Oxidative Coupling of 17β-Estradiol:  Inventory of Oligomer Products and Configuration Assignment of Atropoisomeric C4-Linked Biphenyl-Type Dimers and Trimers

• Published in: Journal of organic chemistry Vol. 69; no. 17; pp. 5652 - 5659
• Main Authors: Pezzella, Alessandro, Lista, Liliana, Napolitano, Alessandra, d'Ischia, Marco
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.08.2004; Amer Chemical Soc
• Subjects: Alicyclic compounds, terpenoids, prostaglandins, steroids; Chemistry; Chemistry, Organic; Exact sciences and technology; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Steroids; STEROIDS; QUINONES; ESTRADIOL; ESTROGEN; CHEMISTRY; POLYMERIZATION; IDENTIFICATION; NEUROPROTECTION; Steroid; Interconversion; Trimer; Exciton; Hydrogen peroxide; Enzyme; Estrogen; Steric hindrance; NMR spectrometry; Oxidant; Oligomer; Oxidative coupling; Estradiol; Chromatography; Atropoisomerism; Peroxidases; Chirality; Absolute configuration; Phenols; Dimer; Oxidoreductases; Mass spectrometry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0492665

The oxidation chemistry of 17β-estradiol (1) is of central relevance to the nongenomic effects of estrogens and offers valuable prospects in the search for novel steroidal scaffolds of academic and industrial interest. Herein, we report the results of a detailed investigation into the nature of the oligomer products formed by phenolic oxidation of 1. Of the oxidants tested, the peroxidase/H2O2 system proved to be the most effective in inducing conversion of 1 to a complex mixture of oligomer species. Repeated chromatographic fractionation followed by extensive 2D NMR and mass spectrometric analysis allowed identification of a series of phenolic coupling products comprising, besides the C 2-symmetric dimers 2 and 3, a 2,4‘ dimer (4), two O-linked dimers (5, 6), and the novel trimers 7 − 9. All 4-linked biphenyl-type oligomers, i.e., 3 and 7 − 9, occurred as couples of atropoisomers, reflecting steric hindrance at biphenyl linkages. For all atropoisomers, absolute configuration was established by the exciton chirality method and the interconversion energy was determined by dynamic NMR. These results provide the first systematic inventory of oxidative coupling products of 1 and lay the foundation for future studies aimed to develop novel estrogen derivatives based on oligomeric scaffolds.