Cyclobutanecarboxylic Acid in Organic chemistry

Cyclobutanecarboxylic acid is the organic compound with the formula C4H7CO2H. It is a colorless nonvolatile liquid. It can be prepared by decarboxylation of 1,1-cyclobutanedicarboxylic acid. Cyclobutanecarboxylic acid is an intermediate in organic synthesis. For example, it is a precursor to cyclobutylamine.

Palladium(II)-Catalyzed C–H Activation Using Cyclobutanecarboxylic acid

Enantioselective functionalization of prochiral unactivated C–H bonds remains a significant challenge. Although carbenoid and nitrenoid insertion as well as metal insertion processes have been developed to enantioselectively functionalize prochiral C–H bonds, the scope of substrates and transformations falls short of the standard demonstrated in other areas of asymmetric catalysis. In particular, both intra- and intermolecular enantioselective C–H activation reactions are still limited to a few classes of substrates. Alternative approaches of C–H activation followed by asymmetric carbometalation or hydrometalation to construct chiral centers have also met with difficulties. Enantiopure cyclobutanes are important structural features found in many bioactive natural products. Many methods have been developed for the asymmetric synthesis of chiral cyclobutanes. However, the enantioselective construction of cyclobutanes with chiral quaternary stereocenters is still limited. Although elegant methods to construct quaternary stereocenters on cyclobutyl rings have been recently reported by Toste and Stoltz, but these methods are applicable to the synthesis of cyclobutanones only. We envisioned that a Pd(II)-catalyzed enantioselective C–H functionalization of cyclobutanecarboxylic acid derivatives could offer a new and complementary method. Herein we report the first example of enantioselective coupling of cyclobutanes with arylboron reagents using a chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligand, providing a new route for the synthesis of cyclobutanes with chiral quaternary stereocenters. The feasibility of using this ligand to achieve enantioselective C(sp3)–H activation of prochiral gem-dimethyl groups is also demonstrated.[1]

We began our studies by investigating the reactivity of 1-ethyl-1-cyclobutanecarboxylic acid derivative 1a with an electron-deficient amide directing group. Initially we focused on the C–H cross-coupling reactions with phenylboronic acid pinacol ester using mono-N-protected amino acid (MPAA) ligands. Modest yields and enantioselectivities of the C–H coupling reactions were obtained using commercially available MPAA ligands such as N-Boc-leucine (L1–5). Surprisingly, chiral MPAA ligand L6, which gave enantioselectivities in excess of 90% ee with a broad range of cyclopropanecarboxylic acid substrates, gave a significantly lower yield (37%) and enantioselectivity (32% ee) with the cyclobutanecarboxylic acid substrate 1a. With the optimized reaction conditions in hand, we explored the substrate scope of this method (Table 3). The reaction was found to work well with a variety of arylboronic acid pinacol esters (2a–m). Trifluoromethyl- or fluoro- phenylboronic acid pinacol esters are amenable to the reaction conditions (2e–g). Functional groups such as aryl chlorides and bromides (2h, 2i), esters (2j), ethers (2k), and anilides (2l) are well tolerated. Although the presence of an α-hydrogen to amide carbonyl group decreased the yield and ee (2c), the reaction worked well with various 1-substituted 1-cyclobutanecarboxylic acid derivatives (2n–s).

The enantioselective cross-coupling of n-butyl substituted substrate gave 72% yield and 88% ee (2n). Sterically hindered 1-(isopropyl)-1-cyclobutane (2o) and 1-(cyclopentyl)-1-cyclobutane (2p) substrates are functionalized in high yield and ee, demonstrating that this reaction can be used to prepare highly sterically congested quaternary all-carbon stereocenters on cyclobutanes. Heteroatom substituents such as halogens (2q), oxygen (2r), and nitrogen (2s) are tolerated on the exocyclic alkyl side chain of the cyclobutane substrate. In summary, intermolecular enantioselective functionalization of C(sp3)–H bonds are demonstrated with amide substrates derived from cyclobutanecarboxylic acids. The key to the success of this method was the discovery of a new class of chiral ligands, MPAHA, which were derived from mono-N-protected amino acids. These chiral MPAHA ligands have also shown promise for further development of new methods for stereoselective functionalization of acyclic unactivated C(sp3)–H bonds.

Relationships of cyclobutane-based small molecule αvβ3 antagonists

The integrin family of cell surface extracellular matrix binding proteins are key to several physiological processes involved in tissue development, as well as cancer proliferation and dissemination. They are therefore attractive targets for drug discovery with cancer and non-cancer applications. We have developed a new integrin antagonist chemotype incorporating a functionalised cyclobutane ring as the central scaffold in an arginine–glycine–aspartic acid mimetic structure. Here, we report the synthesis of cyclobutanecarboxylic acids and cyclobutylamines with tetrahydronaphthyridine and aminopyridine arginine mimetic sidechains and masked carboxylic acid aspartic acid mimetic sidechains of varying length. Effective αvβ3 antagonists and new aspartic acid mimetics were identified in cell-based adhesion and invasion assays. A lead compound selected based on in vitro activity (IC50 < 1 μM), stability (t1/2 > 80 minutes) and synthetic tractability was well-tolerated in vivo. These results show the promise of this synthetic approach for developing αvβ3 antagonists and provide a firm foundation to progress into advanced preclinical evaluation prior to progression towards the clinic. Additionally, they highlight the use of functionalised cyclobutanes as metabolically stable core structures and a straightforward and robust method for their synthesis. This important contribution to the medicinal chemists' toolbox paves the way for increased use of Cyclobutanecarboxylic acid in drug discovery.

References

[1]Xiao KJ, Lin DW, Miura M, Zhu RY, Gong W, Wasa M, Yu JQ. Palladium(II)-catalyzed enantioselective C(sp³)-H activation using a chiral hydroxamic acid ligand. J Am Chem Soc. 2014 Jun 4;136(22):8138-42. doi: 10.1021/ja504196j. Epub 2014 May 19. PMID: 24815880; PMCID: PMC4063184.

[2]Throup A, Zraikat MS, Gordon A, Jafarinejad Soumehsaraei S, Haase KD, Patterson LH, Cooper PA, Hanlon K, Loadman PM, Sutherland M, Shnyder SD, Sheldrake HM. Sidechain structure-activity relationships of cyclobutane-based small molecule αvβ3 antagonists. RSC Med Chem. 2024 Sep 13;15(10):3616–24. doi: 10.1039/d4md00306c. Epub ahead of print. PMID: 39281803; PMCID: PMC11393731.

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