sulfoxide (S)-1 and imines 2a-n. Synthesis of the

amines anti-3 and syn-45

SOpTol

Me

SOpTol

Y

NHR'

Ar

R

H

1) LDA

2) Ar-CR=NR'

anti-3a-n(S)-1

SOpTol

Y

NHR'

Ar

R

H

syn-4a, 4f

+

A solution of n-BuLi (0.6 mmol, 2.3 M in hexane) was added to iPr2NH (0.9

mmol) in THF (3 mL) at 0 C. After stirring for 15 min, the mixture was cooled to 78

C. A solution of the corresponding (S)-1 (0.5 mmol) in THF (2 mL) was added. After

stirring for 15 min, the corresponding N-arylimine 2 (0.5 mmol; the corresponding

imines in each case are indicated below) in THF (1 mL) was added at 78 C. When the

reaction was complete (20-30 min), the resulting reaction mixture was hydrolyzed (1

mL H2O), extracted (3x10 mL Et2O), washed (2x10 mL NaCl sat.), dried (MgSO4), and

the solvent was removed under reduced pressure. Compounds were purified by means

of flash silica gel column chromatography (the eluent used in each case is indicated

below). Yields for each case are given below.

(1R,2S)-N-(4-Methoxyphenyl)-1-phenyl-2-{[( S)-p-tolylsulfinyl]phenyl)}

propylamine (syn-4a).5This compound was obtained as a major diastereoisomer from

the starting materials imine 2a and (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield:

50%; brown solid; mp: 161-163 C. []D20:-8.5 (c 0.6, CHCl3). IR (NaCl):3320, 1511,

1238, 1028 cm-1. 1H-RMN (300 MHz): 7.63 (dd,J= 7.7, 1.5 Hz, 1H), 7.43-7.11 (m,

13H), 6.67 (d,J= 8.9 Hz, 1H), 6.43 (d,J= 8.9 Hz, 2H), 4.63 (bs, 1H), 4.50 (d,J= 5.9

Hz, 1H), 4.07 (dq,J= 7.0, 5.9 Hz, 1H), 3.70 (s, 3H), 2.41 (s, 3H), 1.31 (d,J= 7.0 Hz,

3H). 13C-NMR (75MHz, CDCl3): 151.8, 143.9, 142.9, 141.6, 141.5, 140.8, 131.4,

5 Garca Ruano, J. L.; Aleman, J.; Alonso, I.; Parra, A.; Marcos, V.; Aguirre, J. Chem. Eur. J. 2007, 13,6179.

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129.7, 128.9, 128.0, 127.9, 127.5, 126.8, 127.4, 125.5, 114.8, 114.6, 114.5, 63.5, 55.6,

40.4, 21.2, 17.9. Anal. Calcd for C29H29NO2S1:C, 76.45; H, 6.42; N, 3.07; S, 7.02;

Found: C, 76.00; H, 6.31; N, 3.18; S, 6.73.

(1S,2S)-N-(4-Methoxyphenyl)-1-phenyl-2-{[( S)-p-tolylsulfinyl]phenyl)}propylamine

(anti-3a).5This compound was obtained as a minor diastereoisomer from the starting

materials imine 2a and (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield: 28%;

brown solid; mp: 161-162 C. []D20: +144.7 (c 0.5, CHCl3). IR (NaCl):3321, 1511,

1237, 1028 cm-1. 1H-RMN (300 MHz): 8.01 (d,J= 7.6 Hz, 1H), 7.61-7.10 (m, 13H),

6.57 (d, J= 9.0 Hz, 1H), 6.17 (d, J= 9.0 Hz, 2H), 4.40 (bs, 1H), 4.20 (d, J= 9.7 Hz,

1H), 3.64 (s, 3H), 3.59 (dq,J= 10.0, 7.0 Hz, 1H), 2.41 (s, 3H), 0.74 (d,J= 7.0 Hz, 3H).

13C-NMR (75MHz, CDCl3): 151.1, 145.2, 142.8, 141.0, 140.4, 132.4, 129.9, 128.3,

127.6, 127.5, 127.3, 127.1, 126.9, 125.6, 114.4 (2C), 113.9 (2C), 64.2, 55.6, 40.4, 21.3,

19.4.

(1R,2S)-N-(4-Methoxyphenyl)-1-(4-methoxyphenyl)-2-{[( S)-p-

tolylsulfinyl]phenyl)}propylamine (anti-3b) This compound was obtained as the sole

diastereoisomer from the starting materials imine 2b and (S)-1. Chromatography: n-

hexane-AcOEt 3:1; yield: 61%; brown solid; mp: 81-83 C. []D20: +13.4 (c 0.5,

CHCl3). IR (NaCl):3320, 1610, 1511, 1241, 1030 cm-1. 1H-RMN (300 MHz): 7.62

(dd, J= 7.7, 1.5 Hz, 1H), 7.45-7.30 (m, 3H), 7.26-7.18 (m, 4H), 7.05 (d, J= 8.7 Hz,

2H), 6.73 (d,J= 8.7 Hz, 2H), 6.64 (d,J= 9.0 Hz, 2H), 6.42 (d,J= 9.0 Hz, 2H), 4.44 (d,

J= 6.0 Hz, 1H), 4.01 (dc,J= 7.0, 6.0 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 2.40 (s, 3H),

1.28 (d, J = 7.0 Hz, 3H). 13C-NMR (75MHz, CDCl3): 158.4, 151.7, 144.4, 142.9,

141.7, 141.1, 131.4, 130.0, 129.6, 129.0, 128.5, 127.9, 127.5, 125.5, 116.3, 114.6,

114.5, 113.4, 63.1, 55.6, 55.0, 40.5, 21.2, 18.1

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(1R,2S)-N-(4-Methoxyphhenyl)-1-(4-methylphenyl)-2-{[( S)-p-

tolylsulfinyl]phenyl)}propylamine (anti-3c). This compound was obtained as a minor

diastereoisomer from the starting materials imine 2c and (S)-1. Chromatography: n-

hexane-AcOEt 2:1; yield: 26%; brown solid; mp: 132-134C. []D20: +23.9 (c 0.4,

MeOH). IR (NaCl):3323, 1510, 1237, 1058 cm-1. 1H-RMN (300 MHz): 7.99 (d,J=

7.4 Hz, 1H), 7.57 (d,J= 8.3 Hz, 2H), 7.50-7.40 (m, 3H), 7.35-7.20 (m, 4H), 7.15 (d,J=

7.8 Hz, 2H), 6.55 (d,J= 9.0 Hz, 2H), 6.14 (d,J= 9.0 Hz, 2H), 4.27 (bs, 1H), 4.15 (d, J

= 10.2 Hz, 1H), 3.63 (s, 3H), 3.54 (dc,J= 10.2, 6.9 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H),


141.3, 139.7, 136.6, 132.3 (2C), 130.0, 129.0, 127.5, 127.4, 127.2, 125.9, 125.7, 124.4,

113.9, 64.1, 55.6, 40.6, 21.0, 19.5. Anal. Calcd for C24H22NO2S: C, 76.72; H, 6.65; N,

2.98; S, 6.83; Found: C, 75.41; H, 6.55; N, 2.81; S, 7.20.

(1R,2S)-N-(4-Methoxyphenyl)-1-(4-chlorophenyl)-2-{[( S)-p-

tolylsulfinyl]phenyl)}propylamine (anti-3d). This compound was obtained as a minor

diastereoisomer from the starting materials imine 2d and (S)-1. Chromatography: n-

hexane-AcOEt 2:1; yield: 21%; yellow solid; mp: 136-138C. []D20: +13.8 (c 1.0,

CHCl3).1H-RMN (300 MHz): 7.90 (d,J= 6.4 Hz, 1H), 7.50-7.35 (m, 5H), 7.25-7.22

(m, 6H), 6.50 (d,J= 6.8 Hz, 2H), 6.09 (d,J= 6.7 Hz, 2H), 4.60 (bs, 1H), 4.08 (dd, J=

6.2, 3.8 Hz, 1H), 3.59 (s, 3H), 3.55-3.47 (m, 1H), 2.33 (s, 3H), 0.60 (d,J= 6.9 Hz, 3H).

13C-NMR (75MHz, CDCl3): 151.1, 145.3, 141.9, 141.8, 141.6, 141.2, 141.1, 132.7,

132.6, 129.9, 128.9, 128.6, 128.1, 127.8, 127.0, 125.4, 114.5, 113.9, 63.9, 55.7, 40.1,

21.3, 19.1.

