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Volume 67 
Part 3 
Pages o100-o103  
March 2011  

Received 23 October 2010
Accepted 20 December 2010
Online 8 February 2011

Optically active diaryl tetrahydroisoquinoline derivatives

aSchool of Pharmacy and Pharmacology, University of KwaZulu Natal, Durban 4000, South Africa, and bSchool of Chemistry, University of KwaZulu Natal, Durban 4000, South Africa
Correspondence e-mail: maguireg@ukzn.ac.za

In (1R,3S)-6,7-dimethoxy-3-(methoxydiphenylmethyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, C31H31NO3, (I)[link], and (1R,3S)-2-benzyl-3-[diphenyl(trimethylsiloxy)methyl]-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, C40H43NO3Si, (II)[link], the absolute configurations have been confirmed to be R and S at the isoquinoline 1- and 3-positions, respectively, by NMR spectroscopy experiments. Both structures have monoclinic (P21) symmetry and the N-containing six-membered ring assumes a half-chair conformation. The asymmetric unit of (I)[link] contains one molecule, while (II)[link] has two molecules within the asymmetric unit. These structures are of interest with respect to the conformation around the exocyclic C-C bond: (I)[link] displays an ap (antiperiplanar) conformation, while (II)[link] displays an sc-exo (synclinal) conformation around this bond. These conformations are significant for stereocontrol when these compounds are used as catalysts. Various C-H...[pi] and C-H...O bonds link the molecules together in the crystal structure of (I)[link]. In the crystal structure of (II)[link], three intermolecular C-H...[pi] hydrogen bonds help to establish the packing.

Comment

The tetrahydroisoquinoline (TIQ) molecule and its derivatives have been widely investigated due to their biological and pharmaceutical properties. Given our recent success with TIQ-based ligands for catalytic asymmetric transfer hydrogenation of prochiral ketones, Henry reactions and hydrogenation of olefins (Peters et al., 2010[Peters, B. K., Chakka, S. K., Naicker, T., Maguire, G. E. M., Kruger, H. G., Andersson, P. G. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 679-687.]). We decided to investigate the potential of TIQ derivatives as organocatalysts. Compound (I)[link] has recently been synthesized and evaluated as a novel iminium-activated organocatalyst in an asymmetric Diels-Alder reaction (Naicker, Petzold et al., 2010[Naicker, T., Petzold, K., Singh, T., Arvidsson, P. I., Kruger, H. G., Maguire, G. E. M. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 2859-2867.]). Compound (II)[link] is novel and is the precursor to the same class of organocatalysts based on a (1R,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline backbone.

Derived from commercially available L-DOPA, the absolute stereochemistry of (I)[link] and (II)[link] was confirmed to be R and S at the C1 and C9 positions by 1H NMR, as shown in Figs. 1[link] and 2[link], respectively.

[Scheme 1]

Both structures have monoclinic (P21) symmetry. Compound (I)[link] has a single molecule in the asymmetric unit, while (II)[link] has two molecules within the asymmetric unit. Molecule (I)[link] has a methyl group at the O3 position, whilst (II)[link] has a trimethylsilyl group in this position. In addition, (II)[link] has a benzyl group on the N atom.

In the structure of (I)[link], intermolecular C-H...[pi] and C-H...O interactions involving atoms O1 and O2 link the molecules into extended chains which run parallel to the b axis (Table 1[link] and Fig. 3[link]). In the chain, the molecules are arranged so that their tails, linked by the C-H...O interactions, point towards the core of the chain and their heads protrude to the outer edges of the chain, with adjacent molecules alternating from side-to-side. The C-H...[pi] interactions link the heads of those molecules lying on the same side of the chain core.

In the structure of (II)[link], each independent molecule displays an intramolecular C-H...[pi] interaction, while a single intermolecular C-H...[pi] interaction involving C35A-H links just the two independent molecules (Table 2[link]). An extended network of interactions is not present. The crystal packing of (II)[link] reveals that the pseudosymmetry relates the two independent molecules within the asymmetric unit resulting in a layered packing along the a axis (Fig. 4[link]).

From the crystal structures, it is evident that the N-containing six-membered rings assume half-chair conformations (Figs. 1[link] and 2[link]). This result differs from two analogous compounds, namely (1R,3S)-methyl 2-benzyl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate and (1R,3S)-methyl 6,7-dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, which assume half-boat conformations (Naicker et al., 2009[Naicker, T., McKay, M., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2009). Acta Cryst. E65, o3278.]; Naicker, Govender et al., 2010a[Naicker, T., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2010a). Acta Cryst. E66, o3105.]). The current study confirms our previous postulation that the change in conformation is a result of the introduction of the phenyl groups at the C1 position.

According to the Cambridge Structural Database (Version 5.31; Allen, 2002[Allen, F. H. (2002). Acta Cryst. B58, 380-388.]), the only other crystal structure of a tetrahydroisoquinoline derivative with diaryl substitution at the C10 position is compound (III)[link] (see Scheme[link]), which we reported recently (Naicker, Govender et al., 2010b[Naicker, T., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2010b). Acta Cryst. E66, o638.]). In this crystal structure, the methanol O atom is a free OH group. Due to the lack of analogous structures, these diaryl tetrahydroisoquinoline alcohols were compared with proline diaryl alcohols (Seebach et al., 2008[Seebach, D., Groselj, U., Badine, D. M., Schweizer, W. B. & Beck, A. K. (2008). Helv. Chim. Acta, 91, 1999-2034.]). Compound (III)[link] displays a similar conformation to its proline analogue, which displays a gauche or sc-endo (synclinal) conformation around the O3-C10-C9-N1 bond, with the OH group partially covering the piperidine ring with a torsion angle of -77.0 (2)°.

Compound (I)[link] displays an ap (antiperiplanar) conformation around the exocyclic C9-C10 bond, with an O3-C10-C9-N1 torsion angle of 171.5 (1)°. This conformation has only been found in a few examples of N-amino prolinol methyl esters (Seebach et al., 2008[Seebach, D., Groselj, U., Badine, D. M., Schweizer, W. B. & Beck, A. K. (2008). Helv. Chim. Acta, 91, 1999-2034.]).

Proline diphenyl OTMS (OTMS is trimethylsiloxy) analogues exhibit an sc-exo conformation around the exocyclic ethane bond, with a torsion angle of 61.0°. Both molecules of (II)[link] (Fig. 2[link]) display an sc-endo conformation, with torsion angles of -81.1 (3) and -84.8 (2)°. A possible reason for this change could be that the benzyl group on the N atom forces the phenyl rings at the C10 atom to be the furthest away from it, hence adopting the sc-endo conformation.

Proline diaryl alcohols have been used as successful chiral catalysts by exploiting the same rotation along the C9-C10 bond (Diner et al., 2008[Diner, P., Kjaersgaard, A., Lie, M. A. & Jorgensen, K. A. (2008). Chem. Eur. J. 14, 122-127.]). This change, which is brought about by different groups on the methanol O atom, makes the current study particularly useful. This feature is found in (I)[link] which, when tested for its catalytic activity in the Diels-Alder reaction, showed poor yields. The structural data demonstrated how we could improve the catalytic reactivity by reducing the steric bulk of the ligand. A successful catalyst was obtained by removing the phenyl moieties from (I)[link] (Naicker, Petzold et al., 2010[Naicker, T., Petzold, K., Singh, T., Arvidsson, P. I., Kruger, H. G., Maguire, G. E. M. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 2859-2867.]).

[Figure 1]
Figure 1
The molecular structure of (I)[link], showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms have been omitted for clarity.
[Figure 2]
Figure 2
The molecular structure of (II)[link], showing the atom-numbering scheme. There are two molecules in the asymmetric unit, labelled with suffixes A and B. Displacement ellipsoids are drawn at the 50% probability level. H atoms and some atom labels have been omitted for clarity.
[Figure 3]
Figure 3
A partial projection of the structure of (I)[link], viewed along [010]. Dashed lines indicate intermolecular interactions. H atoms not involved in intermolecular interactions have been omitted for clarity.
[Figure 4]
Figure 4
A partial projection of the structure of (II)[link], viewed along [100]. The top and bottom layers contain only B molecules, while the central layer contains A molecules. Dashed lines indicate intermolecular interactions. H atoms not involved in intermolecular interactions have been omitted for clarity.

