The Synthesis of Functionalized Dimethylphosphinoyl Cyclopropanes and Cyclobutanes

Authors

DOI:

https://doi.org/10.24959/ophcj.23.299237

Keywords:

dimethylphosphine oxides, cyclopropane, cyclobutane, amines, carboxylic acids

Abstract

A simple preparative approach to a series of functionalized dimethylphosphinoyl-containing cyclopropanes and cyclobutanes has been developed; it is based on cyclocondensation of dimethylphosphinoyl acetonitrile with 1,2- and 1,3-dibromoalkanes. Synthetic procedures for obtaining nitriles, amines and carboxylic acids containing in their structure small saturated cyclic rings of cyclopropane or cyclobutane and a dimethylphosphine oxide fragment, which are popular in drug design, have been developed.

Supporting Agency

  • The authors received no specific funding for this work.

Downloads

Download data is not yet available.

References

  1. Bauer, M. R.; Di Fruscia, P.; Lucas, S. C. C.; Michaelides, I. N.; Nelson, J. E.; Storer, R. I.; Whitehurst, B. C. Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 2021, 12, 448 - 471. https://doi.org/10.1039/D0MD00370K.
    |
  2. Talele, T. T. The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules. J. Med. Chem. 2016, 59, 8712 - 8756. https://doi.org/10.1021/acs.jmedchem.6b00472.
    |
  3. Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529 - 2591. https://doi.org/10.1021/jm1013693.
    |
  4. Reichelt, A.; Gaul, C.; Frey, R. R.; Kennedy, A.; Martin, S. F. Design, Synthesis, and Evaluation of Matrix Metalloprotease Inhibitors Bearing Cyclopropane-Derived Peptidomimetics as P1′ and P2′ Replacements. J. Am. Chem. Soc. 2002, 124, 205 - 215. https://doi.org/10.1021/jo0110698.
    |
  5. Wipf, P.; Xiao, J. Convergent Approach to (E)-Alkene and Cyclopropane Peptide Isosteres. Org. Lett. 2005, 7, 103 - 106. https://doi.org/10.1021/ol0477529.
    |
  6. Qiao, J. X.; Cheney, D. L.; Alexander, R. S.; Smallwood, A. M.; King, S. R.; He, K.; Rendina, A. R.; Luettgen, J. M.; Knabb, R. M.; Wexler, R. R.; Lam, P. Y. S. Achieving structural diversity using the perpendicular conformation of alpha-substituted phenylcyclopropanes to mimic the bioactive conformation of ortho-substituted biphenyl P4 moieties: Discovery of novel, highly potent inhibitors of Factor Xa. Bioorg. Med. Chem. Lett. 2008, 18, 4118 - 4123. https://doi.org/10.1016/j.bmcl.2008.05.095.
    |
  7. Hobbs, H.; Bravi, G.; Campbell, I.; Convery, M.; Davies, H.; Inglis, G.; Pal, S.; Peace, S.; Redmond, J.; Summers, D. Discovery of 3‑Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway. J. Med. Chem. 2019, 62, 6972 - 6984. https://doi.org/10.1021/acs.jmedchem.9b00348.
    |
  8. van der Kolk, M. R.; Janssen, M. A. C. H.; Rutjes, F. P. J. T.; Blanco-Ania, D. Cyclobutanes in Small-Molecule Drug Candidates. ChemMedChem 2022, 17, e202200020. https://doi.org/10.1002/cmdc.202200020.
    |
