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

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.