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(1S,2S)-N-(4-Methoxyphenyl)-1-(4-nitrilephenyl)-2-{[(S)-p-

tolylsulfinyl]phenyl)}propylamine (anti-3e). This compound was obtained as a minor

diastereoisomer from the starting materials imine 2e and (S)-1. Chromatography: n-

hexane-AcOEt 2:1; yield: 28%; brown oil. []D20: +114.2 (c 0.96, CHCl3). 1H-RMN

(300 MHz): 7.56 (d,J= 8.1 Hz, 1H), 7.47-7.40 (m, 3H), 7.28-7.22 (m, 7H), 6.98-6.88

(m, 5H), 4.76 (d, J= 9.3 Hz, 1H), 3.85 (s, 3H), 3.41 (t, J= 7.9 Hz, 1H), 2.48 (s, 3H),


136.9, 133.4, 129.8 (2C), 129.1 (2C), 128.5, 127.5, 127.2, 124.3 (2C), 123.1, 118.7,

114.3, 107.7, 77.9, 55.3, 46.2, 21.1, 17,4. MS (FAB+) m/z 481 (M+1, 100), 480 (73),

459 (34), 415 (46). HRMS (M+H)+ calcd for C30H28N2O2S: 481.1949; Found:

481.1943.

(1S,2S)-N-Phenyl-1-(4-methoxyphenyl)-2-{[( S)-p-tolylsulfinyl]phenyl)}propylamine

(anti-3f).5 This compound was obtained as a minor diastereoisomer from the starting

materials imine 2f and (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield: 25%;

yellow oil; []D20:+138.1 (c 1.2, CHCl3). IR (NaCl): 3324, 2930, 1605, 1504 cm

-1. 1H-

NMR (300 MHz): 7.96 (d,J= 7.3 Hz, 1H), 7.65-7.20 (m, 10H), 6.93 (t, J= 8.5 Hz,

1H), 6.88 (d,J= 8.5 Hz, 2H), 6.47 (t,J= 7.3 Hz, 1H), 6.30 (d,J= 7.7 Hz, 2H), 4.80 (d,

J= 6.1 Hz, 1H), 4.16 (dd,J= 10.5, 6.9 Hz, 1H), 3.80 (s, 3H), 3.54 (dq,J= 10.5, 6.9 Hz,

1H), 2.38 (s, 3H), 0.67 (t, J= 6.9 Hz, 3H). 13C-NMR (75MHz, CDCl3): 158.6, 147.0,

145.5, 141.9, 141.8, 141.3, 134.6, 132.5 (2C), 130.0, 128.6, 128.4, 127.7, 126.9, 125.5,

116.1, 113.7, 112.8, 62.9, 55.1, 40.4, 21.3, 19.3. Anal. Calcd for C29H29NO2S: C, 76.45;

H, 6.42; N, 3.07; S, 7.02; Found: C, 76.55; H, 6.41; N, 3.30; S, 7.20.


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(1R,2S)-N-Phenyl-1-(4-methoxyphenyl)-2-{[(S)-p-tolylsulfinyl]phenyl)}

propylamine (syn-4f).5This compound was obtained as a major diastereoisomer from

the starting materials imine 2fand (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield:

36%; yellow oil; []D20: -10.8 (c 0.5, CHCl3). IR (NaCl):3321, 1602, 1510, 1247, 1027

cm-1. 1H-RMN (300 MHz): 7.59 (dd, J= 7.7, 1.6 Hz, 1H), 7.37 (td, J= 7.4, 1.5 Hz,

1H), 7.31 (td, J= 7.6, 1.5 Hz, 1H), 7.22-7.08 (m, 5H), 7.07-6.99 (m, 4H), 6.70 (d, J=

6.7 Hz, 2H), 6.60 (t,J= 7.3 Hz, 1H), 6.43 (dd,J= 8.0, 1.0 Hz, 2H), 4.86 (bs, 1H), 4.48

(d,J= 5.6 Hz, 1H), 3.98 (dq,J= 7.2, 5.6 Hz, 1H), 3.75 (s, 3H), 2.37 (s, 3H), 1.23 (d, J

= 7.2 Hz, 3H).

13

C-NMR (75MHz, CDCl3): 158.5, 147.5, 143.9, 143.0, 141.1, 140.9,

133.2, 131.5, 129.7, 129.2, 128.9, 128.5, 128.1, 127.6, 125.5, 117.2, 113.6, 62.3, 55.1,

40.5, 21.3, 18.2.

(1S,2S)-N-Phenyl-1-phenyl-2-{[(S)-p-tolylsulfinyl]phenyl)}propylamine (anti-3g).5

This compound was obtained as a major diastereoisomer from the starting materials

imine 2g and (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield: 66%; brown solid;

mp: 165-167 C. []D20: +146.9 (c 1.0, CHCl3). IR (NaCl): 3310, 3024, 1608, 1521,

1504 cm-1. 1H-NMR (300 MHz): 7.96 (d, J= 7.5 Hz, 1H), 7.55-7.48 (m, 5H), 7.45-

7.19 (m, 7H), 6.92 (t,J= 7.4 Hz, 2H), 6.45 (t,J= 7.3 Hz, 1H), 6.20 (d,J= 7.7 Hz, 2H),

4.88 (d, J= 4.4 Hz, 1H), 4.20 (dd, J= 10.2, 4.8 Hz, 1H), 3.57 (dq, J= 10.1, 6.8 Hz,

1H), 2.36 (s, 3H), 0.65 (d,J= 6.8 Hz, 3H). 13C-NMR (75MHz, CDCl3): 147.0, 145.4,

142.6, 141.9, 141.8, 141.3, 132.5 (2C), 130.0, 128.6 (2C), 128.3, 127.8, 127.5 (2C),

127.1, 126.9, 125.5, 63.4, 40.2, 21.3, 19.3. Anal. Calcd for C28H27NOS:C, 79.02; H,

6.39; N, 3.29; S, 7.53; Found: C, 78.56; H, 6.39; N, 3.29; S, 7.53.


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N-((1S,2S)-1-(4-Chlorophenyl)-2-(2-(p-tolylsulfinyl)phenyl)propyl)benzenamine

(anti-3h). This compound was obtained as a major diastereoisomer from the starting

materials imine 2h and (S)-1. Chromatography: n-hexane-AcOEt 3:1; yield: 61%; white

solid; mp: 163-165 C. []D20:+166.2 (c 1.0, CHCl3). 1H-NMR (300 MHz): 7.60 (d,J

= 6.9 Hz, 1H), 7.23-7.10 (m, 5H), 7.03-6.94 (m, 6H), 6.60 (t, J= 7.5 Hz, 2H), 6.16 (t,J

= 7.0 Hz, 1H), 5.90 (d,J= 7.8 Hz, 2H), 4.87 (d,J= 6.9 Hz, 1H), 3.85 (dd,J= 6.9, 3.2

Hz, 1H), 3.33-3.22 (m, 1H), 2.06 (s, 3H), 0.27 (d, J= 6.9 Hz, 3H). 13C-NMR (75MHz,

CDCl3): 146.8, 145.6, 141.9, 141.8, 141.5, 141.1, 132.8, 132.7, 129.9, 128.8, 128.7,

128.6, 128.5, 127.9, 126.9, 125.2, 116.4, 112.8, 63.3, 39.9, 21.3, 18.9. MS (FAB+) m/z481 (M+1, 100), 480 (73), 459 (34), 415 (46). HRMS (M+H)+ calcd for C28H26ClNOS:

481. 1949; Found: 481.1943.

(1S,2S)-N-Phenyl-1-(4-nitrilephenyl)-2-{[(S)-p-tolylsulfinyl]phenyl)}propylamine

(anti-3i).5 This compound was obtained as the sole diastereoisomer from the starting

materials imine 2i and (S)-1. Chromatography: n-hexane-AcOEt 1:1; yield: 90%; white

solid; mp: 84-86 C (Et2O). []D20:+138.8 (c 1.1, CHCl3). IR (NaCl): 3297, 2298, 1557,

1518, 1496 cm-1; 1H-NMR (300 MHz): 7.92 (dd,J= 8.3, 1.0 Hz, 1H), 7.64 (d,J= 8.3

Hz, 2H), 7.58 (d,J= 8.3 Hz, 2H), 7.55-7.48 (m, 2H), 7.46 (d,J= 8.2 Hz, 2H), 7.45-7.35

(m, 2H), 7.29 (d,J= 8.2 Hz, 2H), 6.97 (t,J= 7.4 Hz, 2H), 6.52 (t,J= 7.3 Hz, 1H), 6.28

(dd,J= 8.7, 1.1 Hz, 2H), 5.64 (d,J= 7.1 Hz, 1H), 4.28 (dd,J= 10.2, 7.1 Hz, 1H), 3.68

(dq, J = 10.2, 7.0, 1H), 2.38 (s, 3H), 0.55 (d, J = 7.0 Hz, 3H). 13C-NMR (75MHz,

CDCl3): 148.9, 146.4, 145.3, 141.5, 141.4, 140.9, 132.9, 132.2, 129.8, 129.0, 128.7,

128.2, 128.0, 126.9, 124.7, 118.7, 116.5, 112.5, 110.8, 63.5, 39.2, 21.1, 18.4.


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4-Chloro-N-((1S,2S)-1-(4-methoxyphenyl)-2-(2-(p-

tolylsulfinyl)phenyl)propyl)benzenamine (anti-3j). This compound was obtained as a

major diastereoisomer from the starting materials imine 2j and (S)-1. Chromatography:

n-hexane-AcOEt 2:1; yield: 45%; white solid; mp: 160-162 C (Et2O). []D20:+54.6 (c

0.37, CHCl3).1H-NMR (300 MHz): 7.81 (d,J= 6.4 Hz, 1H), 7.64 (d,J= 8.3 Hz, 2H),

7.42-7.30 (m, 5H), 7.16 (d,J= 8.6 Hz, 3H), 6.78-6.74 (m, 3H), 6.02 (d,J= 8.8 Hz, 2H),

5.13 (d,J= 6.8 Hz, 1H), 4.05-3.95 (m, 1H), 3.70 (s, 3H), 3.49-3.44 (m, 1H), 2.26 (s,

3H), 0.48 (d,J= 6.9 Hz, 3H). 13C-NMR (75MHz, CDCl3): 145.9, 141.8, 141.7, 141.1,

134.2, 132.8, 129.9 (2C), 129.9 (2C), 128.5, 128.4, 127.9, 126.9, 126.0, 125.2, 113.8,

113.8, 63.5, 55.2, 40.1, 21.3, 18.4. MS (FAB+) m/z 490 (M+1, 53), 489 (28), 459

(100), 415 (82). HRMS (M+H)+ calcd for C29H28ClNO2S: 490.1616 Found: 490.1608.

4-Chloro-N-((1S,2S)-1-phenyl-2-(2-(p-tolylsulfinyl)phenyl)propyl)benzenamine

(anti-3k).5 This compound was obtained as a major diastereoisomer from the starting

materials imine 2k and (S)-1. Chromatography: n-hexane-AcOEt 1:1; yield: 49%;

yellow solid; mp: 166.5-168.5 C. []D20: +153.5 (c 1.0, CHCl3). IR (NaCl): 3311,

1599, 1492, 1320, 1016, 1012 cm-1. 1H-NMR (300 MHz): 7.91 (d, J= 7.6 Hz, 1H),

7.53-7.20 (m, 8H), 7.16 (d, J= 8.6 Hz, 2H), 6.86 (d, J= 8.9 Hz, 2H), 6.86 (d, J= 8.9

Hz, 2H), 6.18 (d,J= 8.7 Hz, 2H), 5.42 (d, J= 7.2 Hz, 1H), 4.13 (dd, J= 10.3, 7.2 Hz,

1H), 3.61 (dc, J = 10.3, 6.9 Hz), 2.34 (s, 3H), 0.57 (d, J = 6.9 Hz, 3H). 13C-NMR

(75MHz, CDCl3): 145.8, 145.7, 142.2, 141.7, 140.9, 132.8 (2C), 129.8, 128.6, 128.6,

128.3, 127.9, 127.4, 127.2, 126.8, 125.0, 120.4, 113.7, 64.0, 39.8, 21.2, 18.8. Anal.

Calcd for C28H26ClNOS:C, 73.10; H, 5.70; N, 3.04; S, 6.97; Found: C: 72.67; H, 5.64;

N, 3.08; S, 6.70.


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4-Chloro-N-((1S,2S)-1-(4-chlorophenyl)-2-(2-(p-

tolylsulfinyl)phenyl)propyl)benzenamine (anti-3l). This compound was obtained as a

major diastereoisomer from the starting materials imine 2l and (S)-1. Chromatography:

n-hexane-AcOEt 6:1; yield: 50%; yellow solid; mp: 176-178 C. []D20:+122.8 (c 0.47,

CHCl3).1H-NMR (300 MHz): 7.82 (d,J= 7.4 Hz, 1H), 7.48-7.45 (m, 3H), 7.36 (t,J=

7.0 Hz, 3H), 7.26-7.18 (m, 5H), 6.80 (d,J= 8.9 Hz, 2H), 6.11 (d,J= 8.9 Hz, 2H), 5.56

(d,J= 7.1 Hz, 1H), 4.03 (dd,J= 6.9, 3.3 Hz, 1H), 3.57-3.52 (m, 1H), 2.30 (s, 3H), 0.45

(d, J= 7.0 Hz, 3H).

13

C-NMR (75MHz, CDCl3): 145.9, 145.5, 141.6, 141.5, 141.1,

140.9, 133.0, 132.9, 129.9, 129.2, 128.8, 128.6, 128.5, 128.1, 126.9, 124.8, 120.8,

113.7, 63.6, 39.6, 21.2, 18.5. MS (FAB+) m/z 481 (M+1, 9), 460 (21), 459 (100), 415

(98).

4-Cyano-N-((1S,2S)-1-(4-methoxyphenyl)-2-(2-(p-

tolylsulfinyl)phenyl)propyl)benzenamine (anti-3m). This compound was obtained as

a major diastereoisomer from the starting materials imine 2m and (S)-1.

Chromatography: n-hexane-AcOEt 5:1; yield: 64%. []D20:+463.3 (c 1.24, CHCl3).

1H-

NMR (300 MHz): 7.75 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 4.0 Hz, 2H), 7.32-7.04

(m,7H), 6.79 (d, J= 8.7 Hz, 2H), 6.62-6.52 (m, 2H), 6.20 (d,J= 8.9 Hz, 2H), 4.13 (s,

1H), 4.04-4.01 (m, 1H), 3.99 (s, 3H), 3.71-3.52 (m, 1H), 2.24 (s, 3H), 0.36 (d,J= 7.0

Hz, 3H). 13C-NMR (75MHz, CDCl3): 158.9, 150.5, 146.5, 141.3, 141.1, 140.7, 133.7,

133.3, 133.0, 129.9, 129.8, 128.3, 126.8, 124.4, 120.3, 114.3, 113.9, 112.3, 97.0, 76.9,

63.4, 55.1, 39.5, 21.4, 18.3. HRMS (M+H)+ calcd for C30H28N2O2S: 480.1851; Found:

480.1838.

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4-Cyano-N-((1S,2S)-1-phenyl-2-(2-(p-tolylsulfinyl)phenyl)propyl)benzenamine

(anti-3n).5 This compound was obtained as a major diastereoisomer from the starting

materials imine 2n and (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield: 85%;

yellow solid; mp: 188-190 C. []D20: +152.8 (c 0.8, CHCl3). IR (NaCl):3300, 2229,

1608, 1540 cm-1.1H-NMR (300 MHz): 7.85 (d,J= 7.7 Hz, 2H), 7.60-7.20 (m, 10H),

7.16 (d,J= 8.6 Hz, 2H), 6.72 (d, J= 7.1 Hz, 1H), 6.28 (d, J= 8.7 Hz, 2H), 4.14-4.10

(m, 1H), 3.62 (dc, J= 10.3, 6.9 Hz, 1H), 2.36 (s, 3H), 0.45 (d, J= 6.9 Hz, 1H). 13C-

NMR (75MHz, CDCl3): 150.4, 146.4, 141.6, 141.2, 141.0, 140.7, 133.3, 133.0, 130.0,

129.9, 128.5, 128.4, 127.5, 127.2, 126.9, 124.4, 120.7, 112.2, 97.1, 64.0, 39.3, 21.1,

18.2. Anal. Calcd for C29H26N2OS:C, 77.30; H, 5.82; N, 6.22; S, 7.12; Found: C, 76.96;

H, 5.83; N, 6.22; S, 7.12.