  9. Huang, W.-S.; Liu, S.; Zou, D.; Thomas, M.; Wang, Y.; Zhou, T.; Romero, J.; Kohlmann, A.; Li, F.; Qi, J.; Cai, L.; Dwight, T. A.; Xu, Y.; Xu, R.; Dodd, R.; Toms, A.; Parillon, L.; Lu, X.; Anjum, R.; Zhang, S.; Wang, F.; Keats, J.; Wardwell, S. D.; Ning, Y.; Xu, Q.; Moran, L. E.; Mohemmad, Q. K.; Jang, H. G.; Clackson, T.; Narasimhan, N. I.; Rivera, V. M.; Zhu, X.; Dalgarno, D.; Shakespeare, W. C. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J. Med. Chem. 2016, 59, 4948 - 4964. https://doi.org/10.1021/acs.jmedchem.6b00306.
    |
  10. Markham, A. Brigatinib: First Global Approval. Drugs 2017, 77 (10), 1131 - 1135. https://doi.org/10.1007/s40265-017-0776-3.
    |
  11. Yu, H.; Yang, H.; Shi, E.; Tang, W. Development and Clinical Application of Phosphorus-Containing Drugs. Med. Drug Discov. 2020, 8, 100063. https://doi.org/10.1016/j.medidd.2020.100063.
  12. Finkbeiner, P.; Hehn, J. P.; Gnamm, C. Phosphine Oxides from a Medicinal Chemist’s Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery. J. Med. Chem. 2020, 63, 7081 - 7107. https://doi.org/10.1021/acs.jmedchem.0c00407.
    |
  13. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752 - 6756. https://doi.org/10.1021/jm901241e.
    |
  14. Lovering, F. Escape from Flatland 2: complexity and promiscuity. Med. Chem. Commun. 2013, 4, 515. https://doi.org/10.1039/C2MD20347B.
  15. Wei, W., Cherukupalli, S., Jing, L., Liu, X., Zhan, P. Fsp3: A new parameter for drug-likeness. Drug Discov. Today 2020, 25, 1839 - 1845. https://doi.org/10.1016/j.drudis.2020.07.017.
    |
  16. Aleksandrova, A. M.; Bezgubenko, L. V.; Cherednichenko, A. S.; Onysko, P. P.; Rassukana, Yu. V. Convenient preparative approaches to biorelevant dimethylphosphinoyl-derived compounds with the use of (trimethylsilyl)dimethylphosphinite. Phosphorus, Sulfur, Silicon Relat. Elem. 2022, 197 (5-6), 571 - 573. https://doi.org/10.1080/10426507.2021.2025054.
  17. Fedyk, A.; Slobodyanyuk, E. Y.; Stotska, O.; Vashchenko, B. V.; Volochnyuk, D. M.; Sibgatulin, D. A.; Tolmachev, A. A.; Grygorenko, O. O. Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico-Chemical Properties. Eur. J. Org. Chem. 2021, 6591 - 6603. https://doi.org/10.1002/ejoc.202100581.
  18. Fedyk, A. V.; Chalyk, B. A. The synthesis of functionalized 4,5-dihydroisoxazoles decorated with the dimethylphosphinoyl group. Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2), 41 - 52. https://doi.org/10.24959/ophcj.23.283988.
  19. Rol, N. C.; Clague, A. D. H. 13C NMR Spectroscopy of Cyclopropane Derivatives. Org. Magn. Reson. 1981, 16 (3). https://doi.org/10.1002/mrc.1270160304.
  20. Fliegl, H.; Sundholm, D.; Taubert, S.; Jusélius, J.; Klopper, W. Magnetically Induced Current Densities in Aromatic, Antiaromatic, Homoaromatic, and Nonaromatic Hydrocarbons. J. Phys. Chem. A 2009, 113, 8668 - 8676. https://doi.org/10.1021/jp9029776.
    |

Downloads

Published

2023-12-10

How to Cite

(1)
Aleksandrova, A. M.; Cherednichenko, A. S.; Rassukana, Y. V. The Synthesis of Functionalized Dimethylphosphinoyl Cyclopropanes and Cyclobutanes. J. Org. Pharm. Chem. 2023, 21, 36-42.

Issue

Vol. 21 No. 4 (2023)

Section

Original Researches

License

Copyright (c) 2024 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).