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.