(1S,2S)-N-(3,4-Dimethoxyphenyl)-1-phenyl-2propylamine (anti-3o).5 This

compound was obtained as a minor diastereoisomer from the starting materials imine 2o

and (S)-1. Chromatography: n-hexane-AcOEt 2:1; yield: 21%; yellow solid; mp: 90-92

C. []D20: +128.4 (c 0.4, CHCl3).

1H-NMR (300 MHz): 7.93 (d, J = 8.3 Hz, 1H),

7.52-7.22 (m, 12H), 6.47 (d,J= 8.6 Hz, 2H), 5.83 (d,J= 2.5 Hz, 2H), 5.70 (dd,J= 8.6,

2.3 Hz, 1H), 4.66 (bs, 1H), 4.13 (d, J= 10.1 Hz, 1H), 3.65 (s, 3H), 3.59 (dc, J= 10.1,

6.9 Hz, 1H), 2.34 (s, 3H), 0.64 (d,J= 6.9 Hz, 3H). 13C-NMR (75MHz, CDCl3): 149.5,

145.5, 142.9, 142.1, 141.9, 141.1, 140.5, 132.5, 129.9, 128.3, 127.8 (2C), 127.7, 127.4,

127.1 (2C), 126.9, 125.4, 113.0, 103,5, 98.8, 64.5, 56.5, 55.4, 40.2, 21.2, 19.1. Anal.

Calcd for C30H31NO3S:C, 74.20; H, 6.43; N, 2.88; S, 6.60; Found: C: 74.00; H, 6.31; N,

3.18; S, 6.73.


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(1S,2S)-N-(3,4-Dimethoxyphenyl)-1-(4-cyanophenyl)-2propylamine (anti-3p). This

compound was obtained as a unique diastereoisomer from the starting materials imine

2p and (S)-1. Chromatography: n-hexane-AcOEt 1:1; yield: 62%; orange solid; mp: 90-

92 C. []D20:+48.5 (c 0.7, CHCl3).1H-NMR (300 MHz): 7.78 (d, J= 7.3 Hz, 1H),

7.52 (d,J= 8.1 Hz, 2H), 7.45-7.39 (m, 4H), 7.31 (d, J= 8.1 Hz, 3H), 7.15 (d, J= 8.0

Hz, 2H), 6.39 (d,J= 8.6 Hz, 1H), 5.80 (d,J= 6.1 Hz, 1H), 5.61 (dd, J= 6.0, 2.3 Hz,

1H), 5.20-5.19 (m, 1H), 5.18 (bs, 1H), 4.20-4.25 (m, 1H), 3.59 (s, 3H), 3.56 (s, 3H),

2.24 (s, 3H), 0.42 (d, J = 6.9 Hz, 3H). 13C-NMR (75MHz, CDCl3): 149.7, 149.3,

145.5, 141.6, 141.5, 141.5, 140.9, 140.8, 132.9, 132.2, 129.8, 129.1, 128.2, 128.1,126.9, 124.7, 118.7, 112,9, 110.9, 103.1, 98.9, 64.4, 56.6, 55.5, 39.3, 21.1, 18.4.

(1S,2S)-N-Phenyl)-1-(4-trifluorometylphenyl)-2-{[(S)-p-

tolylsulfinyl]phenyl)}propylamine (anti-3q).5 This compound was obtained as a

unique diastereoisomer from the starting materials imine 2q and (S)-1.

Chromatography: n-hexane-AcOEt 2:1; yield: 69%; white solid; mp: 94-96 C. []D20:

+145.6 (c 1, CHCl3). 1H-NMR (300 MHz): 7.96 (d, J= 7.4 Hz, 1H), 7.65-7.35 (m,

10H), 7.32 (d,J= 8.0 Hz, 2H), 7.01-6.95 (m, 1H), 6.52 (t,J= 7.4 Hz, 1H), 6.29 (d,J=

8.7 Hz, 2H), 5.46 (d,J= 7.8 Hz, 1H), 4.30 (dd,J= 10.2, 7.8 Hz, 1H), 3.69 (dc,J= 10.2,

7.0 Hz, 1H), 2.40 (s, 3H), 0.60 (d, J = 10.2 Hz, 3H). 13C-NMR (75MHz, CDCl3):

147.3, 146.7, 145.5, 141.7 (2C), 132.9, 129.9, 128.7 (2C), 128.0, 127.8, 126.9, 125.4,

125.2 (c,JC-F= 25.1 Hz), 125.0, 120.6 (c,JC-F= 269.8 Hz), 116.4, 112.5, 63.5, 39.6, 21.2,

18.7.


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(1R,2S)-N-(2,4,6-Trimethoxyphenyl)-2-phenyl-2-{[(S)-p-tolylsulfinyl]

phenyl)}ethylamine (syn-4o).5 This compound was obtained as the sole

diastereoisomer from the starting materials imine 3o and (S)-1. Chromatography: n-

hexane-AcOEt 3:1; yield: 60%; yellow solid; mp: 73.5-75.5 C; IR(NaCl)= 3317, 1604,

1503, 1461, 1411, 1149, 1028 cm-1. []D20: -63.0 (c 0.5, EtOH). 1H-NMR (300 MHz,

CDCl3): 7.80 (dd,J= 7.9, 1.3 Hz, 1H), 7.62 (d,J= 8.2 Hz, 2H), 7.52 (td,J= 7.3, 1.4

Hz, 1H), 7.38 (td,J= 7.8, 1.2 Hz, 1H), 7.28 (d,J= 8.2 Hz, 2H), 7.28-7.15 (m, 6H), 5.94

(s, 2H), 4.73 (bs, 1H), 4.00-3.95 (m, 2H), 3.66 (s, 3H), 3.61 (s, 6H), 2.39 (s, 3H), 0.95

(d, J= 6.9 Hz, 3H).

13

C-NMR (75 MHz, CDCl3): 154.0, 151.4, 145.7, 143.2, 142.7,

142.1, 140.8, 131.4, 129.7, 127.6, 127.5, 127.4, 126.9, 126.5, 126.4, 125.8, 119.8, 91.6,

63.4, 55.7, 55.2, 40.5, 21.2, 20.5. Anal. Calcd for C31H33NO4S:C, 72.20; H, 6.45; N,

2.72; S, 6.22; Found: C, 71.98; H, 6.32; N, 2.70; S, 6.18.

(1R,2S)-N-(2,4,6-Trimethoxyphenyl)-2-(4-methoxyphenyl)-2-{[(S)-p-tolylsulfinyl]

phenyl)}ethylamine (syn-4p).5 This compound was obtained as a major

diastereoisomer from the starting materials imine 3p and (S)-1. Chromatography: n-

hexane-AcOEt 3:1; yield: 76%; yellow solid; mp: 135-137 C; []D20: -72.5 (c 1.0,

CHCl3);1H-NMR (300 MHz, CDCl3): 7.73 (d,J= 6.7 Hz, 1H), 7.40 (d,J= 8.1 Hz,

2H), 7.25-7.19 (m, 1H), 7.14-6.97 (m, 4H), 6.66 (t,J= 8.5 Hz, 2H), 7.02 (d,J= 8.5 Hz,

2H), 5.97 (s, 2H), 4.78 (t, J= 7.4 Hz, 1H), 3.65 (s, 3H), 3.63 (s, 6H), 3.60 (s, 3H), 3.25

(dd, J= 6.8, 6.7 Hz, 1H), 3.07 (dd, J= 7.6, 7.4 Hz, 1H), 2.26 (s, 3H). 13C-NMR (75

MHz, CDCl3): 158.2, 154.6, 152.3, 151.2, 143.5, 141.8, 141.0, 137.9, 135.2, 130.4,

129.7, 127.6, 127.3, 125.6, 124.7, 118.8, 113.2, 91.2, 60.7, 55.6, 55.2, 54.9, 39.7, 21.2.


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S14

N-((SS,2S,3S)-1,1,1-Trifluoro-3-(2-(p-tolylsulfoxide)phenyl)butan-2-yl)-4-amine

(anti-11). This product was obtained by means of a standard procedure.6 Yield: 72%;

brown; []D20:-19.3 (c 1.1, CHCl3);

1H-NMR (300 MHz, CDCl3): 7.79 (d,J= 7.4 Hz,

1H), 7.44-7.19 (m, 7H), 4.06-4.04 (m, 1H), 3.61-3.58 (m, 1H), 3.25-3.24 (m, 1H), 2.30

(s, 3H), 1.12 (m, 3H). 13C-NMR (75 MHz, CDCl3): 143.7, 142.9, 141.5, 141.4, 132.2,

129.9, 127.7, 127.3, 127.2, 125.7, 58.5 (q, JCF=28.4 Hz), 35.3, 29.7, 21.3, 19.4.19F-

NMR (CDCl3, 282.4 MHz): -73.6 (s, 3F). HRMS (M+H)+ calcd for C17H19F3NOS:

342.1130; Found: 542.1139.

