Metalloradical Catalysis Research Articles

Highly Diastereoselective Radical Cyclopropanation of Olefins via Cobaloxime‐Based Metalloradical Catalysis

Highly Diastereoselective Radical Cyclopropanation of Olefins via Cobaloxime‐Based Metalloradical Catalysis

Dynamic stereomutation of vinylcyclopropanes with metalloradicals

The ever increasing demands for greater sustainability and lower energy usage in chemical processes call for fundamentally new approaches and reactivity principles. In this context, the pronounced prevalence of odd-oxidation states in less precious metals bears untapped potential for fundamentally distinct reactivity modes via metalloradical catalysis1–3. Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release—a transformation that serves widely as a mechanistic probe (radical clock)4 for the intermediacy of radicals5—we herein show that a metal-based radical, that is, a Ni(I) metalloradical, triggers reversible cis/trans isomerization instead of opening. The isomerization proceeds under chiral inversion and, depending on the substitution pattern, occurs at room temperature in less than 5 min, requiring solely the addition of the non-precious catalyst. Our combined computational and experimental mechanistic studies support metalloradical catalysis as origin of this profound reactivity, rationalize the observed stereoinversion and reveal key reactivity features of the process, including its reversibility. These insights enabled the iterative thermodynamic enrichment of enantiopure cis/trans mixtures towards a single diastereomer through multiple Ni(I) catalysis rounds and also extensions to divinylcyclopropanes, which constitute strategic motifs in natural product- and total syntheses6. While the trans-isomer usually requires heating at approximately 200 °C to trigger thermal isomerization under racemization to cis-divinylcyclopropane, which then undergoes facile Cope-type rearrangement, the analogous contra-thermodynamic process is herein shown to proceed under Ni(I) metalloradical catalysis under mild conditions without any loss of stereochemical integrity, enabling a mild and stereochemically pure access to seven-membered rings, fused ring systems and spirocycles.

Metalloradical Catalysis: General Approach for Controlling Reactivity and Selectivity of Homolytic Radical Reactions

AbstractSince Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and utilization of chemical reactions rooted in two‐electron heterolytic ionic chemistry. While one‐electron homolytic radical chemistry is both rich in fundamental reactivities and attractive with practical advantages, the synthetic application of radical reactions has been long hampered by the formidable challenges associated with the control over reactivity and selectivity of high‐energy radical intermediates. To fully harness the untapped potential of radical chemistry for organic synthesis, there is a pressing need to formulate radically different concepts and broadly applicable strategies to address these outstanding issues. In pursuit of this objective, researchers have been actively developing metalloradical catalysis (MRC) as a comprehensive framework to guide the design of general approaches for controlling over reactivity and stereoselectivity of homolytic radical reactions. Essentially, MRC exploits the metal‐centered radicals present in open‐shell metal complexes as one‐electron catalysts for homolytic activation of substrates to generate metal‐entangled organic radicals as the key intermediates to govern the reaction pathway and stereochemical course of subsequent catalytic radical processes. Different from the conventional two‐electron catalysis by transition metal complexes, MRC operates through one‐electron chemistry utilizing stepwise radical mechanisms.

Enantio- and Diastereoselective Cyclopropanation of Alkenes by Iron(III)-Based Metalloradical Catalysis

Enantio- and Diastereoselective Cyclopropanation of Alkenes by Iron(III)-Based Metalloradical Catalysis

Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism.

Metalloradical catalysis (MRC) exploits the metal-centred radicals present in open-shell metal complexes as one-electron catalysts for the generation of metal-stabilized organic radicals-key intermediates that control subsequent one-electron homolytic reactions. Cobalt(II) complexes of porphyrins, as stable 15e-metalloradicals with a well-defined low-spin d7 configuration, have dominated the ongoing development of MRC. Here, to broaden MRC beyond the use of Co(II)-based metalloradical catalysts, we describe systematic studies that establish the operation of Fe(III)-based MRC and demonstrate an initial application for asymmetric radical transformations. Specifically, we report that five-coordinate iron(III) complexes of porphyrins with an axial ligand, which represent another family of stable 15e-metalloradicals with a d5 configuration, are potent metalloradical catalysts for olefin cyclopropanation with different classes of diazo compounds via a stepwise radical mechanism. This work lays a foundation and mechanistic blueprint for future exploration of Fe(III)-based MRC towards the discovery of diverse stereoselective radical reactions.

Catalytic Olefin Cyclopropanation with In Situ-Generated Dialkyl Diazomethanes via Co(II)-Based Metalloradical Catalysis

Catalytic Olefin Cyclopropanation with In Situ-Generated Dialkyl Diazomethanes via Co(II)-Based Metalloradical Catalysis

Asymmetric Radical Bicyclization for Stereoselective Construction of Tricyclic Chromanones and Chromanes with Fused Cyclopropanes.

Asymmetric radical bicyclization processes have been developed via metalloradical catalysis (MRC) to stereoselectively construct chiral chromanones and chromanes bearing fused cyclopropanes. Through optimization of a versatile D2-symmetric chiral amidoporphyrin ligand platform, a Co(II)-metalloradical system can homolytically activate both diazomalonates and α-aryldiazomethanes containing different alkene functionalities under mild conditions for effective radical bicyclization, delivering cyclopropane-fused tricyclic chromanones and chromanes, respectively, in high yields with excellent control of both diastereoselectivities and enantioselectivities. Combined computational and experimental studies, including the electron paramagnetic resonance (EPR) detection and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) trapping of key radical intermediates, shed light on the working details of the underlying stepwise radical mechanisms of the Co(II)-catalyzed bicyclization processes. The two catalytic radical processes provide effective synthetic tools for stereoselective construction of valuable cyclopropane-fused chromanones and chromanes with newly generated contiguous stereogenic centers. As a specific demonstration of synthetic application, the Co(II)-catalyzed radical bicyclization has been employed as a key step for the first asymmetric total synthesis of the natural product (+)-Radulanin J.

Understanding Off-Cycle and Deactivation Pathways in Radical-Type Carbene Transfer Catalysis.

Transition metal radical-type carbene transfer catalysis is a sustainable and atom-efficient method to generate C-C bonds, especially to produce fine chemicals and pharmaceuticals. A significant amount of research has therefore been devoted to applying this methodology, which resulted in innovative routes toward otherwise synthetically challenging products and a detailed mechanistic understanding of the catalytic systems. Furthermore, combined experimental and theoretical efforts elucidated the reactivity of carbene radical complexes and their off-cycle pathways. The latter can imply the formation of N-enolate and bridging carbenes, and undesired hydrogen atom transfer by the carbene radical species from the reaction medium which can lead to catalyst deactivation. In this concept paper, we demonstrate that understanding off-cycle and deactivation pathways not only affords solutions to circumvent them, but can also uncover novel reactivity for new applications. In particular, considering off-cycle species involved in metalloradical catalysis can stimulate further development of radical-type carbene transfer reactions.

Metalloradical approach for concurrent control in intermolecular radical allylic C-H amination.

Although they offer great potentials, the high reactivity and diverse pathways of radical chemistry pose difficult problems for applications in organic synthesis. In addition to the differentiation of multiple competing pathways, the control of various selectivities in radical reactions presents both formidable challenges and great opportunities. To regulate chemoselectivity and regioselectivity, as well as diastereoselectivity and enantioselectivity, calls for the formulation of conceptually new approaches and fundamentally different governing principles. Here we show that Co(II)-based metalloradical catalysis enables the radical chemoselective intermolecular amination of allylic C-H bonds through the employment of modularly designed D2-symmetric chiral amidoporphyrins with a tunable pocket-like environment as the supporting ligand. The reaction exhibits a remarkable convergence of regioselectivity, diastereoselectivity and enantioselectivity in a single catalytic operation. In addition to demonstrating the unique opportunities of metalloradical catalysis in controlling homolytic radical reactions, the Co(II)-catalysed convergent C-H amination offers a route to synthesize valuable chiral α-tertiary amines directly from an isomeric mixture of alkenes.

Asymmetric radical cyclopropanation of alkenes

Metalloradical catalysis (MRC), which utilizes metal-centered radicals to homolytically activate substrates for catalytic generation of metal-stabilized organic radicals as key intermediates, has emerged as a conceptually new approach for controlling both reactivity and stereoselectivity of radical reactions. As the first application of MRC, Co(II) complexes of chiral porphyrins, as stable 15e-metalloradicals, have been demonstrated as effective catalysts for asymmetric cyclopropanation of alkenes with diazo compounds via a stepwise radical mechanism.

Combined radical and ionic approach for the enantioselective synthesis of β-functionalized amines from alcohols.

Chiral amines are among the most important organic compounds and have widespread applications. Enantioselective construction of chiral amines is a major aim in organic synthesis. Among synthetic methods, direct functionalization of omnipresent C-H bonds with common organic nitrogen compounds represents one of the most attractive strategies. However, C-H amination strategies are largely limited to constructing a specific type of N-heterocycles or amine derivatives. To maximize the synthetic potential of asymmetric C-H amination, we report here an approach that unites the complementary reactivities of radical and ionic chemistry for streamlined synthesis of functionalized chiral amines. This synthesis merges the development of an enantioselective radical process for 1,5-C(sp 3)-H amination of alkoxysulfonyl azides via Co(II)-based metalloradical catalysis with an enantiospecific ionic process for ring-opening of the resulting five-membered chiral sulfamidates by nucleophiles. Given that alkoxysulfonyl azides are derived from the corresponding alcohols, this approach offers a powerful synthetic tool for enantioselective β-C-H amination of common alcohols while converting the hydroxy group to other functionalities through formal nucleophilic substitution.

Metalloradical Activation of In Situ-Generated α-Alkynyldiazomethanes for Asymmetric Radical Cyclopropanation of Alkenes.

α-Alkynyldiazomethanes, generated in situ from the corresponding sulfonyl hydrazones in the presence of a base, can serve as effective metalloradicophiles in Co(II)-based metalloradical catalysis (MRC) for asymmetric cyclopropanation of alkenes. With D2-symmetric chiral amidoporphyrin 2,6-DiMeO-QingPhyrin as the optimal supporting ligand, the Co(II)-based metalloradical system can efficiently activate different α-alkynyldiazomethanes at room temperature for highly asymmetric cyclopropanation of a broad range of alkenes. This catalytic radical process provides a general synthetic tool for stereoselective construction of alkynyl cyclopropanes in high yields with high both diastereoselectivity and enantioselectivity. Combined computational and experimental studies offer several lines of evidence in support of the underlying stepwise radical mechanism for the Co(II)-catalyzed olefin cyclopropanation involving a unique α-metalloradical intermediate that is associated with two resonance forms of α-Co(III)-propargyl radical and γ-Co(III)-allenyl radical. The resulting enantioenriched alkynyl cyclopropanes, as showcased with several stereospecific transformations, may serve as valuable chiral building blocks for stereoselective organic synthesis.

Radical differentiation of two ester groups in unsymmetrical diazomalonates for highly asymmetric olefin cyclopropanation

Diazomalonates have been demonstrated as effective metalloradicophiles for asymmetric radical olefin cyclopropanation via Co(II)-metalloradical catalysis (MRC). Supported by D 2-symmetric chiral amidoporphyrin ligand, Co(II)-based metalloradical system can efficiently activate unsymmetrical methyl phenyl diazomalonate (MPDM) with effective differentiation of the two ester groups for asymmetric cyclopropanation, enabling stereoselective construction of 1,1-cyclopropanediesters bearing two contiguous chiral centers, including all-carbon quaternary stereogenic center. The Co(II)-catalyzed asymmetric cyclopropanation, which operates at room temperature without slow addition of the diazo compound, is generally applicable to broad-ranging olefins and tolerates various functionalities, providing a streamlined synthesis of chiral 1,1-cyclopropanediesters in high yields with both high diastereoselectivity and enantioselectivity. Combined computational and experimental studies support the underlying stepwise radical mechanism for Co(II)-catalyzed cyclopropanation. In addition to functioning as 1,3-dipoles for forming five-membered structures, enantioenriched (E)-1,1-cyclopropanediesters serve as useful building blocks for stereoselective synthesis of different cyclopropane derivatives. In addition, the enantioenriched (E)-1,1-cyclopropanediesters can be stereoselectively converted to (Z)-diastereomers.

Regioselectivity in metalloradical catalyzed C[sbnd]H bond activation: A theoretical study

Pure quantum mechanical calculations were performed to find out the origin of regioselectivity under the metalloradical catalysis (MRC) by Co(II) -porphyrin, which showed regioselectivity is the inherent property of the aminyl radical generated from the sulfamoyl azide substrate. Different conformational analysis for the transition state from α- CoIII-aminyl radical to ζ-CoIII-alkyl radical formation have been studied to find out the most stable conformation for the preferable selectivity. The outcome of our study completely agrees with the reported experimental results.

New Catalytic Radical Process Involving 1,4-Hydrogen Atom Abstraction: Asymmetric Construction of Cyclobutanones.

