Couty's azetidine synthesis
Couty's azetidine synthesis is one of the most efficient synthesis of azetidines named after French organic chemist François Couty from University of Versailles Saint-Quentin-en-Yvelines. It enables an easy synthesis of a broad range of enantiopure azetidines from readily available β-amino alcohols by their chlorination followed by deprotonation and a 4-exo-trig ring closure.[1]
It was originally reported from N-alkyl- or N-aryl-[2] N-cyanomethylated β-aminoalcohols but other electron-withdrawing groups such as esters[3] or phosphonates[4] are also suitable and the chloride can be replaced by a Michael acceptor.[5] Over the years, the Couty's azetidine synthesis was shown to be efficient to access a variety of enantiopure azetidines and 2-cyano-azetidines were shown to be excellent scaffolds and building blocks in heterocyclic chemistry and for molecular diversity. It was notably extensively utilized by the Broad Institute of MIT and Harvard for the synthesis and profiling of a collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries,[6] and by Galapagos NV for the discovery and optimization of an azetidine library for the development of free fatty acid receptor 2 (FFA2) antagonists.[7]
References
[edit]- ^ Agami, Claude; Couty, François; Evano, Gwilherm (2002). "A straightforward synthesis of enantiopure 2-cyano azetidines from beta-amino alcohols". Tetrahedron: Asymmetry. 13 (3): 297-302. doi:10.1016/S0957-4166(02)00076-9.
- ^ Quinodoz, Pierre; Drouillat, Bruno; Wright, Karen; Marrot, Jérôme; Couty, François (2016). "N-Arylazetidines: Preparation through Anionic Ring Closure". J. Org. Chem. 81 (7): 2899–3710. doi:10.1021/acs.joc.6b00169. PMID 26932242.
- ^ Couty, François; Evano, Gwilherm; Rabasso, Nicolas (2003). "Synthesis of enantiopure azetidine 2-carboxylic acids and their incorporation into peptides". Tetrahedron: Asymmetry. 14 (16): 2407-2412. doi:10.1016/S0957-4166(03)00493-2.
- ^ Agami, Claude; Couty, François; Rabasso, Nicolas (2002). "An efficient asymmetric synthesis of azetidine 2-phosphonic acids". Tetrahedron Letters. 43 (26): 4633-4636. doi:10.1016/S0040-4039(02)00868-7.
- ^ Carlin-Sinclair, Abel; Couty, François; Rabasso, Nicolas (2003). "Asymmetric Synthesis of Functionalized Azetidines through Intramolecular Michael Additions". Synlett. 2003 (5): 726–728. doi:10.1055/s-2003-38353.
- ^ Lowe, Jason; Lee, Maurice; Akella, Lakshmi; Davoine, Emeline; Donckele, Etienne; Durak, Landon; Duvall, Jeremy; Gerard, Baudouin; Holson, Edward (2012). "Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries". Journal of Organic Chemistry. 77 (17): 7187–7311. doi:10.1021/jo300974j. PMC 3454511. PMID 22853001.
- ^ Pizzonero, Mathieu; Dupont, Sonia; Babel, Marielle; Beaumont, Stéphane; Bienvenu, Natacha; Blanqué, Roland; Cherel, Laëtitia; Christophe, Thierry; Crescenzi, Benedetta; De Lemos, Elsa; Delerive, Philippe; Deprez, Pierre; De Vos, Steve; Djata, Fatoumata; Fletcher, Stephen (2014). "Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic". Journal of Medicinal Chemistry. 57 (23): 10044–10057. doi:10.1021/jm5012885. PMID 25380412.