Study of the Tautomerism of 3-Hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one by NMR and Computational Studies

GUILLERMO M. CHANS; ELIZABETH L. MOYANO; MARIA T. BAUMGARTNER

Riviera Maya

Conferencia; 11th Latin American Conference on Physical Organic Chemistry (CLAFQO-11); 2011

Arylcyclohex-1,3-diones show different biologic activity according to their substitution; as an  example, it can be mentioned the â-triketone 3-hydroxy-2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohex-2-en-1-one (NTBC), which is the first effective drug for the therapy of Tyrosinemia Type I.1 This disease is the result of a defect in the last catalytic step of tyrosine catabolism, the reaction of fumarylacetoacetase. The keto-enol tautomerization is among the most well studied subjects both from experimental and theoretical points of view. In a great number of compounds that have biological activity, this is related to their structure. Therefore, it is important to determine the optimal tautomeric form, which is a consequence of the relative stability of the tautomers and the substituent effect.2 Our particular focus is the study of the tautomerism of a thienyl-carbonyl derivative of cyclohexane-1,3-dione, because the presence of an heterocyclic system and specifically the sulfur heteroatom could alter the metabolic effect and perhaps improve the therapeutic properties of these type of compounds. Even that it is known that potent HPPD inhibitors have the aryl-acylcyclohexanedione nucleus, as in the case of NTBC, heteroaryl-acylcyclohexanediones are also potential candidates of active substances. Hence, it is not surprising that thiophene structure either as the central ring or as part of a central fused ring system plays an important role in pharmaceutical and medicinal applications and drug discovery.3 To extend our knowledge, we investigated the calculating method, the size of basis sets, and solvent effects on the tautomerization processes of triketones. We aimed at checking if NMR measurements, supported by computational calculations, could provide new information on the preferred solution structure of an NTBC analog. The present work documents the first computational study of the energy barriers of 2-acylcycloalkane-1,3-diones, as well as the first experimental NMR work in such compounds. 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one 1 has been synthesized,4 and is estimated to show antityrosinemic activity according to its structural analogy with NTBC. For this reason, we performed a complete conformational study of such molecule, using Nuclear Magnetic Resonance (NMR) as a powerful experimental tool, and by computational calculations, with ab initio and DFT methods (Gaussian 03 program). A total of 56 isomers were analyzed in gas phase using HF/6-31G*, resulting in 6 most stable isomers (2 triketones and 4 monoenols). From these results, we could confirm that only monoenols have the lowest energy in solution, being the most stables ones the two tautomers, the endocyclic and exocyclic enols (1a and 1c), with their respective rotamers (1b and 1d) (Scheme 1). According thermodinamical analysis and rotation (1a-1b, 1c-1d) and tautomerism barriers (1a-1c, 1b-1d) studies in gas phase and solution (CHCl3 and water), it was determined that the endocyclic enol 1a would be the major isomer (> 95 %).  In the 1H NMR spectrum, the absence of a signal of a methine proton (corresponding to a triketone structure) and the presence of a signal at 17.28 ppm, indicated that the major species is an enol, whose chemical shift is consistent with an intramolecular hydrogen bond between the enol group and the carbonylic oxygen. On the other hand, in the NOESY experiment at low temperature, a NOE effect was observed between OH and methylenic hydrogens, indicating that the enol is endocyclic.