Steroids | 2019
Concise synthesis of 2-methoxyestradiol from 17β-estradiol through the C(sp2)-H hydroxylation
Abstract
Graphical abstract 2‐Methoxyestradiol has been synthesized from 17&bgr;‐estradiol with 51% overall yield. Figure. No Caption available. HighlightsFour steps to the synthesis of 2‐methoxyestradiol with 51% overall yield.The key step is the ruthenium‐catalyzed ortho‐C(sp2)‐H hydroxylation of phenol carbamate.Our approach to access 2‐methoxyestradiol is amenable to scale preparation. Abstract A four‐step route for the synthesis of 2‐methoxyestradiol (5) starting from 17&bgr;‐estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium‐catalyzed ortho‐C(sp2)‐H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl2(p‐cymene)]2 as the catalyst, PhI(OAc)2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co‐solvent, the hydroxyl group could be singly installed at the 2‐position of 3‐dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2‐methoxyestradiol (5).