Сyclobutanes are heavily exploited in organic synthesis as subunits for natural product preparation, ring-opening, and ring-contraction reactions.1 In medicinal chemistry, the introduction of a cyclobutane fragment is often used to achieve a conformational restriction.2 Unlike a double bond or a cyclopropane unit, the cyclobutane ring does not disturb the electronic properties and, consequently, the reactivity of a biologically active molecule.
Although cyclobutane derivatives have been less commonly exploited in drug discovery to date, there are five marketed and several experimental drugs containing the cyclobutane ring.3 For example, Boceprevir 1, a protease inhibitor used as a treatment for hepatitis C and semisynthetic analgesic Nalbuphine 2 shown in Figure 1 are classical cyclobutane-containing medications. Carboplatin 3, a drug used for treatment of different types of cancer, was approved and commercialized in 2011. A selective inhibitor of alcohol dehydrogenase 1A 4 is an experimental drug. Recent evaluations of biological activity in a series of thiazole-based agents showed that the introduction of a cyclobutane fragment into the thiazole ring led to significantly improved antifungal and antibacterial activities in the сompound 5 (Figure 1).4
Along with drug discovery, the cyclobutane derivatives have found important applications in materials science, e.g., to produce stress-responsive polymers,6 and supramolecular chemistry.6
Figure 1. Marketed drugs and some other biologically active compounds containing the cyclobutane moiety
The representative set of cyclobutane derivatives available from Life Chemicals is listed below. To explore the full data set, please send your request to firstname.lastname@example.org.
- (a) Wang, M.; Lu, P. Org. Chem. Front. 2018, 5, 254-259. (b) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485-1537.
- Radchenko, D. S.; Pavlenko, S. O.; Grygorenko, O. O.; Volochnyuk, D. M.; Shishkina, S. V.; Shishkin, O. V.; Komarov, I. V. J. Org. Chem. 2010, 75, 5941–5952.
- www.drugbank.ca; accessed on September 2019.
- Cukurovali, A.; Yilmaz, I.; Gur, S.; Kazaz, C. Eur. J. Med. Chem. 2006, 41, 201–207.
- Kean, Z. S.; Niu, Z.; Hewage, G. B.; Rheingold, A. L.; Craig, S. L. J. Am. Chem. Soc. 2013, 135, 13598−13604.
- Rua, F.; Boussert, S.: Parella, T.; Dıez-Perez, I.; Branchadell, V.; Giralt, E.; Ortuno, R. M. Org. Lett. 2007, 9, 3643-3645.