Cyclopropanations via Heme Carbenes: Basic Mechanism and Effects of Carbene Substituent, Protein Axial Ligand, and Porphyrin Substitution

Abstract

Catalytic carbene transfer to olefins is a useful approach to synthesize cyclopropanes, which are key structural motifs in many drugs and biologically active natural products. While catalytic methods for olefin cyclopropanation have largely relied on rare transition-metal-based catalysts, recent studies have demonstrated the promise and synthetic value of iron-based heme-containing proteins for promoting these reactions with excellent catalytic activity and selectivity. Despite this progress, the mechanism of iron-porphyrin and hemoprotein-catalyzed olefin cyclopropanation has remained largely unknown. Using a combination of quantum chemical calculations and experimental mechanistic analyses, the present study shows for the first time that the increasingly useful C═C functionalizations mediated by heme carbenes feature an Fe-based, nonradical, concerted nonsynchronous mechanism, with early transition state character. This mechanism differs from the Fe-based, radical, stepwise mechanism of heme-dependent monooxygenases. Furthermore, the effects of the carbene substituent, metal coordinating axial ligand, and porphyrin substituent on the reactivity of the heme carbenes was systematically investigated, providing a basis for explaining experimental reactivity results and defining strategies for future catalyst development. Our results especially suggest the potential value of electron-deficient porphyrin ligands for increasing the electrophilicity and thus the reactivity of the heme carbene. Metal-free reactions were also studied to reveal temperature and carbene substituent effects on catalytic vs noncatalytic reactions. This study sheds new light into the mechanism of iron-porphyrin and hemoprotein-catalyzed cyclopropanation reactions and it is expected to facilitate future efforts toward sustainable carbene transfer catalysis using these systems.

Mechanistic Investigation of Biocatalytic Heme Carbenoid Si−H Insertions

“…In addition, it is available for all transition metals, which may allow direct comparisons of effects of a vast amount of metal centers. The alternative use of an all‐electron basis for the metal center was recently found to yield qualitatively same conclusions of geometric, electronic, and energetic features for heme carbene reactions, and therefore supports the use of LanL2DZ basis here, which may help direct comparisons with late transition metals in future studies, for which ECP basis is more readily available and commonly used.…”

“…This Fe II feature is consistent with experimental reaction studies where the starting heme proteins were reduced to the catalytically competent ferrous form, and experimental spectroscopic studies using UV/Vis and NMR spectroscopies, X‐ray crystallography,− and XANES (directly sensitive to Fe oxidation state) which show that IPC has a dominant Fe II feature (i. e. closed‐shell singlet). The proposed concerted mechanism is reminiscent of that proposed for rhodium‐ and iridium‐carbenoid Si−H insertions and heme carbene cyclopropanations …”

“…Modification of the axial ligand coordinating the heme cofactor has provided an effective strategy for modulating the reactivity of hemoproteins as biocatalysts for carbene transfer reactions . More recently, we established that substitution of the conserved histidine axial ligand (His93) with an Asp residue is well tolerated in the myoglobin scaffold and results in a functional biocatalyst for olefin cyclopropanation .…”

Highly Diastereo‐ and Enantioselective Synthesis of Nitrile‐Substituted Cyclopropanes by Myoglobin‐Mediated Carbene Transfer Catalysis

“…The present strategy offers unprecedented degrees of stereocontrol compared to previously reported chemocatalytic strategies (Scheme 1), along with high TON, scalability, and a broad substrate scope that extends beyond that of Mb-catalyzed cyclopropanations with α-diazoesters. [9c, 9d] The latter feature may stem from a higher reactivity of the heme-carbene intermediate [20] generated from acetonitrile, an aspect that will be addressed in future studies. Describing the first example of a biocatalytic reaction involving diazoacetonitrile, this study paves the way to the application of this reagent in the context of other metalloprotein-catalyzed carbene transfer reactions.…”

Highly Diastereo‐ and Enantioselective Synthesis of Nitrile‐Substituted Cyclopropanes by Myoglobin‐Mediated Carbene Transfer Catalysis

“…[9c,d] Thel atter feature may stem from ah igher reactivity of the heme-carbene intermediate [20] generated from acetonitrile,a na spect that will be addressed in future studies.Describing the first example of abiocatalytic reaction involving diazoacetonitrile,t his study paves the way to the application of this reagent in the context of other metalloprotein-catalyzed carbene transfer reactions.This capability combined with the versatility of the cyano functional group,as exemplified by the transformations of Scheme 2, is expected to expand opportunities toward the exploitation of biocatalysis for asymmetric synthesis of pharmaceuticals and other high-value compounds. [9c,d] Thel atter feature may stem from ah igher reactivity of the heme-carbene intermediate [20] generated from acetonitrile,a na spect that will be addressed in future studies.Describing the first example of abiocatalytic reaction involving diazoacetonitrile,t his study paves the way to the application of this reagent in the context of other metalloprotein-catalyzed carbene transfer reactions.This capability combined with the versatility of the cyano functional group,as exemplified by the transformations of Scheme 2, is expected to expand opportunities toward the exploitation of biocatalysis for asymmetric synthesis of pharmaceuticals and other high-value compounds.…”