Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Preparation of cyclohexene isotopologues and stereoisotopomers from benzene

Abstract

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington’s disease2, was recently approved by the United States’ Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Methods for the deuteration of benzene.
Fig. 2: Formation of tungsten-bound cyclohexene from benzene.
Fig. 3: Synthesis of isotopologues and stereoisotopomers of the cyclohexene complex 7.
Fig. 4: Examples of functionalized cyclohexene isotopomer complexes.

Data availability

All data are available in the main text and Supplementary Information, including NMR spectra, experimental details, crystallographic information, DFT calculations, rotational spectroscopy and HRMS data. Supplementary crystallographic data for this paper (4, 7, 9 (X-ray) and 45 (neutron)) can be obtained from the Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk/structures (CCDC 1885723-1885725 and 1972890).

References

  1. Gant, T. G. Using deuterium in drug discovery: leaving the label in the drug. J. Med. Chem. 57, 3595–3611 (2014).

    Article  CAS  Google Scholar 

  2. Dean, M. & Sung, V. W. Review of deutetrabenazine: a novel treatment for chorea asociated with Huntington’s disease. Drug Des. Devel. Ther. 12, 313–319 (2018).

    Article  CAS  Google Scholar 

  3. Thibblin, A. & Ahlberg, P. Reaction branching and extreme kinetic isotope effects in the study of reaction mechanisms. Chem. Soc. Rev. 18, 209–224 (1989).

    Article  CAS  Google Scholar 

  4. Thibblin, A. Unusually large kinetic deuterium isotope effects on oxidation reactions. 1. the mechanism of hydroxide-catalysed permanganate oxidation of PhCD(CF3)OH and PhCD(CH3)OH in water. J. Phys. Org. Chem. 8, 186–190 (1995).

    Article  CAS  Google Scholar 

  5. Nelson, S. D. & Trager, W. F. The use of deuterium isotope effects to probe the active site properties, mechanism, of cyctochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab. Dispos. 31, 1481–1497 (2003).

    Article  CAS  Google Scholar 

  6. Loh, Y. Y. et al. Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science 358, 1182–1187 (2017).

    Article  ADS  CAS  Google Scholar 

  7. Pony Yu, R., Hesk, D., Rivera, N., Pelczer, I. & Chirik, P. J. Iron-catalysed tritiation of pharmaceuticals. Nature 529, 195–199 (2016).

    Article  ADS  Google Scholar 

  8. Baldwin, J. E., Kiemle, D. J. & Kostikov, A. P. Quantitative analyses of stereoisomeric 3,4-d 2-cyclohexenes in the presence of 3,6-d 2-cyclohexenes. J. Org. Chem. 74, 3866–3874 (2009).

    Article  CAS  Google Scholar 

  9. Eisen, M. S. & Marks, T. J. Supported organoactinide complexes as heterogeneous catalysts. A kinetic and mechanistic study of facile arene hydrogenation. J. Am. Chem. Soc. 114, 10358–10368 (1992).

    Article  CAS  Google Scholar 

  10. Jones, R. A. & Seeberger, M. H. Synthesis of polymer-supported transition metal catalysts via phosphido linkages: heterogeneous catalysts for the hydrogenation of aromatic compounds under mild conditions. J. Chem. Soc. Chem. Commun. 373–374 (1985).

  11. Joannou, M. V., Bezdek, M. J. & Chirik, P. J. Pyridine(diimine) molybdenum-catalyzed hydrogenation of arenes and hindered olefins: insights into precatalyst activation and deactivation pathways. ACS Catal. 8, 5276–5285 (2018).

    Article  CAS  Google Scholar 

  12. Harman, W. D. & Taube, H. The selective hydrogenation of benzene to cyclohexene on pentaammineosmium(II). J. Am. Chem. Soc. 110, 7906–7907 (1988).

    Article  CAS  Google Scholar 

  13. Liebov, B. K. & Harman, W. D. Group 6 dihapto-coordinate dearomatization agents for organic synthesis. Chem. Rev. 117, 13721–13755 (2017).

    Article  CAS  Google Scholar 

  14. Welch, K. D. et al. Large-scale syntheses of several synthons to the dearomatization agent {TpW(NO)(PMe3)} and convenient spectroscopic tools for product analysis. Organometallics 26, 2791–2794 (2007).

    Article  CAS  Google Scholar 

  15. Lankenau, A. W. et al. Enantioenrichment of a tungsten dearomatization agent utilizing chiral acids. J. Am. Chem. Soc. 137, 3649–3655 (2015).

    Article  CAS  Google Scholar 

  16. Harrison, D. P. et al. Hyperdistorted tungsten allyl complexes and their stereoselective deprotonation to form dihapto-coordinated dienes. Organometallics 30, 2587–2597 (2011).

    Article  CAS  Google Scholar 

  17. Lis, E. C. et al. The uncommon reactivity of dihapto-coordinated nitrile, ketone, and alkene ligands when bound to a powerful π-base. Organometallics 25, 5051–5058 (2006).

    Article  CAS  Google Scholar 

  18. Arashiba, K. et al. Electrophilic O-methylation of a terminal nitrosyl ligand attained by an early−late heterobimetallic effect. Organometallics 25, 560–562 (2006).

