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

作者：Menta S; Carradori S; Siani G; Secci D; Mannina L; Sobolev A P; Cirilli R^*; Pierini M^*

来源：RSC Advances, 2016, 6(75): 71262-71272.

DOI：10.1039/c6ra13727j

The kinetics of the thermal isomerization of some diastereomers of three chiral 1,3,4 thiadiazoline derivatives, selected as case studies of structures resulting from mono-alkyl substitution of the anancomeric 4-acetyl-2-acetamido-1,3,4-thiadiazolinyl-spiro-cyclohexane (TsC) framework, have 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 t-butyl group on the C2 or C3 position with respect to the spiro junction generates 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 rationalized by DFT calculations and Linear Solvation Energy Relationships (LSER) analyses. The achieved elucidation should make it possible to plan a more rational synthesis of this kind of pharmacologically active compounds, thus affording a practical tool that is useful for controlling the involved stereochemistry and spiro-junction lability.

• 出版日期2016