Mechanism and stereoselectivity in metal and enzyme catalyzed carbene insertion into X-H and C(sp2)-H bonds.

Constructing highly proficient C-X (X = O, N, S, etc.) and C-C bonds by leveraging TMs (transition metals) (Fe, Cu, Pd, Rh, Au, etc.) and enzymes to catalyze carbene insertion into X-H/C(sp2)-H is a highly versatile strategy. This is primarily achieved through the in situ generation of metal carbenes from the interaction of TMs with diazo compounds. Over the last few decades, significant advancements have been made, encompassing a wide array of X-H bond insertions using various TMs. These reactions typically favor a stepwise ionic pathway where the nucleophilic attack on the metal carbene leads to the generation of a metal ylide species. This intermediate marks a critical juncture in the reaction cascade, presenting multiple avenues for proton transfer to yield the X-H inserted product. The mechanism of C(sp2)-H insertion reactions closely resembles those of X-H insertion reactions and thus have been included here. A major development in carbene insertion reactions has been the use of engineered enzymes as catalysts. Since the seminal report of a non-natural "carbene transferase" by Arnold in 2013, "P411", several heme-based enzymes have been reported in the literature to catalyze various abiological carbene insertion reactions into C(sp2)-H, N-H and S-H bonds. These enzymes possess an extraordinary ability to regulate the orientation and conformations of reactive intermediates, facilitating stereoselective carbene transfers. However, the absence of a suitable stereochemical model has impeded the development of asymmetric reactions employing a lone chiral catalyst, including enzymes. There is a pressing need to investigate alternative mechanisms and models to enhance our comprehension of stereoselectivity in these processes, which will be crucial for advancing the fields of asymmetric synthesis and biocatalysis. The current review aims to provide details on the mechanistic aspects of the asymmetric X-H and C(sp2)-H insertion reactions catalyzed by Fe, Cu, Pd, Rh, Au, and enzymes, focusing on the detailed mechanism and stereochemical model. The review is divided into sections focusing on a specific X-H/C(sp2)-H bond type catalyzed by different TMs and enzymes.

Oxidized Bridged Carbenoids as Viable Intermediates in a Fe(III) Catalyzed C-H Insertion Reaction.

Fe catalyzed carbene insertion reactions present an efficient route for direct C-H functionalization. The use of Fe(III) in place of the widely used Fe(II) presents several benefits. However, the mechanistic understanding of Fe(III) severely lags behind Fe(II) complexes. One of the major unsolved issues relates to the formation of bridged versus terminal metallocarbenes. Even though the oxidized bridged carbenoid complexes have been isolated and found to be thermodynamically more stable, they are generally considered a dead end for the catalytic cycle. In the current report, the formation and the subsequent reactions of the bridged carbenoid complexes for an Fe(TPP)Cl catalyzed C(sp2 )-H insertion are investigated. Using DFT calculations, it is observed that both mono and bis oxidized bridged carbenoid complexes can participate in the catalytic cycle. Importantly, for the first time, a mechanistic pathway showing that these bridged species are not a dead end in Fe catalysis is presented. Their existence in other reactions might be more prevalent than what is currently believed. The current study will have important implications in utilizing Fe(III) complexes for other insertion reactions, especially for heme containing enzymes which necessarily need to be carried out under anaerobic/reducing conditions.

Investigating the Nature of the Onium Ylide and Michael Acceptor in a Rhodium(I)-Catalyzed Multicomponent Reaction.

We computationally study the mechanistic pathway for the synthetically valuable cascading N-H functionalization followed by the C-C bond-forming reaction. The impetus to study such multicomponent reactions catalyzed by Rh(I) arises from the highly fluxional nature of the onium ylide involved, which is often not amenable to experimental detection. Our results throw light on an interesting mechanistic paradigm where the binding of the ylide to the metal plays a crucial role. The study provides some much-needed insights to expand the scope of these highly valuable methodologies to a broader range of asymmetric reactions.

Does an Enol Pathway Preclude High Stereoselectivity in Iron-Catalyzed Indole C-H Functionalization via Carbene Insertion?

C-H functionalization of indoles via Fe carbenoids presents an attractive strategy to obtain biologically important structural motifs. However, obtaining good stereoselectivity with Fe has been a significant challenge. It is unclear whether the low selectivity is due to a radical pathway or an ionic mechanism involving metal-free species. We therefore present a density functional theory (DFT) study of indole alkylation with diazoacetates catalyzed by Fe(ClO4)TMEDA/spirobisoxazoline and myoglobin. We explore three mechanistic pathways: nucleophilic, radical, and oxocarbenium routes. The nucleophilic pathway is the most feasible with the formation of an enol species that tautomerizes to furnish the alkylated indole. While this mechanism is routinely proposed, the stereochemical model has been conspicuously absent until now. We show that the conventionally invoked enol pathway is not responsible for the low enantiomeric excess. The enol intermediate can stay coordinated to the catalyst via different binding sites placing the enol in proximity to the chiral environment and affecting the stereoselective proton transfer. Both the binding strength and the chiral environment are crucial for obtaining high selectivity. Our study provides the much needed insights for the modest-low selectivities of Fe systems and could help in expediting the discovery of an efficient catalytic system. These mechanistic underpinnings could also be applicable to other metal (Rh, Pd, Cu, etc.)-catalyzed X-H insertion reactions.

