The synthesis of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-ol

Authors

DOI:

https://doi.org/10.24959/ophcj.26.353627

Keywords:

bicyclic compounds, [2 2] cycloaddition, lactams, building blocks

Abstract

 An approach to the synthesis of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-ol, a promising amino alcohol building block for drug discovery, has been described. The method is based on [2+2] the cycloaddition of tert-butyl vinyl ether and a ketene generated in situ from a glutaric acid derivative, as well as the intramolecular lactam formation as the key steps. Although the [2+2] cycloaddition step and further transformations proceeded without any notable stereoselectivity, the title compound was synthesized in an amount greater than 30 g with a high diastereomeric purity. This was provided by the physical properties of the intermediate (±)-(1R,6R,7R)-7-(tert-butoxy)-2-azabicyclo­[4.2.0]octan-3-one that was easily separated by crystallization.

Supporting Agency

  • The work was supported by Enamine Ltd. and Enamine CF. O. O. G. received funding from the Ministry of Education and Science of Ukraine, grant No. 25BF037-01 (0125U002249).

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References

  1. Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk, D. M.; Tolmachev, A. A.; Komarov, I. V. Bicyclic Conformationally Restricted Diamines. Chem. Rev. 2011, 111 (9), 5506–5568. https://doi.org/10.1021/cr100352k.
    | |
  2. Grygorenko, O. O.; Volochnyuk, D. M.; Vashchenko, B. V. Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances. Eur. J. Org. Chem. 2021, 2021 (47), 6478–6510. https://doi.org/10.1002/ejoc.202100857.
    |
  3. Shearer, J.; Castro, J. L.; Lawson, A. D. G.; MacCoss, M.; Taylor, R. D. Rings in Clinical Trials and Drugs: Present and Future. J. Med. Chem. 2022, 65 (13), 8699–8712. https://doi.org/10.1021/acs.jmedchem.2c00473.
    | |
  4. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014, 57 (14), 5845–5859. https://doi.org/10.1021/jm4017625.
    | |
  5. McVeigh, M. S.; Sorrentino, J. P.; Hands, A. T.; Garg, N. K. Access to Complex Scaffolds Through [2 + 2] Cycloadditions of Strained Cyclic Allenes. J. Am. Chem. Soc. 2024, 146 (22), 15420–15427. https://doi.org/10.1021/jacs.4c03369.
    | |
  6. Zhang, Z.; Zhang, S.-L.; Wu, C.; Li, H.-H.; Zha, L.; Shi, J.; Liu, X.; Qin, H.-L.; Tang, W. Sulfur-Fluoride Exchange (SuFEx)-Enabled Lead Discovery of AChE Inhibitors by Fragment Linking Strategies. Eur. J. Med. Chem. 2023, 257, 115502. https://doi.org/10.1016/j.ejmech.2023.115502.
    | |
  7. Huang, X.; Brubaker, J.; Zhou, W.; Biju, P. J.; Xiao, L.; Shao, N.; Huang, Y.; Dong, L.; Liu, Z.; Bitar, R.; Buevich, A.; Jung, J.; Peterson, S. L.; Butcher, J. W.; Close, J.; Martinez, M.; MacCoss, R. N.; Zhang, H.; Crawford, S.; McCormick, K. D.; Aslanian, R.; Nargund, R.; Correll, C.; Gervais, F.; Qiu, H.; Yang, X.; Garlisi, C.; Rindgen, D.; Maloney, K. M.; Siliphaivanh, P.; Palani, A. Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma. ACS Med. Chem. Lett. 2018, 9 (7), 679–684. https://doi.org/10.1021/acsmedchemlett.8b00145.
    | |
  8. Henning, H.; Bartels, H. Photochemie von Aminoketonen;: Norrish‐II‐Reaktionen von N‐Tosyl‐piperidinylketonen. Z. Chem. (Stuttgart, Ger.) 1983, 23 (12), 455–456. https://doi.org/10.1002/zfch.19830231225.
  9. Kolleth, A.; Lumbroso, A.; Tanriver, G.; Catak, S.; Sulzer-Mossé, S.; De Mesmaeker, A. Synthesis of 4-Membered Ring Alkaloid Analogues via Intramolecular [2+2] Cycloaddition Involving Keteniminium Salt Intermediates. Tetrahedron Lett. 2017, 58 (30), 2904–2909. https://doi.org/10.1016/j.tetlet.2017.06.033.
    |
  10. Nosyk, D. A.; Lukyanenko, S. Yu.; Granat, D. S.; Skrypnik, D.; Chigrinov, V.; Liashuk, O. S.; Shishkina, S. V.; Savchenko, T.; Yurchenko, O. O.; Grygorenko, O. O. Synthesis and Physicochemical Characterization of 2‐Azabicyclo[3.2.0]Heptane Building Blocks. Eur. J. Org. Chem. 2025, 28 (47), e202500970. https://doi.org/10.1002/ejoc.202500970.
    |
  11. Armarego, W. L. F.; Chai, C. Purification of Laboratory Chemicals, 5th ed.; Elsevier: Oxford, 2003.

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Published

2026-04-23

How to Cite

(1)
Nosyk, D. A.; Lukyanenko, S. Y.; Granat, D. S.; Yurchenko, O. O.; Grygorenko, O. O. The Synthesis of (±)-(1R,6R,7R)-2-azabicyclo[4.2.0]octan-7-Ol. J. Org. Pharm. Chem. 2026, 24, 23-28.

Issue

Vol. 24 No. 1 (2026): Issue in Progress

Section

Original Researches

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