4-Chloro-N-((1S,2S)-1-(4-chlorophenyl)-2-(2-(p-

tolylsulfinyl)phenyl)propyl)benzenamine (16; Ref. 12, Scheme 1). This compound

was obtained as the sole diastereoisomer from the starting materials imine 2b and (S)-

15.6 Chromatography: n-hexane-AcOEt 2:1; yield: 38%; orange oil. []D

20: +28.7 (c

0.47, CHCl3).1H-NMR (300 MHz): 7.46 (d,J=8.1 Hz, 2H), 7.37 (s, 1H), 7.21-7.16

(m, 7H), 6.64 (s, 1H), 6.43 (d,J= 8.9 Hz, 2H), 6.00 (d,J= 8.9 Hz, 2H), 3.88 (s, 3H),

3.80 (d, J= 8.9 Hz, 1H), 3.70 (s, 3H), 3.70-3.52 (s, 3H), 3.47-3.37 (m, 1H), 2.27 (s,

3H), 0.71 (d,J= 7.0 Hz, 3H). 13C-NMR (75MHz, CDCl3): 151.9, 151.4, 148.0, 142.5,

142.4, 141.5, 141.4, 137.4, 133.6, 130.0, 128.3, 127.6, 127.2, 125.8, 114.4, 114.13,

109.8, 109.3, 64.4, 56.0, 40.4, 21.3, 19.2. HRMS (M+H)+ calcd for C31H34NO4S:

516.21960; Found: 516.2209.

General procedure for Synthesis of the amines syn-A

SOpTol

Me

1) LDA

(S)-1

SOpTol

NH

syn-A CF3

N

OMe

2)

F3C

OMe

6 Garca Ruano, J. L.; Alemn, J.; Cataln, S.; Marcos, V.; Monteagudo, S.; Parra, A.; del Pozo, C.;Fustero, S.Angew. Chem. Int. 2008, 47, 7941.

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(1S,2S)-N-(4-Methoxyphenyl)-1-(4-trifluoromethylphenyl)-2-{[(S)-p-

tolylsulfinyl]phenyl)}propylamine (syn-A). This compound was obtained as the sole

diastereoisomer from the starting materials (S)-1 and imine corresponding.

Chromatography: n-hexane-AcOEt 4:1; yield: 40%; orange oil. 1H-NMR (300 MHz):

7.52 (d,J=8.1 Hz, 1H), 7.50-7.24 (m, 5H), 7.19-7.16 (m, 2H), 7.12-7-00 (m, 4H), 6.54

(d,J= 6.6 Hz, 2H), 6.26 (d, J= 6.5 Hz, 2H), 4.41 (d, J= 5.9 Hz, 2H), 3.93 (t,J= 6.6

Hz, 1H), 3.58 (s, 3H), 2.29 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). 13C-NMR (75MHz,

CDCl3): 152.2, 145.9, 143.4, 142.8, 141.2, 141.1, 140.8, 131.6, 130.1, 129.8, 129.1,

128.9, 128.4, 127.9, 127.8, 127.7, 126.8, 125.1, (c, JC-F= 69.4 Hz), 114.7, 63.5, 55.7,

40.2, 21.3, 18.0.

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General procedure for Synthesis of the amines syn-B

SOpTol

Me

1) LDA

(S)-1

SOpTol

NH

syn-B CF3

N

OMe

2)

F3C

OMe

OMe

OMe











(1S,2S)-N-(4-Dimethoxyphenyl)-1-(4-trifluoromethylphenyl)-2-{[(S)-p-

tolylsulfinyl]phenyl)}propylamine (syn-B). This compound was obtained as the sole

diastereoisomer from the starting materials (S)-1 and imine corresponding.

Chromatography: n-hexane-AcOEt 4:1; yield: 75%; orange oil.

1

H-NMR (300 MHz):

7.81 (d,J=6.3 Hz, 1H), 7.51-744 (m, 4H), 7.34-7.32 (m, 5H), 7.18-7-15 (m, 2H), 6.40

(dd,J= 6.1, 2.3 Hz, 1H), 5.80-5.78 (m, 1H), 5.65-5.61 (m, 1H), 4.17-4.07 (m, 1H), 3.61

(s, 3H), 3.58 (s, 3H), 2.26 (s, 3H), 0.46 (d,J= 7.1 Hz, 3H). 13C-NMR (75MHz, CDCl3):

149.7, 147.6, 145.6, 144.3, 141.7, 141.2, 141.0, 140.8, 132.9(2C), 129.9(2C), 128.0,

127.8(2C), 126.9, 125.4 (c, JC-F= 70.8 Hz), 124.9, 113.1, 103.2, 98.9, 64.3, 56.6, 55.5,

39.6, 21.2, 18.8.

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NMR studies

Low temperature NMR experiments were performed to study the conformational

behaviour ofanti-15, anti-3a, anti-3b and anti-3fin a Bruker DRX-500 spectrometer. In

all cases, 1 mg of the corresponding compound was dissolved in 0,6 ml of THF-d8 to

get solutions between 1,2-1,3 mM concentration. In this manner, intermolecular

associations were avoided. Prior to every measurement, temperature calibration was

performed with the standard low temperature calibration MeOH 4%/MeOD sample.

Figure 1: 1H NMR spectra of the anti-3f, anti-3b, anti-3a and anti-15 compounds

showing the differences in chemical shift for the same type aromatic rings in each

compound

Compound anti-15 was studied by 1D-Selective NOE experiments, using the

standard double pulse field gradient echo pulse sequence provided by Bruker, in a 5

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S18

mm BBI probe equipped with x,y,z gradients. A mixing time of 600ms with 4096

scans was employed.

Figure 2: 1D Selective NOE: both protons B1 and B2 are inverted. THF-d8, 273 K, 500MHz

Compounds anti-3a, anti-3b and anti-3f were studied by NOESY experiments,

using the standard pulse sequences provided by Bruker, in a 5 mm QNP probe with

a mixing time of 400ms.

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S19

ppm

4.04.55.05.56.06.57.07.58.0 ppm

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

NH

CHNH

CHMe

D2

D1

A3

C2

C1

A2A1

B2

B1

A4

D3

SONH

O

D1

D2

A3

A4

A

B

C

D

A1

A2

B1B2

C1

C2

D3

anti-3a

Figure 3: NOESY spectrum of compound anti-3a. Conditions: mixing time 400 ms,THF-d8, 183 K, 500 MHz

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SONH

O

OD1

D2

A3

A4

A

B

C

D

A1

A2

B1B2

C1

C2

ppm

4.04.55.05.56.06.57.07.5 ppm

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

NH CHNHCHMe

D2D1

A3/A4

C2

C1A2A1

B2

B1

anti-3b

Figure 4: NOESY spectrum of compound anti-3b. Conditions: mixing time 400 ms,THF-d8, 195 K, 500 MHz

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ppm

4.04.55.05.56.06.57.07.5 ppm

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

NH

CHNHCHMe

D2D1

A3

C2

C1A2

A1B2

B1

B3

A4S

ONH

OD1D2

A3

A4

A

B

C

D

A1

A2

B1 B2C1

C2

B3

anti-3f

Figure 5: NOESY spectrum of compound anti-3f. Conditions: mixing time 400 ms,THF-d8, 195 K, 500 MHz

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Molecular mechanics calculations

Molecular mechanics calculations were performed using the MM3* force field as

integrated in Macromodel. Two force field were employed, namely MM3* and OPLS95

for the conformational searches for compound anti-3a, using a bulk dielectric constant

of 20 Debyes. A Monte-Carlo approach was employed to generate all the possible

conformers around the different torsional degrees of freedom of the molecule, including

the O-Me groups. Every generated geometry was exhaustively optimized by conjugate

gradients until convergence was achieved. Conformers within a threshold of 5 kcal/mol

of the global minimum were kept for further analysis and comparison with the NMR

data. Both force fields provided basically the same results in terms of geometries and

relative energies. Only the MM3* results are presented in the discussion.

Table 1: Comparation of the experimental NOE data of compounds anti-3b and anti-3f with thecalculated key interproton distances () found for the lower energy conformers of compound anti-3bDistances from

MM3*calculations A4-D1 A4-B1 A4-CHNH A4-CHMe B1-D1 B1-C1 B1-CHMe CH-CHOrientationanti-3b - conf1 4,08 3,86 2,16 3,77 2,64 4,36 4,86 antianti-3b - conf2 4,05 3,98 2,23 3,78 2,63 2,94 4,85 antianti-3b - conf3 4,07 2,45 2,28 3,77 3,72 3,28 4,55 antianti-3b - conf4 4,04 4,9 4,5 2,15 2,63 >6 4,9 antianti-3b - conf5 3,57 3,97 4,1 3,7 2,97 >6 4,35 gaucheanti-3b - conf6 2,83 3,69 4,06 3,79 2,74 >6 4,35 gaucheanti-3b - conf7 4,5 5,2 2,22 3,79 2,3 3,44 2,12 antianti-3b - conf8 3,88 5,51 3,97 3,74 2,84 3,37 4,43 gaucheanti-3b - conf9 3,7 3,38 4,08 3,77 4,05 >6 3,89 gaucheanti-3b - conf10 2,95 3,28 4,03 3,78 3,91 >6 3,8 gauche

NMR NOEintensities A4-D1 A4-B1 A4-CHNH A4-CHMe B1-D1 B1-C1 B1-CHMe JCH-CHanti-3f m w s w ms ? w 7 Hzanti-3b m w s w ms - w 7 Hz

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Table 2: Comparation of the experimental NOE data of compounds anti-15 and anti-3a with the keyinterproton distances () determined from their X-Ray structuresanti-15 A4-B1 A4-CHNH A4-CHMe B1-C1 B1-CHMe JCH-CH

Distances fromX-Ray structure 3,65 2,31 3,58 5,42 4,07 anti

NMR NOEintensities w s m - ms 10 Hz

anti-3a A4-D1 A4-B1 A4-CHNH A4-CHMe B1-D1 B1-C1 B1-CHMe JCH-CH

Distances fromX-Ray structure 4,32 4,54 2,62 3,56 2,84 5,27 4,55 anti

NMR NOEintensities ? m s w m m m 10 Hz

conf1

conf2

AB

C

D

Superimposition

conf1/conf2

(A)

conf10

conf6

A

B

C

D

Superimposition

conf6/conf10

(B)

(C) conf3

conf4conf7

A

A

B

B

Figure 6: representation of the MM3* calculated low energy conformers ofanti-3b. (A)

Representation of the anti-type conformers, conf1 and conf2, and their superimposition

showing differences in the orientation of C ring. (B) Representation of the gauche-type

conformers, conf6 and conf10, and their superimposition showing ,-stacking between

C and D rings and differences in the orientation of B ring. (C) Representation of the

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minor conformers conf3, conf4 and conf7 contributing to the conformational equilibria

of compunds anti-3a andanti-15, withthe key protons resalted

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X-Ray structure ofanti-3a.7

Figure 8. Ortep diagram for compound anti-3a

7

CCDC 730583 contains the supplementary crystallographic data of compound anti-3a. These data canbe obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the CambridgeCrystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44(1223)336-033, e-mail: [email protected]].

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Figure 9. Ortep diagram for compound anti-3a showing the intermolecular,-stacking

Table 3. Crystal data and structure refinement for datos_m.

Project name: 2009_A Alejandro_Parra PMP 100K NE 131_00058

Project path: F:\2009_A\Alejandro_Parra\131_00058\work\datos_m.

Identification code datos_m

Empirical formula C29 H29 N O2 S

Formula weight 455.59

Temperature 100(2) K

Wavelength 1.54178

Crystal system Orthorhombic

Space group P2(1)2(1)2(1)

Unit cell dimensions a = 9.7621(2) = 90.

b = 10.4752(2) = 90.

c = 24.1815(5) = 90.

Volume 2472.80(9) 3Z 4

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Density (calculated) 1.224 Mg/m3

Absorption coefficient 1.355 mm-1

F(000) 968

Crystal size 0.20 x 0.15 x 0.10 mm3

Theta range for data collection 3.66 to 71.27.Index ranges -11

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Table 4. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (2x 103)

for datos_m. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________S(1) 3729(1) 7313(1) 375(1) 27(1)

C(1) 3705(1) 5740(1) 671(1) 26(1)

C(2) 2471(1) 5230(1) 850(1) 28(1)

C(3) 2432(1) 3986(1) 1044(1) 29(1)

C(4) 3620(2) 3242(1) 1065(1) 29(1)

C(5) 4843(1) 3779(1) 883(1) 31(1)

C(6) 4893(1) 5024(1) 680(1) 29(1)

C(7) 3569(2) 1895(1) 1276(1) 38(1)

C(8) 2962(1) 8169(1) 940(1) 27(1)

C(9) 1695(2) 8698(1) 802(1) 33(1)

C(10) 944(2) 9341(1) 1203(1) 39(1)

C(11) 1480(2) 9457(1) 1730(1) 39(1)

C(12) 2745(2) 8939(1) 1859(1) 33(1)

C(13) 3523(1) 8274(1) 1471(1) 27(1)

C(14) 4880(1) 7672(1) 1635(1) 27(1)

C(15) 4714(2) 6829(2) 2148(1) 36(1)

C(16) 6014(1) 8689(1) 1710(1) 26(1)

C(17) 6967(1) 10429(1) 1117(1) 25(1)

C(18) 7348(1) 10783(1) 583(1) 28(1)

C(19) 8036(1) 11915(1) 476(1) 30(1)

C(20) 8371(1) 12727(1) 908(1) 29(1)

C(21) 8042(1) 12371(1) 1446(1) 29(1)

C(22) 7367(1) 11232(1) 1551(1) 28(1)

C(23) 9111(2) 14360(2) 293(1) 46(1)

C(24) 7347(1) 8073(1) 1897(1) 28(1)C(25) 7898(2) 8332(2) 2414(1) 33(1)

C(26) 9089(2) 7729(2) 2590(1) 40(1)

C(27) 9732(2) 6850(2) 2255(1) 41(1)

C(28) 9192(2) 6582(2) 1738(1) 39(1)

C(29) 8014(2) 7194(2) 1558(1) 34(1)

N(1) 6150(1) 9364(1) 1188(1) 27(1)

O(1) 5211(1) 7668(1) 311(1) 31(1)

O(2) 8994(1) 13904(1) 844(1) 37(1)________________________________________________________________________________

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Table 5. Bond lengths [] and angles [] for datos_m.

_____________________________________________________

S(1)-O(1) 1.5016(10)

S(1)-C(1) 1.7964(14)

S(1)-C(8) 1.7967(14)C(1)-C(6) 1.382(2)

C(1)-C(2) 1.387(2)

C(2)-C(3) 1.385(2)

C(2)-H(2) 0.963(18)

C(3)-C(4) 1.398(2)

C(3)-H(3) 0.949(17)

C(4)-C(5) 1.392(2)

C(4)-C(7) 1.501(2)

C(5)-C(6) 1.394(2)

C(5)-H(5) 0.95(2)

C(6)-H(6) 1.008(18)

C(7)-H(7A) 0.96(3)

C(7)-H(7B) 0.98(3)

C(7)-H(7C) 0.98(3)

C(8)-C(9) 1.3957(19)

C(8)-C(13) 1.401(2)

C(9)-C(10) 1.390(2)

C(9)-H(9) 0.932(18)

C(10)-C(11) 1.381(3)

C(10)-H(10) 0.95(2)

C(11)-C(12) 1.385(2)

C(11)-H(11) 0.91(2)

C(12)-C(13) 1.393(2)

C(12)-H(12) 1.000(19)

C(13)-C(14) 1.5193(19)C(14)-C(15) 1.5317(19)

C(14)-C(16) 1.5469(18)

C(14)-H(14) 0.963(17)

C(15)-H(15A) 0.97(2)

C(15)-H(15B) 0.97(2)

C(15)-H(15C) 0.97(2)

C(16)-N(1) 1.4527(17)

C(16)-C(24) 1.5211(19)C(16)-H(16) 0.950(16)

C(17)-N(1) 1.3821(17)

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C(17)-C(18) 1.395(2)

C(17)-C(22) 1.4016(19)

C(18)-C(19) 1.387(2)

C(18)-H(18) 0.93(2)

C(19)-C(20) 1.387(2)C(19)-H(19) 0.925(18)

