Predictable Selectivity in Remote C−H Oxidation of Steroids: Analysis of Substrate Binding Mode

Abstract

Predictability is a key requirement to encompass late‐stage C−H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp3)−H oxidation, as it requires distinguishing a specific C−H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C−H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host‐guest adduct by NMR analysis. These analyses indicate which remote C−H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late‐stage C(sp3)−H oxidation of amino‐steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.

Site and Enantioselective Aliphatic C−H Oxidation with Bioinspired Chiral Complexes

“…Interestingly the model employed to explain the site selectivity of a particular methylenic group in the oxidation of linear amines is simply based in the number of C−C bonds between this methylene and the amine moiety, and can be used to predict the site of oxidation of more complex organic molecules. This has been shown in the selective oxidation of aminosteroids [35] . NMR analysis of the structure of the substrate‐complex adduct (where the paramagnetic Mn center is replaced by the diamagnetic Zn to permit the NMR analysis) shows that C15 (or C16) sites (8‐9 C−C bonds away from the amine) are in proximity to the catalytic center, as early predicted by the simple model.…”

“…This has been shown in the selective oxidation of aminosteroids. [35] NMR analysis of the structure of the substrate-complex adduct (where the paramagnetic Mn center is replaced by the diamagnetic Zn to permit the NMR analysis) shows that C15 (or C16) sites (8-9 CÀ C bonds away from the amine) are in proximity to the catalytic center, as early predicted by the simple model. Selective catalytic oxidation largely concentrating at the predicted sites is then observed when the substrate was subjected to oxidation with supramolecular iron (R)-Fe( CR pdp) and manganese (S)-Mn-( CR pdp) catalysts (Scheme 9, right).…”

“… Supramolecular vs non‐directed oxidation of aminoesteroids (GC determined yields and selectivities) [35] …”

“…Supramolecular vs non-directed oxidation of aminoesteroids (GC determined yields and selectivities). [35] Scheme 10. Supramolecular vs non directed oxidation with the Fe Twz pdp catalyst.…”

Remote Amino Acid Recognition Enables Effective Hydrogen Peroxide Activation at a Manganese Oxidation Catalyst

“…Previously described C 2 symmetric catalysts containing and devoid of two crown ether receptors ( CR M [17a] and H M [18] or TIPS M [11b] respectively, M=Fe, Mn, Zn; Figure 2) were chosen for the study. In addition, we synthesized a family of C 1 symmetric complexes CR,X M that combine one crown‐ether containing pyridine (Figure 2) with a second arm bearing different groups that affect the steric and/or the electronic properties ( CR,TIPS M , CR,TMS M , [17c] CR,Bz M, CR,DMM M , CR,Me2N M ) of the catalyst [19] . Details on the preparation and characterization of the complexes are collected in the Supporting Information.…”