Experimental and Theoretical Studies on the Rearrangement of 2-Oxoazepane [alpha],[alpha]-Amino Acids into 2'-Oxopiperidine [beta]2,3,3-Amino Acids: An Example of Intramolecular Catalysis

• Published in: Chemistry : a European journal 2015-02, Vol.21 (6), p.2489
• Main Authors: Nunez-Villanueva, Diego, Bonache, M Ángeles, Lozano, Laura, Infantes, Lourdes, Elguero, José, Alkorta, Ibon, Garcia-Lopez, M Teresa, Gonzalez-Muniz, Rosario, Martin-Martinez, Mercedes
• Format: Article
• Language: English
• Subjects: Amino acids; Catalysis; Chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201405640

Enantiopure [beta]-amino acids represent interesting scaffolds for peptidomimetics, foldamers and bioactive compounds. However, the synthesis of highly substituted analogues is still a major challenge. Herein, we describe the spontaneous rearrangement of 4-carboxy-2-oxoazepane [alpha],[alpha]-amino acids to lead to 2'-oxopiperidine-containing [beta]2,3,3-amino acids, upon basic or acid hydrolysis of the 2-oxoazepane [alpha],[alpha]-amino acid ester. Under acidic conditions, a totally stereoselective synthetic route has been developed. The reordering process involved the spontaneous breakdown of an amide bond, which typically requires strong conditions, and the formation of a new bond leading to the six-membered heterocycle. A quantum mechanical study was carried out to obtain insight into the remarkable ease of this rearrangement, which occurs at room temperature, either in solution or upon storage of the 4-carboxylic acid substituted 2-oxoazepane derivatives. This theoretical study suggests that the rearrangement process occurs through a concerted mechanism, in which the energy of the transition states can be lowered by the participation of a catalytic water molecule. Interestingly, it also suggested a role for the carboxylic acid at position4 of the 2-oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis.