New theoretical insights on tautomerism of hyperforin—a prenylated phloroglucinol derivative which may be responsible for St. John’s wort ( Hypericum perforatum ) antidepressant activity

Abstract

The thermodynamic aspects of keto-enol tautomerism of hyperforin were investigated theoretically using density functional theory methods. At the B3LYP/aug-cc-pVTZ//B3LYP/aug-cc-pVDZ level of theory the enol tautomer dominates the tautomeric mixture and the second enol tautomer 1OH-HB has Gibbs free energy higher by 1.2 kcal/mol, despite possessing an intramolecular hydrogen bond. The purely keto tautomer is less stable by 3.3 kcal/mol compared with the 1OH tautomer, which means that the percentage of the keto tautomer in the tautomeric mixture is only about 0.4%. This is a different picture than in the parent compound of hyperforin-the phloroglucinol, where the keto tautomer is more stable than corresponding enol 1OH tautomer by 0.6 kcal/mol. To explain this difference, several in-between model molecules reflecting gradual transformation from phloroglucinol to hyperforin were build, and all the tautomeric forms were optimized for each molecule. It turned out that the addition of an aliphatic three-carbon bridge to phloroglucinol ring is crucial for the reversal of the tautomer stability order to that for hyperforin. The probable reason is the unfavorable strain in the keto tautomer introduced by the carbon bridge, which forces a specific geometric configuration which destabilizes in consequence the keto tautomer. This picture of hyperforin tautomerism underlines the dominance of enol tautomers, which can be important when studying the antidepressant activity of hyperforin-its interactions with neurotransmitters receptors.

Hydroxyl Group‐Enabled Highly Efficient Ligand for Pd‐Catalyzed Telomerization of 1,3‐Butadiene with CO2

“…Reducing the usage of DIPEA additive also led to inferior outcomes (entry 6). Given the fact that the keto tautomer of phloroglucinol is more stable than the enol form, [ 21 ] these results suggested the direct participation of phenolic hydroxyl group into the catalytic cycle of telomerization. Considering that tertiary amines were frequently applied as the absorbents for CO 2 capture, [ 22 ] we deduced that for the Pd/PPh 3 system, adding tertiary amine probably enhanced the CO 2 concentration of solution.…”

H/D Exchange Processes in Flavonoids: Kinetics and Mechanistic Investigations

“…Although our observed rate constants (k i , i = 1, 2, 3, 4, 5) and the corresponding ∆G ‡ values are not related to true elementary reaction steps (i.e., involving single transition states), they can be considered a simple sequence of elementary steps with one of them as the ratedetermining step. Assuming the well-known and largely accepted mechanism involving keto-enol tautomerism of 1,3,5 activated aromatic systems [24], we propose that deuterated keto-analogues (4ab and 4ac) could be the putative transient intermediates leading to the detectable intermediates 4b (k 1 ) and 4c (k 2 ) in the two competitive divergent processes 4a → 4b and 4a → 4c, respectively. Similarly, 4bd and 4cd could be the transient putative intermediates of the two convergent pathways, 4b → 4d regulated by k 4 and 4c → 4d regulated by k 5 leading to the end-product 4d.…”

Theoretical and Experimental Evidence of Two‐Step Tautomerization in Hypericin

“…[ 41,42 ] But, the complex photo physics are a blessing and a curse, as it is difficult to pin down the origin of a specific change. However, time‐dependent density functional theory (TD‐DFT) offers a solid theoretical framework to correlate with the experimental data and permits to calculate isomer energies, [ 43 ] transition states, [ 44 ] and the transition dipole moment (TDM). [ 45 ]…”