Direct regio- and stereoselective mono- and polyoxyfunctionalization of estrone derivatives at C(sp3)-H bonds

Transition Metal-Catalyzed Direct Stereoselective Oxygenations of C(sp3)–H Groups

“…Further, the currently available general approaches for modulating the regioselectivity of C­(sp 3 )–H oxidation of steroids and terpenoids (e.g., by changing the catalysts’ sterics and chirality, and the central atom, cocatalytic additives, solvent, or supramolecular recognition) should be tested and adapted for a broader scope of potentially interesting classes of complex substrates of natural origin, including alkaloids, peptides, amides, etc., as well as synthetic compounds of interest for drug discovery. In addition, while at present we have learned how to oxidize aliphatic C­(sp 3 )–H groups of molecules that also contain aromatic C­(sp 2 )–H groups with sufficient chemo- and stereoselectivity, ,, the opposite is not the case (yet recent contributions inspire some optimism − ). The “alternative rebound mechanism” introduces another dimension into catalytic C–H functionalization: while the C–H activation regio- and stereoselectivity is governed by the architecture of the chiral ligand, the nature of the novel C–X group depends on the nature of the cocatalytic additive.…”

“…120,121 More recently, the late-stage catalytic oxidative C−H functionalization of estrone 3-acetate, 17α-and 17β-estradiol 3-acetates in the presence of bioinspired nonheme Mn complexes of the types 32, 37−39 (Figure 19) was reported. 122 Changing the catalysts' chirality from (S,S)-to (R,R)-diverted the oxidation regioselectivity from preferential C9α-hydroxylation to C6α-hydroxylation, with high diastereoselectivity (α:β = 95:5) and in synthetically acceptable isolated yields (Figure 23). Applying different catalytic protocols in a sequence, one could obtain various mono-and dioxygenated metabolites (Figure 23).…”

Selective Hydroxylation of C(sp3)−H Bonds in Steroids

“…Taking this work further, the Bryliakov group recently explored a series of Mn catalysts bearing different ligands of the PDP and amino-tris-pyridylmethyl (TPA) families on the oxidation of estrone acetate, 17α-and 17β-estradiol 3acetates. [152] They discovered that the reaction could be effectively directed towards either C6α-hydroxylation, C9αhydroxylation, C6-ketonisation or 9-11-destauration/C12α-hydroxylation upon tuning of the sterics of the ligand and the absolute chirality. In the case of the 17α-and 17β-estradiol 3acetates, oxidation of the C17 alcohol to the ketone could be prevented by using HFIP as a reaction solvent.…”

“…Intriguingly, they observed a regioselectivity switch from C9α‐hydroxylation to C6‐ketonisation upon changing the absolute chirality of the Mn complex (Scheme 26). Taking this work further, the Bryliakov group recently explored a series of Mn catalysts bearing different ligands of the PDP and amino‐tris‐pyridylmethyl (TPA) families on the oxidation of estrone acetate, 17α‐ and 17β‐estradiol 3‐acetates [152] . They discovered that the reaction could be effectively directed towards either C6α‐hydroxylation, C9α‐hydroxylation, C6‐ketonisation or 9–11‐destauration/C12α‐hydroxylation upon tuning of the sterics of the ligand and the absolute chirality.…”

Manganese-Catalyzed Regioselective C–H Lactonization and Hydroxylation of Fatty Acids with H2O2

“…Selective aliphatic C–H oxygenation is a challenging transformation holding high practical promise in organic synthesis. − In the past decade, manganese complexes bearing bis-amino-bis-pyridine ligands were established as robust and selective catalysts for direct oxygenations of C­(sp 3 )–H groups with “green” oxidant H 2 O 2 . − The distinctive feature of these manganese-based catalysts systems has been the use carboxylic acid additives in order to tune the catalyst activity as well as chemo-, regio-, and stereoselectivity. ,− This is explained by the involvement of the carboxylic acid molecule in the heterolytic cleavage of the peroxide O–O bond of the initially formed manganese­(III) hydroperoxo intermediate, leading to the elusive [Mn V O­(O 2 CR)] 2+ active species . Nonetheless, the possibility of oxidation of the carboxylic acid itself was rarely considered.…”