Experimental

To (1R,3S)-2-benzyl-3-(1,1-diphenylethyl)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (0.4 g, 0.72 mmol), derived from L-DOPA (Naicker, Petzold et al., 2010[Naicker, T., Petzold, K., Singh, T., Arvidsson, P. I., Kruger, H. G., Maguire, G. E. M. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 2859-2867.]), in MeOH-THF (1:1 v/v, 20 ml) was added half an equivalent by mass of 10% palladium on carbon Pd/C under hydrogen (approximately 1 atm). The reaction was stirred for 2 h. The crude product was obtained by filtering the Pd/C through a plug of Celite and the filtrate was then concentrated to dryness. The resulting residue was purified by column chromatography (50:50 EtOAc-hexane, RF = 0.6) to yield (I)[link] as a white solid [yield 0.2 g, 60%; m.p. 463-465 K; [[alpha]]20D -10.0 (c 0.11 in CHCl3)]. Recrystallization from ethyl acetate afforded colourless crystals suitable for X-ray analysis. IR (neat, [nu]max, cm-1): 2934, 1514, 1448, 1244, 1224, 1063, 698; 1H NMR (400 MHz, CDCl3, [delta], p.p.m.): 7.47-7.12 (m, 12H), 7.08 (t, J = 7.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 6.65 (s, 1H), 6.40 (s, 1H), 5.23 (s, 1H), 3.95 (dd, J = 11.5 and 3.6 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 2.92-2.75 (m, 4H), 2.52 (dd, J = 16.2 and 11.5 Hz, 3H).

To a stirred solution of [(1R,3S)-3-(hydroxydiphenylmethyl)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl](phenyl)methanone (0.6 g, 1.1 mmol), derived from L-DOPA (Naicker, Petzold et al., 2010[Naicker, T., Petzold, K., Singh, T., Arvidsson, P. I., Kruger, H. G., Maguire, G. E. M. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 2859-2867.]), in dry dichloromethane (20 ml) and triethylamine (0.18 ml, 1.3 mmol), trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.33 mmol) was added dropwise at 273 K under an inert atmosphere. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was washed with water, the organic extracts were combined and dried over anhydrous Na2SO4, and the solvent was removed in vacuo. The resulting residue was purified by column chromatography (20:80 EtOAc-hexane, RF = 0.55) to afford (II)[link] as a white solid [yield 0.5 g, 75%; m.p. 458-460 K; [[alpha]]20D 57.58 (c 0.33 in CHCl3)]. Recrystallization from acetone afforded colourless crystals suitable for X-ray analysis. IR (neat, [nu]max, cm-1): 2956, 1513, 1245, 839, 696; 1H NMR (400 MHz, CDCl3, [delta], p.p.m.): 7.17 (m, 14H), 6.84 (m, 5H), 6.63 (m, 2H), 6.36 (s, 1H), 4.57 (s, 1H), 4.38 (d, J = 13.63 Hz, 1H), 4.24 (dd, J = 3.38 and 12.13 Hz, 1H), 4.00 (s, 3H), 3.73 (s, 3H), 3.39 (dd, J = 4.32 and 12.58 Hz, 1H), 3.31 (d, J = 13.85 Hz, 1H), 2.29 (dd, J = 3.38 and 16.88 Hz, 1H), 0.0 (s, 9H).

Compound (I)[link]

Crystal data
  • C31H31NO3

  • Mr = 465.57

  • Monoclinic, P 21

  • a = 11.4071 (14) Å

  • b = 6.4750 (8) Å

  • c = 16.961 (2) Å

  • [beta] = 101.707 (2)°

  • V = 1226.7 (3) Å3

  • Z = 2

  • Mo K[alpha] radiation

  • [mu] = 0.08 mm-1

  • T = 173 K

  • 0.22 × 0.14 × 0.09 mm

Data collection
  • Bruker APEXII DUO diffractometer

  • Absorption correction: multi-scan (SADABS; Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) Tmin = 0.645, Tmax = 0.746

  • 11498 measured reflections

  • 3737 independent reflections

  • 3191 reflections with I > 2[sigma](I)

  • Rint = 0.051

Refinement
  • R[F2 > 2[sigma](F2)] = 0.043

  • wR(F2) = 0.108

  • S = 1.05

  • 3737 reflections

  • 320 parameters

  • 2 restraints

  • H atoms treated by a mixture of independent and constrained refinement

  • [Delta][rho]max = 0.23 e Å-3

  • [Delta][rho]min = -0.23 e Å-3

Table 1
Hydrogen-bond geometry (Å, °) for (I)[link]

Cg is the centroid of the C18-C23 ring.

D-H...A D-H H...A D...A D-H...A
C11-H11A...Cgi 0.98 2.57 3.45 (2) 150
C30-H30A...O1ii 0.98 2.54 3.356 (2) 140
C30-H30A...O2ii 0.98 2.59 3.400 (2) 140
Symmetry codes: (i) x, y+1, z; (ii) [-x, y-{\script{1\over 2}}, -z+1].

