Regiodivergent Outcomes in Metal-Catalyzed Aliphatic C-H Azidations of Estrone Derivatives

            New late-stage C-H functionalization reactions that are compatible with structurally complex and clinically useful natural products are of great interest to the pharmaceutical industry. This is due, in part, to the ability of nitrogen-containing functionality to modulate the binding affinity and physicochemical properties of drug candidate molecules. However, until recently, chemical methods to convert an alkyl (and, in particular, a tertiary) C-H bond into an alkyl carbon-nitrogen bond were lacking. This problem is further exacerbated by the fact that enzymes generally do not catalyze aminations of C-H bonds (for an exception to this rule, see this recent report). Earlier in 2015, two new synthetic methods for the metal-catalyzed azidation of aliphatic C-H bonds were received with great interest and enthusiasm by the chemical community. Interestingly, although the C-H azidation methodologies are mechanistically related, their application to differentially protected estrone derivatives produces regiodivergent outcomes (see Scheme above). In one case, the benzylic tertiary position (C9) reacts primarily and, in the other, the secondary C6 C-H position is functionalized (for details, see below).

            The method reported by the laboratory of John Groves at Princeton University is a manganese-catalyzed process that uses sodium azide as the azide source. Mechanistically, this chemistry is analogous to Groves’ previously disclosed manganese-catalyzed C-H fluorination wherein a fluoride ligand axial to manganese transfers fluorine to a carbon-centered radical derived from the hydrocarbon substrate. For azidation, the fluoride is simply replaced by an azide source (NaN₃). The substrate radical is then trapped by the in situ-generated Mn(IV)-azide complex to construct the carbon-nitrogen bond. Both manganese porphyrins as well as Mn salen-type Jacobsen catalysts are competent participants in the catalytic cycle and the novel azidation protocol can be run under air. Under the optimized reaction conditions, estrone acetate is converted predominantly to a C9-a-azide. A diazidation product wherein both benzylic positions (C6 and C9) are functionalized is also observed as a major side product.

            John Hartwig’s group has also developed a method for late-stage azidation of tertiary and benzylic C-H bonds using an iron catalyst and Zhdankin’s hypervalent azidoiodinane reagent. For a nice introductory overview of Hartwig’s technology, see this blog post. Azidation of TBS-protected estrone, under the iron-catalyzed conditions, furnishes the corresponding C6-a-azide in modest yield. The stereodivergent nature of the two related azide-forming processes is somewhat striking.

            On a somewhat unrelated note, the laboratory of Timothy Newhouse at Yale University has disclosed a new palladium-catalyzed methodology for a,b-dehydrogenation of esters and nitriles. The method nicely complements (and, in some cases, exceeds) earlier, more classical approaches to achieve a,b-unsaturation such as the Saegusa-Ito oxidation or the Sharpless selenoxide elimination (later extended by Grieco). The novel reaction from the Yale group is compatible with nitrile substrates derived from estrone (shown above), cholesterol and androstenedione-type steroids.