Artemisinin (Qinghaosu, 1) is a sesquiterpene
lactone endoperoxide isolated from Artemisia annua L. that
Chinese herbalists have traditionally used to treat malaria.
Reduction of artemisinin by NaBH4 produced dihydroartemisinin
(DHA, 2) and yielded a new stereochemically labile
center at C-10, which in turn provided two lactol hemiacetal
interconverting epimers, namely, 2r and 2β. With the aim of
fully investigating the thermodynamics of interconversion, we
gathered the relative abundance of the two epimers within a
wide variety of solvents and rationalized the results by linear
solvation energy relationships (LSER) analysis. Beside the difference in polarity, the better stabilization of 2r in polar solvents was
found to be significantly related to its greater acidity with respect to 2β, which was estimated by two independent theoretical
approaches based on molecular modeling calculations and empirical data, and supported by 1H NMR measurements. On the
contrary, differential effects of cavitational energy have been highlighted as interactions strongly responsible for the small values of
equilibriumconstant measured for the β/Rprocess in the less polar media. Determination of forward and backward epimerization
rate constants in seven media, clearly differing in both permittivity and capacity to be H-bond donors, indicated that, in the
spontaneous process, the transition state of the rate-limiting step develops a significant degree of anionic character, as typically
happens in the base-catalyzed breakdown of hemiacetals
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