Oxidative chemistry of 2-nitro and 4-nitroestradiol: Dichotomous behavior of radical intermediates and novel potential routes for oxyfunctionalization and B-ring fission of steroidal scaffolds.

Oxidation of 4-nitro-17beta-estradiol (1) with the peroxidase/H(2)O(2) system gave the symmetric C(2)-linked dimer (3) through phenoxy radical coupling. Similar oxidation of 2-nitro-17beta-estradiol (2), in which the nitro group is coplanar with the aromatic ring, yielded 9alpha- and 9beta-hydroxy-2-nitro-17beta-estradiol (4a,b), (17beta)-2-nitroestra-1(10),2,4,9(11)-tetraene-3,17-diol (5), and (12alpha,17beta)-2-nitroestra-1(10),2,4,9(11)-tetraene-3,12,17-triol (6). With higher concentrations of H(2)O(2), the novel secoestra-1(10),2,4-trien-9-one derivative 7 was obtained from 2. Theoretical calculations suggested that the peculiar behavior of 2 may be due to the generation of a relatively stable radical intermediate at C(9), which would then be converted to the reactive quinone methide 8. The chemistry described in this paper appears to be an intriguing example of control of the site of substitution over evolution of phenoxy radicals, and opens new vistas toward selective oxyfunctionalization of the estrane skeleton.