An Unexpected Pathway to Enantiomerization of Hemithioketals in Toluene Involving a Dimeric Transition State: A Combined Experimental and Computational Study

5-Alkyl-8-aryl-8-hydroxy-8H-[1,2,4]oxadiazolo[3,4-c][1,4]-thiazin-3-ones (1) and their thioketals (2) represent interesting hits as LTTC blockers as well as inhibitors of MDR1 activity. Compounds 1 contain an unstable chiral centre which can give rise to an enantiomerization process, because of the possible equilibrium with the open-chain forms 4. We have carried out a combined experimental-computational study on the 1/4 equilibrium in toluene by using the 8-(4-bromophenyl)-5-ethyl-8-hydroxy-8H-[1,2,4]oxadiazolo[3,4-c][1,4]-thiazin-3-one (1a), containing two diastereotopic hydrogen atoms. 1H-NMR techniques have allowed to calculate the relevant energy barriers for the enantiomerization process (ca. 20 kcalmol–1). QM computations have individuated a transition state for a concerted asynchronous process occurring on a dimer of 1a with an activation barrier (ca. 23 kcalmol–1) in rather good agreement with the 1H-NMR experimental value, thus showing how a spontaneous mutarotation process could occur in non-polar aprotic solvent.