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Volume 68 
Part 11 
Pages o3225-o3226  
November 2012  

Received 18 October 2012
Accepted 18 October 2012
Online 27 October 2012

Key indicators
Single-crystal X-ray study
T = 193 K
Mean [sigma](C-C) = 0.002 Å
Disorder in main residue
R = 0.040
wR = 0.108
Data-to-parameter ratio = 18.8
Details
Open access

Salvinorin B methoxymethyl ether

aMcLean Hospital, Belmont, MA, USA,bHarvard Medical School, Department of Psychiatry, Boston, MA, USA, and cHarvard University, Department of Chemistry and Chemical Biology, Cambridge, MA, USA
Correspondence e-mail: thomas@munro.com

The title compound [MOM-SalB; systematic name: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-furyl)-9-methoxymethoxy-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octahydro-1H-benzo[f]isochromene-7-carboxylate], C23H30O8, is a derivative of the [kappa]-opioid salvinorin A with enhanced potency, selectivity, and duration of action. Superimposition of their crystal structures reveals, surprisingly, that the terminal C and O atoms of the MOM group overlap with the corresponding atoms in salvinorin A, which are separated by an additional bond. This counter-intuitive isosterism is possible because the MOM ether adopts the `classic anomeric' conformation (gauche-gauche), tracing a helix around the planar acetate of salvinorin A. This overlap is not seen in the recently reported structure of the tetrahydropyranyl ether, which is less potent. The classic anomeric conformation is strongly favoured in alkoxymethyl ethers, but not in substituted acetals, which may contribute to their reduced potency. This structure may prove useful in evaluating models of the activated [kappa]-opioid receptor.

Related literature

For preparation, see: Béguin et al. (2009[Béguin, C., Carlezon, W. A. Jr, Cohen, B. M., He, M., Lee, D. Y.-W., Richards, M. R. & Liu-Chen, L.-Y. (2009). US Patent No. 7,629,475.]). For amended characterization data, see: Munro et al. (2008[Munro, T. A., Duncan, K. K., Xu, W., Wang, Y., Liu-Chen, L.-Y., Carlezon, W. A. Jr, Cohen, B. M. & Béguin, C. (2008). Bioorg. Med. Chem. 16, 1279-1286.]). For structure-activity relationships in vitro, see: Béguin et al. (2012[Béguin, C., Potuzak, J., Xu, W., Liu-Chen, L.-Y., Streicher, J. M., Groer, C. E., Bohn, L. M., Carlezon, W. A. Jr & Cohen, B. M. (2012). Bioorg. Med. Chem. Lett. 22, 1023-1026.]); Munro et al. (2008[Munro, T. A., Duncan, K. K., Xu, W., Wang, Y., Liu-Chen, L.-Y., Carlezon, W. A. Jr, Cohen, B. M. & Béguin, C. (2008). Bioorg. Med. Chem. 16, 1279-1286.]); Prevatt-Smith et al. (2011[Prevatt-Smith, K. M., Lovell, K. M., Simpson, D. S., Day, V. W., Douglas, J. T., Bosch, P., Dersch, C. M., Rothman, R. B., Kivell, B. & Prisinzano, T. E. (2011). MedChemComm, 2, 1217-1222.]). For in vivo pharmacology, see: Baker et al. (2009[Baker, L. E., Panos, J. J., Killinger, B. A., Peet, M. M., Bell, L. M., Haliw, L. A. & Walker, S. L. (2009). Psychopharmacology (Berlin), 203, 203-211.]); Peet & Baker (2011[Peet, M. M. & Baker, L. E. (2011). Behav. Pharmacol. 22, 450-457.]); Wang et al. (2008[Wang, Y., Chen, Y., Xu, W., Lee, D. Y., Ma, Z., Rawls, S. M., Cowan, A. & Liu-Chen, L. Y. (2008). J. Pharmacol. Exp. Ther. 324, 1073-1083.]). For pharmacokinetics and PET imaging of the ethoxymethyl ether, see: Hooker et al. (2009[Hooker, J. M., Munro, T. A., Béguin, C., Alexoff, D., Shea, C., Xu, Y. & Cohen, B. M. (2009). Neuropharmacology, 57, 386-391.]). For structure-activity relationships of salvinorin A, see: Cunningham et al. (2011[Cunningham, C. W., Rothman, R. B. & Prisinzano, T. E. (2011). Pharmacol. Rev. 63, 316-347.]). For crystal structures of related compounds, see: Ortega et al. (1982[Ortega, A., Blount, J. F. & Manchand, P. S. (1982). J. Chem. Soc. Perkin Trans. 1, pp. 2505-2508.]); Prevatt-Smith et al. (2011[Prevatt-Smith, K. M., Lovell, K. M., Simpson, D. S., Day, V. W., Douglas, J. T., Bosch, P., Dersch, C. M., Rothman, R. B., Kivell, B. & Prisinzano, T. E. (2011). MedChemComm, 2, 1217-1222.]); Tidgewell et al. (2006[Tidgewell, K., Harding, W. W., Lozama, A., Cobb, H., Shah, K., Kannan, P., Dersch, C. M., Parrish, D., Deschamps, J. R., Rothman, R. B. & Prisinzano, T. E. (2006). J. Nat. Prod. 69, 914-918.]). For solid-state and bioactive conformations of acetals, see: Anderson (2000[Anderson, J. E. (2000). J. Org. Chem. 65, 748-754.]); Brameld et al. (2008[Brameld, K. A., Kuhn, B., Reuter, D. C. & Stahl, M. (2008). J. Chem. Inf. Model. 48, 1-24.]).

