A Predictably Selective Aliphatic C–H Oxidation Reaction for Complex Molecule Synthesis

Abstract

Realizing the extraordinary potential of unactivated sp3 C-H bond oxidation in organic synthesis requires the discovery of catalysts that are both highly reactive and predictably selective. We report an iron (Fe)-based small molecule catalyst that uses hydrogen peroxide (H2O2) to oxidize a broad range of substrates. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C-H bonds, without the need for directing groups. Additionally, carboxylate directing groups may be used to furnish five-membered ring lactone products. We demonstrate that these three modes of selectivity enable the predictable oxidation of complex natural products and their derivatives at specific C-H bonds with preparatively useful yields. This type of general and predictable reactivity stands to enable aliphatic C-H oxidation as a method for streamlining complex molecule synthesis.

Pathways for Arene Oxidation in Non-Heme Diiron Enzymes: Lessons from Computational Studies on Benzoyl Coenzyme A Epoxidase

“…84 Among the identified BoxB bis(μ-oxo) structures, another interesting feature is exhibited by the H-bis(μ-oxo) isomer: apparently, the negative charge on the pendant oxygen of Glu240 cannot coexist with the strong oxidant in the absence of the hydrogen bond with the Fe1-bound water, and a partial O-O bond between the oxo ligand and the carboxylate oxygen is formed as indicated by the fairly short O-O distance (2.07 Å) and the significant spin population gained by the carboxylate. 85 Importantly, in the synthetic nonheme monoiron system Fe(S,S-PDP), 86 a computational study 87 identified analogous geometric and electronic structure for an unstable local minimum as well as for a transient geometry en route to C-H activation.…”

Chemoenzymatic elaboration of monosaccharides using engineered cytochrome P450 BM3 demethylases

“…Such control enables efficient hydroxylation of C-H bonds lacking any significant stereoelectronic differentiation and augments the means by which synthetic chemists can target otherwise indistinguishable C-H bonds (25).…”

Towards robust alkane oxidation catalysts: electronic variations in non-heme iron(ii) complexes and their effect in catalytic alkane oxidation

“…21 In contrast, some non-heme iron complexes have shown a dramatically different behaviour. Much higher conversions of H 2 O 2 into oxidised products, combined with a more selective oxidation reactivity have been observed with certain non-heme iron(II) complexes containing tetradentate nitrogen-based ligands, which can be classified into the following categories, according to their ligand structure: tripodal tetradentate ligands such as TPA 22,23 and iso-BPMEN, 24 linear tetradentate ligands such as BPMEN, 25 BQEN 26 and (S,S-PDP) 27 and cyclic tetradentate ligands, for example Me2 PyTACN (see Figure 1). 28,29 Several non-heme iron catalysts have shown stereospecific and dioxygenindependent oxidation of alkanes with H 2 O 2 13, 17, 30 and the C-H regio-selectivities and kinetic isotope effects have indicated a more selective oxidant than those responsible for oxidation in Fenton-type systems.…”