Compound (II)[link]

Crystal data
  • C40H43NO3Si

  • Mr = 613.84

  • Monoclinic, P 21

  • a = 11.045 (10) Å

  • b = 17.008 (15) Å

  • c = 18.489 (15) Å

  • [beta] = 105.287 (15)°

  • V = 3350 (5) Å3

  • Z = 4

  • Mo K[alpha] radiation

  • [mu] = 0.11 mm-1

  • T = 100 K

  • 0.22 × 0.12 × 0.10 mm

Data collection
  • Bruker APEXII DUO diffractometer

  • Absorption correction: multi-scan (SADABS; Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) Tmin = 0.976, Tmax = 0.989

  • 37993 measured reflections

  • 17263 independent reflections

  • 11255 reflections with I > 2[sigma](I)

  • Rint = 0.064

Refinement
  • R[F2 > 2[sigma](F2)] = 0.057

  • wR(F2) = 0.124

  • S = 0.99

  • 17263 reflections

  • 812 parameters

  • 1 restraint

  • H-atom parameters constrained

  • [Delta][rho]max = 0.38 e Å-3

  • [Delta][rho]min = -0.41 e Å-3

  • Absolute structure: Flack (1983)

  • Flack parameter: 0.00 (10), 8119 Friedel pairs

Table 2
Hydrogen-bond geometry (Å, °) for (II)[link]

Cg1, Cg2, Cg3 and the centroids of the C26B-C31B, C32A-C37A and C32B-C37B rings, respectively.

D-H...A D-H H...A D...A D-H...A
C35A-H35A...Cg1i 0.95 2.80 3.669 (3) 152
C40A-H40A...Cg2 0.98 2.71 3.540 (3) 143
C40B-H40D...Cg3 0.98 2.64 3.449 (4) 140
Symmetry code: (i) x+1, y, z+1.

Atom H1N on N1 of (I)[link] was located in a difference electron-density map and refined isotropically with a simple bond-length restraint of N1-H1N = 0.96 (1) Å. All remaining H atoms were positioned geometrically, with C-H = 0.95 (aromatic), 0.98 (methyl), 0.99 (methylene) or 1.00 Å (methine), and refined as riding on their parent atoms, with Uiso(H) = 1.5Ueq(C) for methyl groups or 1.2Ueq(C) otherwise. For (I)[link], the Flack x parameter (Flack, 1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]) based on refinement with 3080 Friedel pairs was -0.5 (10), which indicated that no conclusions can be drawn regarding the absolute structure. Consequently, the Friedel pairs were merged before the final refinement. For (II)[link], the Flack parameter refined to 0.00 (10) using 8119 Friedel pairs, which indicated that the refined model represents the true absolute configuration and is in accordance with expectation from the known chirality of the starting material in the synthesis.

For both compounds, data collection: APEX2 (Bruker, 2006[Bruker (2006). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2006[Bruker (2006). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]); software used to prepare material for publication: SHELXL97.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: SF3143 ). Services for accessing these data are described at the back of the journal.


Acknowledgements

The authors thank Dr Hong Su of the Chemistry Department of the University of Cape Town for her assistance with the crystallographic data collection.

References

Allen, F. H. (2002). Acta Cryst. B58, 380-388.  [ISI] [CrossRef] [details]
Bruker (2006). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.
Diner, P., Kjaersgaard, A., Lie, M. A. & Jorgensen, K. A. (2008). Chem. Eur. J. 14, 122-127.  [CrossRef] [ChemPort]
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.  [ISI] [CrossRef] [ChemPort] [details]
Flack, H. D. (1983). Acta Cryst. A39, 876-881.  [CrossRef] [details]
Naicker, T., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2010a). Acta Cryst. E66, o3105.  [CrossRef] [details]
Naicker, T., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2010b). Acta Cryst. E66, o638.  [CrossRef] [details]
Naicker, T., McKay, M., Govender, T., Kruger, H. G. & Maguire, G. E. M. (2009). Acta Cryst. E65, o3278.  [CSD] [CrossRef] [details]
Naicker, T., Petzold, K., Singh, T., Arvidsson, P. I., Kruger, H. G., Maguire, G. E. M. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 2859-2867.  [ISI] [CrossRef] [ChemPort]
Peters, B. K., Chakka, S. K., Naicker, T., Maguire, G. E. M., Kruger, H. G., Andersson, P. G. & Govender, T. (2010). Tetrahedron Asymmetry, 21, 679-687.  [ISI] [CrossRef] [ChemPort]
Seebach, D., Groselj, U., Badine, D. M., Schweizer, W. B. & Beck, A. K. (2008). Helv. Chim. Acta, 91, 1999-2034.  [CrossRef] [ChemPort]
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]


Acta Cryst (2011). C67, o100-o103   [ doi:10.1107/S0108270110053357 ]