title: Experimental and theoretical studies on the rearrangement of 2-oxoazepane α,α-amino acids into 2'-oxopiperidine β(2,3,3) -amino acids: an example of intramolecular catalysis.
abstract: Enantiopure β-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 α,α-amino acids to lead to 2'-oxopiperidine-containing β(2,3,3) -amino acids, upon basic or acid hydrolysis of the 2-oxoazepane α,α-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 position 4 of the 2-oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis.
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, 28006 Madrid (Spain).
authors.forename: Diego
authors.initials: D
authors.lastname: Núñez-Villanueva
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Bonache
authors.forename: Laura
authors.initials: L
authors.lastname: Lozano
authors.forename: Lourdes
authors.initials: L
authors.lastname: Infantes
authors.forename: José
authors.initials: J
authors.lastname: Elguero
authors.forename: Ibon
authors.initials: I
authors.lastname: Alkorta
authors.forename: M Teresa
authors.initials: MT
authors.lastname: García-López
authors.forename: Rosario
authors.initials: R
authors.lastname: González-Muñiz
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martín-Martínez
keywords: 2-oxoazepane; 2-oxopiperidine; amino acids; density functional calculations; intramolecular catalysis