C(20)-O(2) 1.3827(17)

C(20)-C(21) 1.390(2)

C(21)-C(22) 1.387(2)

C(21)-H(21) 0.960(18)

C(22)-H(22) 0.941(17)

C(23)-O(2) 1.420(2)

C(23)-H(23A) 0.95(2)

C(23)-H(23B) 0.99(2)

C(23)-H(23C) 0.99(3)

C(24)-C(25) 1.390(2)

C(24)-C(29) 1.394(2)

C(25)-C(26) 1.390(2)

C(25)-H(25) 0.976(19)

C(26)-C(27) 1.378(3)

C(26)-H(26) 0.98(2)

C(27)-C(28) 1.384(3)

C(27)-H(27) 0.96(2)

C(28)-C(29) 1.387(2)

C(28)-H(28) 0.96(2)

C(29)-H(29) 0.923(18)

N(1)-H(1) 0.844(19)

O(1)-S(1)-C(1) 106.34(6)

O(1)-S(1)-C(8) 110.86(6)C(1)-S(1)-C(8) 98.57(6)

C(6)-C(1)-C(2) 120.99(12)

C(6)-C(1)-S(1) 119.55(11)

C(2)-C(1)-S(1) 119.29(10)

C(3)-C(2)-C(1) 119.49(13)

C(3)-C(2)-H(2) 119.0(10)

C(1)-C(2)-H(2) 121.5(10)

C(2)-C(3)-C(4) 120.91(13)C(2)-C(3)-H(3) 119.3(9)

C(4)-C(3)-H(3) 119.6(9)

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C(5)-C(4)-C(3) 118.33(12)

C(5)-C(4)-C(7) 121.04(13)

C(3)-C(4)-C(7) 120.63(13)

C(4)-C(5)-C(6) 121.32(13)

C(4)-C(5)-H(5) 118.9(12)C(6)-C(5)-H(5) 119.6(12)

C(1)-C(6)-C(5) 118.94(13)

C(1)-C(6)-H(6) 118.5(10)

C(5)-C(6)-H(6) 122.5(10)

C(4)-C(7)-H(7A) 114(2)

C(4)-C(7)-H(7B) 113.1(15)

H(7A)-C(7)-H(7B) 106(2)

C(4)-C(7)-H(7C) 109.3(16)

H(7A)-C(7)-H(7C) 110(2)

H(7B)-C(7)-H(7C) 104(2)

C(9)-C(8)-C(13) 122.20(13)

C(9)-C(8)-S(1) 112.77(11)

C(13)-C(8)-S(1) 124.99(10)

C(10)-C(9)-C(8) 119.63(16)

C(10)-C(9)-H(9) 122.1(11)

C(8)-C(9)-H(9) 118.3(11)

C(11)-C(10)-C(9) 119.06(14)

C(11)-C(10)-H(10) 119.4(12)

C(9)-C(10)-H(10) 121.6(12)

C(10)-C(11)-C(12) 120.73(15)

C(10)-C(11)-H(11) 120.2(13)

C(12)-C(11)-H(11) 119.0(13)

C(11)-C(12)-C(13) 122.01(15)

C(11)-C(12)-H(12) 120.2(10)

C(13)-C(12)-H(12) 117.8(10)C(12)-C(13)-C(8) 116.35(13)

C(12)-C(13)-C(14) 120.44(13)

C(8)-C(13)-C(14) 123.18(12)

C(13)-C(14)-C(15) 111.01(11)

C(13)-C(14)-C(16) 111.65(11)

C(15)-C(14)-C(16) 112.17(11)

C(13)-C(14)-H(14) 106.9(9)

C(15)-C(14)-H(14) 108.8(10)C(16)-C(14)-H(14) 106.0(10)

C(14)-C(15)-H(15A) 110.2(12)

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C(14)-C(15)-H(15B) 110.2(11)

H(15A)-C(15)-H(15B) 109.3(16)

C(14)-C(15)-H(15C) 113.5(14)

H(15A)-C(15)-H(15C) 110.6(17)

H(15B)-C(15)-H(15C) 102.7(17)N(1)-C(16)-C(24) 112.68(11)

N(1)-C(16)-C(14) 107.36(10)

C(24)-C(16)-C(14) 110.80(11)

N(1)-C(16)-H(16) 110.5(9)

C(24)-C(16)-H(16) 108.4(9)

C(14)-C(16)-H(16) 107.0(9)

N(1)-C(17)-C(18) 118.95(13)

N(1)-C(17)-C(22) 123.54(12)

C(18)-C(17)-C(22) 117.37(12)

C(19)-C(18)-C(17) 122.01(13)

C(19)-C(18)-H(18) 118.3(12)

C(17)-C(18)-H(18) 119.6(12)

C(18)-C(19)-C(20) 119.84(13)

C(18)-C(19)-H(19) 117.2(11)

C(20)-C(19)-H(19) 122.9(11)

O(2)-C(20)-C(19) 124.47(13)

O(2)-C(20)-C(21) 116.45(12)

C(19)-C(20)-C(21) 119.07(13)

C(22)-C(21)-C(20) 120.87(13)

C(22)-C(21)-H(21) 120.8(10)

C(20)-C(21)-H(21) 118.3(10)

C(21)-C(22)-C(17) 120.72(13)

C(21)-C(22)-H(22) 117.7(10)

C(17)-C(22)-H(22) 121.5(10)

O(2)-C(23)-H(23A) 112.0(12)O(2)-C(23)-H(23B) 104.7(13)

H(23A)-C(23)-H(23B) 108.5(18)

O(2)-C(23)-H(23C) 111.7(14)

H(23A)-C(23)-H(23C) 110.4(19)

H(23B)-C(23)-H(23C) 109.3(19)

C(25)-C(24)-C(29) 118.55(14)

C(25)-C(24)-C(16) 121.03(13)

C(29)-C(24)-C(16) 120.37(13)C(24)-C(25)-C(26) 120.69(15)

C(24)-C(25)-H(25) 118.4(11)

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C(26)-C(25)-H(25) 120.9(11)

C(27)-C(26)-C(25) 120.32(16)

C(27)-C(26)-H(26) 119.2(13)

C(25)-C(26)-H(26) 120.5(13)

C(26)-C(27)-C(28) 119.54(15)C(26)-C(27)-H(27) 118.9(11)

C(28)-C(27)-H(27) 121.6(11)

C(27)-C(28)-C(29) 120.40(16)

C(27)-C(28)-H(28) 120.5(12)

C(29)-C(28)-H(28) 119.0(12)

C(28)-C(29)-C(24) 120.49(15)

C(28)-C(29)-H(29) 121.8(11)

C(24)-C(29)-H(29) 117.7(11)

C(17)-N(1)-C(16) 123.62(11)

C(17)-N(1)-H(1) 115.7(12)

C(16)-N(1)-H(1) 115.1(12)

C(20)-O(2)-C(23) 116.12(12)

_____________________________________________________________

Symmetry transformations used to generate equivalent atoms:

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Table 6. Anisotropic displacement parameters (2x 103) for datos_m. The anisotropic

displacement factor exponent takes the form: -22[ h2a*2U11 + ... + 2 h k a* b* U12 ]

______________________________________________________________________________

U11 U22 U33 U23 U13 U12

______________________________________________________________________________S(1) 29(1) 27(1) 24(1) 0(1) -2(1) 0(1)

C(1) 28(1) 27(1) 23(1) -4(1) -2(1) 0(1)

C(2) 24(1) 31(1) 29(1) -4(1) 0(1) 2(1)

C(3) 25(1) 32(1) 31(1) -1(1) 2(1) -3(1)

C(4) 31(1) 27(1) 29(1) -5(1) -2(1) -1(1)

C(5) 26(1) 29(1) 37(1) -4(1) -1(1) 4(1)

C(6) 24(1) 31(1) 32(1) -4(1) 2(1) -2(1)

C(7) 39(1) 29(1) 46(1) 1(1) 3(1) -1(1)

C(8) 27(1) 22(1) 32(1) 1(1) 2(1) -1(1)

C(9) 29(1) 25(1) 45(1) 3(1) -4(1) -1(1)

C(10) 26(1) 27(1) 64(1) 1(1) 3(1) 2(1)

C(11) 34(1) 26(1) 56(1) -5(1) 17(1) -1(1)

C(12) 36(1) 27(1) 35(1) -3(1) 9(1) -6(1)

C(13) 28(1) 22(1) 31(1) 1(1) 4(1) -4(1)

C(14) 29(1) 27(1) 24(1) 1(1) 0(1) -2(1)

C(15) 39(1) 37(1) 34(1) 10(1) -4(1) -7(1)

C(16) 29(1) 27(1) 22(1) 1(1) -1(1) -1(1)

C(17) 21(1) 27(1) 27(1) 2(1) 0(1) 2(1)

C(18) 28(1) 33(1) 24(1) -2(1) 1(1) 2(1)

C(19) 25(1) 38(1) 28(1) 6(1) 4(1) 1(1)

C(20) 20(1) 31(1) 36(1) 6(1) -1(1) -2(1)

C(21) 25(1) 32(1) 30(1) -2(1) -5(1) -1(1)

C(22) 26(1) 34(1) 23(1) 3(1) -1(1) -2(1)

C(23) 38(1) 48(1) 53(1) 20(1) -5(1) -13(1)

C(24) 28(1) 28(1) 28(1) 5(1) 0(1) -4(1)C(25) 32(1) 38(1) 29(1) 5(1) -2(1) -1(1)

C(26) 34(1) 53(1) 34(1) 12(1) -5(1) -2(1)

C(27) 29(1) 44(1) 50(1) 18(1) 0(1) 3(1)

C(28) 34(1) 34(1) 50(1) 4(1) 7(1) 3(1)

C(29) 32(1) 35(1) 36(1) -1(1) -1(1) -1(1)

N(1) 33(1) 28(1) 21(1) 1(1) -2(1) -4(1)

O(1) 34(1) 31(1) 29(1) -2(1) 5(1) -3(1)

O(2) 33(1) 36(1) 42(1) 9(1) -2(1) -9(1)______________________________________________________________________________

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Table 7. Hydrogen coordinates ( x 104) and isotropic displacement parameters (2x 103)

for datos_m.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

H(1) 6023(19) 8913(17) 903(8) 34(4)

H(2) 1635(19) 5717(17) 837(7) 34(4)

H(3) 1576(18) 3619(15) 1141(7) 25(4)

H(5) 5640(20) 3261(19) 872(8) 41(5)

H(6) 5767(17) 5428(17) 545(7) 30(4)

H(7A) 4420(40) 1430(30) 1238(14) 105(10)

H(7B) 3320(30) 1840(20) 1668(11) 71(7)

H(7C) 2830(30) 1430(30) 1086(11) 77(8)

H(9) 1369(18) 8585(16) 444(7) 31(4)

H(10) 70(20) 9697(19) 1124(8) 44(5)

H(11) 990(20) 9850(20) 2002(9) 48(5)

H(12) 3119(18) 9016(17) 2242(8) 33(4)

H(14) 5167(16) 7146(16) 1329(7) 25(4)

H(15A) 3990(20) 6209(19) 2089(8) 43(5)

H(15B) 5560(20) 6388(19) 2227(8) 39(5)

H(15C) 4550(20) 7310(20) 2486(10) 52(6)

H(16) 5713(15) 9253(14) 1992(6) 17(3)

H(18) 7130(20) 10260(19) 287(8) 41(5)

H(19) 8256(17) 12087(16) 111(8) 31(4)

H(21) 8304(17) 12929(17) 1743(7) 33(4)

H(22) 7152(16) 11041(15) 1921(7) 24(4)

H(23A) 8250(20) 14400(19) 113(8) 40(5)

H(23B) 9470(20) 15240(20) 331(9) 55(6)

H(23C) 9770(30) 13840(20) 73(10) 61(7)H(25) 7420(20) 8933(18) 2654(8) 38(5)

H(26) 9460(20) 7900(20) 2957(10) 59(6)

H(27) 10545(19) 6433(18) 2387(7) 37(5)

H(28) 9610(20) 5954(19) 1505(8) 40(5)

H(29) 7642(18) 7036(16) 1214(8) 33(4)

________________________________________________________________________________

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Table 8. Torsion angles [] for datos_m.

________________________________________________________________

O(1)-S(1)-C(1)-C(6) -13.71(12)

C(8)-S(1)-C(1)-C(6) -128.52(11)

O(1)-S(1)-C(1)-C(2) 171.08(10)C(8)-S(1)-C(1)-C(2) 56.27(11)

C(6)-C(1)-C(2)-C(3) 0.5(2)

S(1)-C(1)-C(2)-C(3) 175.66(10)

C(1)-C(2)-C(3)-C(4) 0.3(2)

C(2)-C(3)-C(4)-C(5) -0.3(2)

C(2)-C(3)-C(4)-C(7) -179.94(14)

C(3)-C(4)-C(5)-C(6) -0.5(2)

C(7)-C(4)-C(5)-C(6) 179.08(14)

C(2)-C(1)-C(6)-C(5) -1.4(2)

S(1)-C(1)-C(6)-C(5) -176.48(11)

C(4)-C(5)-C(6)-C(1) 1.4(2)

O(1)-S(1)-C(8)-C(9) 133.46(10)

C(1)-S(1)-C(8)-C(9) -115.32(10)

O(1)-S(1)-C(8)-C(13) -48.71(13)

C(1)-S(1)-C(8)-C(13) 62.51(12)

C(13)-C(8)-C(9)-C(10) -0.8(2)

S(1)-C(8)-C(9)-C(10) 177.09(11)

C(8)-C(9)-C(10)-C(11) 0.9(2)

C(9)-C(10)-C(11)-C(12) -0.2(2)

C(10)-C(11)-C(12)-C(13) -0.6(2)

C(11)-C(12)-C(13)-C(8) 0.64(19)

C(11)-C(12)-C(13)-C(14) -177.46(13)

C(9)-C(8)-C(13)-C(12) 0.06(18)

S(1)-C(8)-C(13)-C(12) -177.58(10)

C(9)-C(8)-C(13)-C(14) 178.10(12)S(1)-C(8)-C(13)-C(14) 0.46(18)

C(12)-C(13)-C(14)-C(15) 51.91(16)

C(8)-C(13)-C(14)-C(15) -126.06(14)

C(12)-C(13)-C(14)-C(16) -74.06(15)

C(8)-C(13)-C(14)-C(16) 107.98(14)

C(13)-C(14)-C(16)-N(1) -58.87(14)

C(15)-C(14)-C(16)-N(1) 175.81(12)

C(13)-C(14)-C(16)-C(24) 177.71(10)C(15)-C(14)-C(16)-C(24) 52.38(16)

N(1)-C(17)-C(18)-C(19) 172.74(13)

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C(22)-C(17)-C(18)-C(19) -3.2(2)

C(17)-C(18)-C(19)-C(20) 0.4(2)

C(18)-C(19)-C(20)-O(2) -176.69(12)

C(18)-C(19)-C(20)-C(21) 1.9(2)

O(2)-C(20)-C(21)-C(22) 177.47(12)C(19)-C(20)-C(21)-C(22) -1.2(2)

C(20)-C(21)-C(22)-C(17) -1.7(2)

N(1)-C(17)-C(22)-C(21) -171.89(13)

C(18)-C(17)-C(22)-C(21) 3.82(19)

N(1)-C(16)-C(24)-C(25) 125.00(13)

C(14)-C(16)-C(24)-C(25) -114.69(14)

N(1)-C(16)-C(24)-C(29) -57.55(16)

C(14)-C(16)-C(24)-C(29) 62.76(16)

C(29)-C(24)-C(25)-C(26) 0.1(2)

C(16)-C(24)-C(25)-C(26) 177.60(13)

C(24)-C(25)-C(26)-C(27) -0.9(2)

C(25)-C(26)-C(27)-C(28) 0.8(2)

C(26)-C(27)-C(28)-C(29) 0.1(2)

C(27)-C(28)-C(29)-C(24) -0.9(2)

C(25)-C(24)-C(29)-C(28) 0.8(2)

C(16)-C(24)-C(29)-C(28) -176.72(13)

C(18)-C(17)-N(1)-C(16) 161.43(13)

C(22)-C(17)-N(1)-C(16) -22.9(2)

C(24)-C(16)-N(1)-C(17) -64.77(16)

C(14)-C(16)-N(1)-C(17) 172.96(12)

C(19)-C(20)-O(2)-C(23) 9.1(2)

C(21)-C(20)-O(2)-C(23) -169.45(13)

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Symmetry transformations used to generate equivalent atoms:

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Table 9. Hydrogen bonds for datos_m [ and ].

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D-H...A d(D-H) d(H...A) d(D...A)

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