While alkyl radicals have been well demonstrated to undergo both 1,5- and 1,6-hydrogen atom abstraction (HAA) reactions, 1,4-HAA is typically a challenging process both entropically and enthalpically. Consequently, chemical transformations based on 1,4-HAA have been scarcely developed. Guided by the general mechanistic principles of metalloradical catalysis (MRC), 1,4-HAA has been successfully incorporated as a key step, followed by 4-exo-tet radical substitution (RS), for the development of a new catalytic radical process that enables asymmetric 1,4-C-H alkylation of diazoketones for stereoselective construction of cyclobutanone structures. The key to success is the optimization of the Co(II)-based metalloradical catalyst through judicious modulation of D2-symmetric chiral amidoporphyrin ligand to adopt proper steric, electronic, and chiral environments that can utilize a network of noncovalent attractive interactions for effective activation of the substrate and subsequent radical intermediates. Supported by an optimal chiral ligand, the Co(II)-based metalloradical system, which operates under mild conditions, is capable of 1,4-C-H alkylation of α-aryldiazoketones with varied electronic and steric properties to construct chiral α,β-disubstituted cyclobutanones in good to high yields with high diastereoselectivities and enantioselectivities, generating dinitrogen as the only byproduct. Combined computational and experimental studies have shed light on the mechanistic details of the new catalytic radical process, including the revelation of facile 1,4-HAA and 4-exo-tet-RS steps. The resulting enantioenriched α,β-disubstituted cyclobutanones, as showcased with several enantiospecific transformations to other types of cyclic structures, may find useful applications in stereoselective organic synthesis.

Asymmetric Radical Process for General Synthesis of Chiral Heteroaryl Cyclopropanes.

A highly efficient catalytic method has been developed for asymmetric radical cyclopropanation of alkenes with in situ-generated α-heteroaryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the cavity-like environments of newly-synthesized D2-symmetric chiral amidoporphyrins as the supporting ligand, the optimized Co(II)-based metalloradical system is broadly applicable to α-pyridyl and other α-heteroaryldiazomethanes for asymmetric cyclopropanation of wide-ranging alkenes, including several types of challenging substrates. This new catalytic methodology provides a general access to valuable chiral heteroaryl cyclopropanes in high yields with excellent both diastereoselectivities and enantioselectivities. Combined computational and experimental studies further support the underlying stepwise radical mechanism of the Co(II)-based olefin cyclopropanation involving α- and γ-metalloalkyl radicals as the key intermediates.

Controlling Enantioselectivity and Diastereoselectivity in Radical Cascade Cyclization for Construction of Bicyclic Structures.

Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, β-, γ-, and ε-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.

Metalloradical catalysis: A radically different approach for molecular construction

Cindy is currently a graduate student in the Department of Chemistry at Boston College. Under the supervision of Professor Peter Zhang, Cindy's PhD research involves the development of new catalytic radical processes for stereoselective organic synthesis via metalloradical catalysis. Before her graduate study at Boston College, she received her BS degree in chemistry from National Taiwan Normal University and MS degree in organic chemistry from the University of San Francisco under the supervision of Professor Jie Jack Li. Her research interests are in the general area of organic synthesis with a focus on asymmetric catalysis.

Asymmetric radical cyclopropanation of dehydroaminocarboxylates: Stereoselective synthesis of cyclopropyl α-amino acids

A catalytic radical process has been developed for asymmetric cyclopropanation of dehydroaminocarboxylates with in situ-generated α-aryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the environments of D 2-symmetric chiral amidoporphyrin platform as the supporting ligands, the Co(II)-metalloradical system can effectively activate various α-aryldiazomethanes to cyclopropanate different dehydroaminocarboxylates under mild conditions, enabling the stereoselective synthesis of chiral cyclopropyl α-amino acid derivatives. In addition to high yields and excellent enantioselectivities, the Co(II)-catalyzed asymmetric radical cyclopropanation exhibits (Z)-diastereoselectivity, which is the opposite of uncatalyzed thermal reaction. Combined computational and experimental studies support a stepwise radical mechanism for the Co(II)-catalyzed cyclopropanation reaction. The resulting enantioenriched (Z)-α-amino-β-arylcyclopropanecarboxylates, as showcased for the efficient synthesis of dipeptides, may serve as unique non-proteinogenic amino acid building blocks for the design and preparation of novel peptides with restricted conformations.

Metalloradical activation of carbonyl azides for enantioselective radical aziridination

Organic azides have been increasingly employed as nitrogen sources for catalytic olefine aziridination due to their ease of preparation and generation of benign N2 as the only byproduct. Among common organic azides, carbonyl azides have not been previously demonstrated as effective nitrogen sources for intermolecular olefin aziridination despite the synthetic utilities of N-carbonyl aziridines. As a new application of metalloradical catalysis, we have developed a catalytic system that can effectively employ the carbonyl azide TrocN3 for highly asymmetric aziridination of alkenes at room temperature. The resulting enantioenriched N-Trocaziridines have been shown as valuable chiral synthons for stereoselective synthesis of other chiral aziridines and various chiral amines. The Co(II)-based metalloradical system, which proceeds with distinctive stepwise radical mechanism, may provide a general method for asymmetric synthesis of chiral aziridines from alkenes with organic azides.