Stereochemical Effects During [M − H]− Dissociations of Epimeric 11-OH-17β-Estradiols and Distant Electronic Effects of Substituents at C(11) Position on Gas Phase Acidity

The affinity of estradiol derivatives for the estrogen receptor (ER) depends strongly on nature and stereochemistry of substituents in C(11) position of the 17β-estradiol (I). In this work, the stereochemistry effects of the 11α-OH-17β-estradiol (IIIα) and 11β-OH-17β-estradiol (IIIβ) were investigated using CID experiments and gas-phase acidity (ΔH°acid) determination. The CID experiments showed that the steroids decompose via different pathways involving competitive dissociations with rate constants depending upon the α/β C(11) stereochemistry. It was shown that the fragmentations of both deprotonated [IIIα-H]− and [IIIβ-H]− epimers were initiated by the deprotonation of the most acidic site, i.e. the phenolic hydroxyl at C(3). This view was confirmed by H/D exchange and double resonance experiments. Furthermore, the ΔH°acid of both epimers (IIIα and IIIβ), 17β-estradiol (I), and 17-desoxyestradiol (II) was determined using the extended Cooks' kinetic method. The resulting values allowed us to classify steroids as a function of their gas-phase acidity as follows: (IIIβ) ≫ (II) > (I) > (IIIα). Interestingly, the α/β C(11) stereochemistry appeared to influence strongly the gas-phase acidity. This phenomenon could be explained through stereospecific proton interaction with π-orbital cloud of A ring, which was confirmed by theoretical calculation.

Graphical AbstractThe α/β C(11) stereochemistry influence strongly the gas-phase acidity of the 17β-estradiol due to stereospecific proton interaction with π-orbital cloud of A ring.Figure optionsDownload full-size imageDownload high-quality image (62 K)Download as PowerPoint slide