title: The Anancomeric Character of the Pharmacophore 1,3,4-Thiadiazoline Framework in Chiral Spiro-Cyclohexyl Derivatives: Effects on Stereochemistry and Spiro-Junction Lability. Thermodynamic Aspects.
abstract: Three new and easily accessible chiral compounds, containing the pharmacophore 1,3,4-thiadiazoline nucleus joined by a spiro center to a monoalkyl (methyl or t-butyl) substituted cyclohexyl fragment, have been synthesized and fully characterized from the structural and stereochemical point of view. The formation of a spiro-cyclohexyl-thiadiazoline system (sCT) offered the rare opportunity to generate at room temperature both anancomeric structures, displaying alkyl groups bound to the cyclohexyl ring in equatorial position, and other quite stable stereoisomers in which the same alkyl moieties are, instead, inserted in axial position, even for the extreme case represented by the really bulky t-butyl group. DFT calculations led to a clear rationalization of such stereochemical behaviors, pointing out that in all cases they arise from the unexpected strong anancomeric character possessed by the sCT framework in its 4-acetyl substituted version. In consideration of the large number of substances in which the 1,3,4-thiadiazoline heterocycle has been found as the active pharmacophore, the results discussed in this work may provide solid bases to allow a rational design of new chiral bioactive spiro-thiadiazolines characterized by well-defined stereochemical structures and single anancomeric geometries.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Menta
authors.affiliation: Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara , Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.affiliation: Dipartimento di Chimica, Università degli studi di Firenze , Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Faggi
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mannina
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità , Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pierini