Combined Effects on Selectivity in Fe-Catalyzed Methylene Oxidation

Abstract

Methylene C-H bonds are among the most difficult chemical bonds to selectively functionalize because of their abundance in organic structures and inertness to most chemical reagents. Their selective oxidations in biosynthetic pathways underscore the power of such reactions for streamlining the synthesis of molecules with complex oxygenation patterns. We report that an iron catalyst can achieve methylene C-H bond oxidations in diverse natural-product settings with predictable and high chemo-, site-, and even diastereoselectivities. Electronic, steric, and stereoelectronic factors, which individually promote selectivity with this catalyst, are demonstrated to be powerful control elements when operating in combination in complex molecules. This small-molecule catalyst displays site selectivities complementary to those attained through enzymatic catalysis.

Selective oxidation of aliphatic C–H bonds in alkylphenols by a chemomimetic biocatalytic system

“…However, a number of problems are persistently associated with the chemical oxidation of aliphatic C-H bonds in alkylphenols: (i) the requirement of protection/deprotection of the phenolic hydroxyl group under reaction conditions that are distinct from those for oxidation complicates the synthetic process; (ii) it is difficult to delicately control the extent of oxidations (i.e., alcohol vs. aldehyde/ketone vs. carboxylic acid); (iii) the oxidation of an aromatic C-H bond may sometimes occur when using strong oxidants; (iv) the regio-and stereoselective oxidation of an unactivated sp 3 C-H bond (in alkylphenols) remains a central challenge despite recent advances in combined use of specialized directing groups with transition metal catalysts (9)(10)(11) and in biomimetic supramolecular assemblies (12)(13)(14); and (v) chemical oxidants could be associated with significant environmental concerns (2,3). Given these issues, oxidative enzymes with inherent catalytic selectivity and reduced environmental impact may be developed into alternative catalysts for selective oxidation of organic compounds including alkylphenols (15)(16)(17)(18).…”

Direct Selective Oxidative Functionalization of C–H Bonds with H2O2: Mn-Aminopyridine Complexes Challenge the Dominance of Non-Heme Fe Catalysts

“…Within the range of practically promising catalyst systems studied, the Mn-aminopyridine catalysts (1) are used in very small amount (0.1 mol %; structurally similar Fe complexes are typically used in up to 15 mol % loadings [29][30][31][32][33][34]); (2) require a small (1.3 equiv.) excess of the green oxidant-commercially available 30% aqueous H 2 O 2 ; and (3) exhibit reasonably high yields in the oxidation of differently p-substituted cumenes, ensuring high cumyl alcohol selectivity [86].…”

“…First examples of non-heme-Fe-catalyzed oxidations appeared in early 1990s [24,28]; however, the breakthrough was achieved after 2007, when White with co-workers contributed a series of milestone works, presenting the bipyrrolidine-derived non-heme iron catalyst 1 ( Figure 1) and its structural analogs, ensuring reasonably high level of predictability in the selective oxidation of C(sp 3 )-H groups [29][30][31][32][33][34]. In competitive contribution, Costas and co-workers showed that the introduction of additional steric crowd at the pyridine moieties, as well as manipulating with the symmetry of the chiral ligand can divert the oxidation selectivity from 3° C(sp 3 )-H bonds to stronger 2° C(sp 3 )-H bonds, which is critical for the selective oxygenation of complex molecules such as natural products [35][36][37][38].…”

Site-selective hexa-hetero-functionalization of α-cyclodextrin an archetypical C6-symmetric concave cycle

“…This frontier area ultimately aims to transform any group on a given molecule based on their innate reactivity 3 and the tuning of the reagent properties. Some steps towards this goal have been taken in particular with the regioselective C-H activations on complex molecules [4][5][6] , but also the selective functionalization of reactive functions such as OH groups [7][8][9] , or the regioselectivity in cyclization reactions 10,11 .…”