[Scheme 1]

Experimental

Crystal data
  • C23H30O8

  • Mr = 434.47

  • Monoclinic, C 2

  • a = 27.8848 (7) Å

  • b = 6.2415 (2) Å

  • c = 12.8212 (3) Å

  • [beta] = 107.351 (1)°

  • V = 2129.9 (1) Å3

  • Z = 4

  • Mo K[alpha] radiation

  • [mu] = 0.10 mm-1

  • T = 193 K

  • 0.25 × 0.13 × 0.07 mm

Data collection
  • Bruker APEXII CCD diffractometer

  • Absorption correction: multi-scan (SADABS; Bruker, 2004[Bruker (2004). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.975, Tmax = 0.993

  • 27784 measured reflections

  • 6195 independent reflections

  • 5296 reflections with I > 2[sigma](I)

  • Rint = 0.033

Refinement
  • R[F2 > 2[sigma](F2)] = 0.040

  • wR(F2) = 0.108

  • S = 1.04

  • 6195 reflections

  • 330 parameters

  • 181 restraints

  • H-atom parameters constrained

  • [Delta][rho]max = 0.28 e Å-3

  • [Delta][rho]min = -0.16 e Å-3

Data collection: APEX2 (Bruker, 2006[Bruker (2006). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2006[Bruker (2006). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]) and pyMOL (DeLano, 2009[DeLano, W. L. (2009). pyMOL. DeLano Scientific LLC, San Carlos, California, USA.]); software used to prepare material for publication: SHELXTL.


Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: QM2086 ).


Acknowledgements

This work was supported by a grant from the Stanley Medical Research Institute.

References

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Béguin, C., Carlezon, W. A. Jr, Cohen, B. M., He, M., Lee, D. Y.-W., Richards, M. R. & Liu-Chen, L.-Y. (2009). US Patent No. 7,629,475.
Béguin, C., Potuzak, J., Xu, W., Liu-Chen, L.-Y., Streicher, J. M., Groer, C. E., Bohn, L. M., Carlezon, W. A. Jr & Cohen, B. M. (2012). Bioorg. Med. Chem. Lett. 22, 1023-1026.  [PubMed]
Brameld, K. A., Kuhn, B., Reuter, D. C. & Stahl, M. (2008). J. Chem. Inf. Model. 48, 1-24.  [CrossRef] [PubMed] [ChemPort]
Bruker (2004). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
Bruker (2006). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.
Cunningham, C. W., Rothman, R. B. & Prisinzano, T. E. (2011). Pharmacol. Rev. 63, 316-347.  [ISI] [CrossRef] [ChemPort] [PubMed]
DeLano, W. L. (2009). pyMOL. DeLano Scientific LLC, San Carlos, California, USA.
Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.  [CrossRef] [details]
Hooker, J. M., Munro, T. A., Béguin, C., Alexoff, D., Shea, C., Xu, Y. & Cohen, B. M. (2009). Neuropharmacology, 57, 386-391.  [ISI] [CrossRef] [PubMed] [ChemPort]
Munro, T. A., Duncan, K. K., Xu, W., Wang, Y., Liu-Chen, L.-Y., Carlezon, W. A. Jr, Cohen, B. M. & Béguin, C. (2008). Bioorg. Med. Chem. 16, 1279-1286.  [CrossRef] [PubMed] [ChemPort]
Ortega, A., Blount, J. F. & Manchand, P. S. (1982). J. Chem. Soc. Perkin Trans. 1, pp. 2505-2508.  [CrossRef]
Peet, M. M. & Baker, L. E. (2011). Behav. Pharmacol. 22, 450-457.  [ISI] [CrossRef] [ChemPort] [PubMed]
Prevatt-Smith, K. M., Lovell, K. M., Simpson, D. S., Day, V. W., Douglas, J. T., Bosch, P., Dersch, C. M., Rothman, R. B., Kivell, B. & Prisinzano, T. E. (2011). MedChemComm, 2, 1217-1222.  [ChemPort] [PubMed]
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]
Tidgewell, K., Harding, W. W., Lozama, A., Cobb, H., Shah, K., Kannan, P., Dersch, C. M., Parrish, D., Deschamps, J. R., Rothman, R. B. & Prisinzano, T. E. (2006). J. Nat. Prod. 69, 914-918.  [ISI] [CSD] [CrossRef] [PubMed] [ChemPort]
Wang, Y., Chen, Y., Xu, W., Lee, D. Y., Ma, Z., Rawls, S. M., Cowan, A. & Liu-Chen, L. Y. (2008). J. Pharmacol. Exp. Ther. 324, 1073-1083.  [CrossRef] [PubMed] [ChemPort]


Acta Cryst (2012). E68, o3225-o3226   [ doi:10.1107/S1600536812043449 ]

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