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An Unexpected Pathway to Enantiomerization of Hemithioketals in Toluene Involving a Dimeric Transition State: A Combined Experimental and Computational Study
Author(s) -
Bottoni Andrea,
Calvaresi Matteo,
Cosimelli Barbara,
Mazzanti Andrea,
Rambaldi Mirella,
Spinelli Domenico
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201500421
Subject(s) - chemistry , toluene , dimer , computational chemistry , alkyl , aryl , hydrogen bond , stereochemistry , medicinal chemistry , organic chemistry , molecule
5‐Alkyl‐8‐aryl‐8‐hydroxy‐8 H ‐[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‐8 H ‐[1,2,4]oxadiazolo[3,4‐ c ][1,4]thiazin‐3‐one ( 1a ), containing two diastereotopic hydrogen atoms. 1 H‐NMR techniques have allowed to calculate the relevant energy barriers for the enantiomerization process (ca. 20 kcal mol –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 kcal mol –1 ) in rather good agreement with the 1 H‐NMR experimental value, thus showing how a spontaneous mutarotation process could occur in non‐polar aprotic solvent.