    Article  CAS  Google Scholar 

  19. Jamison, C. J. Isotope effects on chemical shifts and coupling constants. eMagRes https://doi.org/10.1002/9780470034590.emrstm0251 (2007).

  20. Pérez, C. et al. Broadband Fourier transform rotational spectroscopy for structure determination: the water heptamer. Chem. Phys. Lett. 571, 1–15 (2013).

    Article  ADS  Google Scholar 

  21. Sharp, W. B., Legzdins, P. & Patrick, B. O. O-Protonation of a terminal nitrosyl group to form an η1-hydroxylimido ligand. J. Am. Chem. Soc. 123, 8143–8144 (2001).

    Article  CAS  Google Scholar 

  22. Llamazares, A., Schmalle, H. W. & Berke, H. Ligand-assisted heterolytic activation of hydrogen and silanes mediated by nitrosyl rhenium complexes. Organometallics 20, 5277–5288 (2001).

    Article  CAS  Google Scholar 

  23. Leong, V. S. & Cooper, N. J. Electrophilic activation of benzene in [Cr 4–C6H6)(CO)3]2−. J. Am. Chem. Soc. 110, 2644–2646 (1988).

    Article  CAS  Google Scholar 

  24. Thompson, R. L., Lee, S., Rheingold, A. L. & Cooper, N. J. Reductive activation of the coordinated benzene in manganese complex [Mn 6-C6H6)(CO)3]+: synthesis and characterization of the η 4-naphthalene complex PPN[Mn 4–C10H8)(CO)3]. Organometallics 10, 1657–1659 (1991).

    Article  CAS  Google Scholar 

  25. Ungureanu, I.; Klotz, P.; Mann, A. Phenylaziridine as a masked 1,3 dipole in reactions with nonactivated alkenes. Angew. Chem. 39, 4615–4617 (1991).

    Article  Google Scholar 

  26. Sarkar, N., Banerjee, A. & Nelson, S. G. [4 + 2] Cycloadditions of N-alkenyl iminium ions: structurally complex heterocycles from a three-component Diels−Alder reaction sequence. J. Am. Chem. Soc. 130, 9222–9223 (2008).

    Article  CAS  Google Scholar 

  27. Shim, S. C., Doh, C. H., Kim, T. J., Lee, H. K. & Kim, K. D. A new and convenient synthesis of N-substituted perhydroazepines from adipaldehyde and primary amines with tetracarbonylhydridoferrate, HFe(CO)4 , as a selective reducing agent. J. Heterocycl. Chem. 25, 1383–1385 (1988).

    Article  CAS  Google Scholar 

  28. Wilson, K. B. et al. Sequential tandem addition to a tungsten–trifluorotoluene complex: a versatile method for the preparation of highly functionalized trifluoromethylated cyclohexenes. J. Am. Chem. Soc. 139, 11401–11412 (2017).

    Article  CAS  Google Scholar 

  29. Murray, R. W., Singh, M., Williams, B. L. & Moncrieff, H. M. Diastereoselectivity in the epoxidation of substituted cyclohexenes by dimethyldioxirane. J. Org. Chem. 61, 1830–1841 (1996).

    Article  CAS  Google Scholar 

  30. Leiris, S., Lucas, M., Dupuy d’Angeac, A. & Morère, A. Synthesis and biological evaluation of cyclic nitrogen mustards based on carnitine framework. Eur. J. Med. Chem. 45, 4140–4148 (2010).

    Article  CAS  Google Scholar 

  31. Wilson, K. B. et al. Highly functionalized cyclohexenes derived from benzene: sequential tandem addition reactions promoted by tungsten. J. Org. Chem. 84, 6094–6116 (2019).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the assistance of E. Ashcraft in collecting HRMS data. The work was funded by the National Institutes of Health (1R01GM132205-01) and the University of Virginia. The single-crystal neutron diffraction experiment performed on TOPAZ using resources at the Spallation Neutron Source, a DOE Office of Science User Facility operated by the Oak Ridge National Laboratory, under contract number DE-AC05-00OR22725 with UT-Battelle, LLC.

Author information

Authors and Affiliations

Authors

Contributions

W.D.H., J.A.S. and K.B.W. conceived the project. K.D.W., W.D.H. and J.A.S. designed the experiments. J.A.S. and K.S.W. prepared the samples and collected NMR and HRMS data. D.A.D. carried out X-ray molecular structure determinations. B.H.P., P.J.K. and R.E.S. conceived and ran the rotational spectroscopy experiments. E.K.P. and K.S.W. carried out DFT calculations. J.A.S. and W.D.H. wrote the manuscript. X.W. collected and processed neutron diffraction data.

Corresponding author

Correspondence to W. Dean Harman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks David Hesk and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

This file contains Supplementary Materials A-N, which includes Supplementary Figures S1-S15 and Supplementary Tables S1-S4.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Smith, J.A., Wilson, K.B., Sonstrom, R.E. et al. Preparation of cyclohexene isotopologues and stereoisotopomers from benzene. Nature 581, 288–293 (2020). https://doi.org/10.1038/s41586-020-2268-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-020-2268-y

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing