This paper describes our efforts in proposing a novel mechanism for the formation of the major degradant of clobetasol propionate under weakly acidic conditions through a comprehensive investigation. In the proposed mechanism, the key Favorskii intermediate plays a critical role. This variation of the original Favorskii rearrangement, which proceeds only under alkaline conditions, has not been reported before. This mechanism enriches the understanding of the degradation chemistry of corticosteroids containing the α-haloketone moiety on their 17-position.

The small-sized cyclic peptides have attracted much research interest in the organic and bioorganic chemistry. In the present study, the mechanism of cyclization of tetrapeptides by an imine-induced ring-closing strategy has been studied in detail using the density functional theory method. The geometries of all the species were fully optimized at the B3LYP/6-31G(d) level. The M06/6-311＋＋G(2df,2p) method is employed to calculate the single point energies. The solvent effect [Trifluoroacetic Acid (TFA) was used as a solvent] was calculated by using SMD (solvation model based on the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent) model. Both the carbonyl transfer-cyclization and the H transfer-cyclization-carbonyl transfer-H transfer mechanism might be responsible for the transformation of the imine reagent to the cyclic peptide product. According to the calculation results, the carbonyl transfer-cyclization mechanism occurs via the carbonyl transfer from O(Ph-) atom to N atom, corresponding to three possible transition states with the barrier height of 20.2, 16.4 and 62.7 kcal/mol, respectively (the second one is the most feasible among different ones). Then the concerted H transfer & CO cyclization step occurs via a six-membered ring transition state. The second step (the concerted H transfer & CO cyclization step) is the rate-determining step, and the overall activation barrier is 28.3 kcal/mol. In contrast, the H transfer-cyclization-carbonyl transfer-H transfer mechanism includes four steps: the hydrogen atom first transferred from oxygen atom to N atom with the breaking of CC to form the intermediate M3 and a CH 3 COH molecule, cyclization via the CO and CC bond formation, the carbonyl transfer from O(Ph-) atom to N atom accompanied with the breaking of C-N, and the transfer of hydrogen atom with the cyclization of C-N then occurred subsequently. In this context, the second step (i.e. cyclization via the CO and CC bond formation) is the rate-determining step, and the overall activation barrier is 40.1 kcal/mol. Accordingly, the carbonyl transfer-cyclization mechanism is relatively more feasible than the H transfer-cyclization-carbonyl transfer-H transfer mechanism, and the rate-limiting step is the concerted H transfer & CO cyclization step with a barrier of 28.3 kcal/mol.