Elucidation of the mechanisms governing the thermal diastereomerization of bioactive chiral 1,3,4-thiadiazoline spiro-cyclohexyl derivatives towards their anancomeric stereoisomers

The kinetic of the thermal isomerization of some diastereomers of three chiral 1,3,4 thiadiazoline derivatives, selected as case studies of structures resulting by mono-alkyl substitution of the anancomeric 4-acetyl-2-acetamido-1,3,4- thiadiazolinyl-spiro-cyclohexane (TsC) framework has been investigated in order to elucidate the possible mechanistic pathways and the structural factors responsible for the observed spiro-junction lability. The insertion of a methyl or a tbutyl group on the C2 or C3 position with respect to the spiro junction generate two stereogenic centres, so that two pairs of enantiomers exist. The first-order rate constants for the isomerization of the less stable enantiomers into the most stable ones have been measured in different solvents and at different temperatures through batch-wise kinetic determinations. The obtained data have been successfully rationalizedby DFT calculations and Linear Solvation Energy Relationships (LSER) analyses. The achieved elucidation should make possible to plan a more rational synthesis of this kind of pharmacologically active compounds, thus affording a practical tool useful to control the involved stereochemistry and spiro-junction