A computational approach to understand the role of metals and axial ligands in artificial heme enzyme catalyzed C-H insertion.

Engineered heme enzymes such as myoglobin and cytochrome P450s metalloproteins are gaining widespread importance due to their efficiency in catalyzing non-natural reactions. In a recent strategy, the naturally occurring Fe metal in the heme unit was replaced with non-native metals such as Ir, Rh, Co, Cu, etc., and axial ligands to generate artificial metalloenzymes. Determining the best metal-ligand for a chemical transformation is not a trivial task. Here we demonstrate how computational approaches can be used in deciding the best metal-ligand combination which would be highly beneficial in designing new enzymes as well as small molecule catalysts. We have used Density Functional Theory (DFT) to shed light on the enhanced reactivity of an Ir system with varying axial ligands. We look at the insertion of a carbene group generated from diazo precursors via N2 extrusion into a C-H bond. For both Ir(Me) and Fe systems, the first step, i.e., N2 extrusion is the rate determining step. Strikingly, neither the better ligand overlap with 5d orbitals on Ir nor the electrophilicity on the carbene centre play a significant role. A comparison of Fe and Ir systems reveals that a lower distortion in the Ir(Me)-porphyrin on moving from the reactant to the transition state renders it catalytically more active. We notice that for both metal porphyrins, the free energy barriers are affected by axial ligand substitution. Further, for Fe porphyrin, the axial ligand also changes the preferred spin state. We show that for the carbene insertion into the C-H bond, Fe porphyrin systems undergo a stepwise HAT (hydrogen atom transfer) instead of a concerted hydride transfer process. Importantly, we find that the substitution of the axial Me ligand on Ir to imidazole or chloride, or without an axial substitution changes the rate determining step of the reaction. Therefore, an optimum ligand that can balance the barriers for both steps of the catalytic cycle is essential. We subsequently used the QM cluster approach to delineate the protein environment's role and mutations in improving the catalytic activity of the Ir(Me) system.

Catalytic Enantioselective Desymmetrizing Fischer Indolization through Dynamic Kinetic Resolution.

The first catalytic enantioselective Fischer indolization of prochiral diketones containing enantiotopic carbonyl groups is developed and shown to proceed through dynamic kinetic resolution (DKR). Catalyzed by the combination of a spirocyclic chiral phosphoric acid and ZnCl2 (Lewis acid assisted Brønsted acid), this direct approach combines 2,2-disubstituted cyclopentane-1,3-diones with N-protected phenylhydrazines to furnish cyclopenta[b]indole derivatives containing an all-carbon quaternary stereocenter with good to excellent enantioselectivities.

Unveiling the importance of catalyst framework and non covalent interactions in an asymmetric Fe-catalyzed O-H insertion: insights from computational tools.

Fe-based catalysts as well as enzymes typically yield low stereoselectivity for carbene insertion into X-H bonds. Here, we have utilized DFT methods to understand the mechanism and unusually high enantioselectivity in an Fe-spiroBox catalyzed carbene insertion reaction into the O-H bond of aliphatic alcohols. Our transition state model shows a unique binding of the reaction intermediates to the chiral catalyst enabled by weak non covalent interactions that is absent in other X-H insertion reactions.

Copper-Catalyzed Aerobic Cross-Dehydrogenative Coupling of ß-Oxime Ether Furan with Indole.

Heterobiaryls serve as relevant structural motifs in many fields of high applicative importance such as drugs, agrochemicals, organic functional materials etc. Cross-dehydrogenative coupling involving direct oxidation of two C-H bonds to construct a C-C bond is actively being pursued as a more benign and 'greener' alternative for synthesizing heterobiaryls. Herein, we report a Cu(I)-catalyzed cross-dehydrogenative coupling of indoles and furans, two of the most important aromatic heterocycles using air as the terminal oxidant. The reaction proceeds with regio- and chemoselectivity to give the cross-coupled products in good to excellent yields generally. A broad substrate scope with respect to both the coupling partners has been demonstrated to prove the generality of this reaction. This represents the hitherto unexplored cross-dehydrogenative coupling methodology to obtain an indole-furan biaryl motif.