Beyond ferryl-mediated hydroxylation: 40 years of the rebound mechanism and C–H activation

Abstract

Since our initial report in 1976, the oxygen rebound mechanism has become the consensus mechanistic feature for an expanding variety of enzymatic C–H functionalization reactions and small molecule biomimetic catalysts. For both the biotransformations and models, an initial hydrogen atom abstraction from the substrate (R–H) by high-valent iron-oxo species (Fen=O) generates a substrate radical and a reduced iron hydroxide, [Fen−1–OH ·R]. This caged radical pair then evolves on a complicated energy landscape through a number of reaction pathways, such as oxygen rebound to form R–OH, rebound to a non-oxygen atom affording R–X, electron transfer of the incipient radical to yield a carbocation, R+, desaturation to form olefins, and radical cage escape. These various flavors of the rebound process, often in competition with each other, give rise to the wide range of C–H functionalization reactions performed by iron-containing oxygenases. In this review, we first recount the history of radical rebound mechanisms, their general features, and key intermediates involved. We will discuss in detail the factors that affect the behavior of the initial caged radical pair and the lifetimes of the incipient substrate radicals. Several representative examples of enzymatic C–H transformations are selected to illustrate how the behaviors of the radical pair [Fen−1–OH ·R] determine the eventual reaction outcome. Finally, we discuss the powerful potential of “radical rebound” processes as a general paradigm for developing novel C–H functionalization reactions with synthetic, biomimetic catalysts. We envision that new chemistry will continue to arise by bridging enzymatic “radical rebound” with synthetic organic chemistry.

Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

“…In this context, it must be emphasized that our microsome and hepatocyte incubations, which certainly hydroxylate CDZ173 based on cytochrome P450, non‐heme diiron hydroxylases and α ‐keto‐glutarate dependent non‐heme iron hydroxylases following an oxygen rebound mechanism are incompatible with the mechanism proposed for a Crabtree ‐type catalyst. If α ‐keto‐glutarate dependent non‐heme iron halogenases following a non‐oxygen rebound mechanism are present in our assays is not addressed.…”

cPCET versus HAT: A Direct Theoretical Method for Distinguishing X–H Bond‐Activation Mechanisms

“…We initiated our studies by analyzing two reactions from the field of bioinorganic chemistry [14] where C(sp 3 )ÀHb ond oxidation occurs either via cPCET,f ollowing the above definition, or aH AT mechanism. Fort he cPCET case,w e selected the well-studied reaction of lipoxygenase, [15] an Fe III À OH active site which breaks one of the C(sp 3 ) À Hb onds of arachidonic acid, and for HATw es elected the C(sp 3 ) À H oxidation event from the oxoiron(IV) intermediate in taurine dioxygenase (TauD-J), [16] which oxidizes aC(sp 3 )ÀHbond of taurine.S tructural depictions for the active sites and transition states for CÀHb ond activation are shown in Figure 1.…”

In Vitro Reconstitution of OxyC Activity Enables Total Chemoenzymatic Syntheses of Vancomycin Aglycone Variants

“…Reactions with substrates 2, 3,a nd 9 demonstrate that the electronic properties of the OxyC reaction are finely tuned. [21][22][23] Cpd Im ay oxidize Hpg3 to yield compound II (cpd II) and the phenolic radical (12), which has significant spin density at the ortho position. [21][22][23] Cpd Im ay oxidize Hpg3 to yield compound II (cpd II) and the phenolic radical (12), which has significant spin density at the ortho position.…”

“…To guide future studies,wepropose the working model shown in Figure 3f,i nw hich reaction of the resting state of the enzyme (10)w ith O 2 and substrate gives rise to compound I (cpd I, 11), as is typical for P450 enzymes. [21][22][23] Cpd Im ay oxidize Hpg3 to yield compound II (cpd II) and the phenolic radical (12), which has significant spin density at the ortho position. Addition into the aromatic system of Dpg delivers the stabilized intermediate 13,which, based on first principles, is more stable than an intermediate that would result from addition of aDpg radical to Hpg.…”