The oxidative cycloaddition of benzamides and alkynes has been developed. The reaction utilizes Rh(III) catalysts in the presence of Cu(II) oxidants, and is proposed to proceed by N−H metalation of ...the amide followed by ortho C−H activation. The resultant rhodacycle undergoes alkyne insertion to form isoquinolones in good yield. The reaction is tolerant of extensive substitution on the amide, alkyne, and arene, including halides, silyl ethers, and unprotected aldehydes as substituents. Unsymmetrical alkynes proceed with excellent regioselectivity, and heteroaryl carboxamides are tolerated leading to intriguing scaffolds for medicinal chemistry. A series of competition experiments shed further light on the mechanism of the transformation and reasons for selectivity.
Expanding the repertoire of reactions available to enzymes is an enduring challenge in biocatalysis. Owing to the synthetic versatility of transition metals, metalloenzymes have been favored targets ...for achieving new catalytic functions. Although less well explored, enzymes lacking metal centers can also be effective catalysts for non-natural reactions, providing access to reaction modalities that compliment those available to metals. By understanding how these activation modes can reveal new functions, strategies can be developed to access novel biocatalytic reactions. This review will cover discoveries in the last two years which access catalytic reactions that go beyond the native repertoire of metal-free biocatalysts.
The past two decades have witnessed explosive growth in the field of catalytic C–H activation. While this reactivity is typically associated with second- and third-row transition metals, first-row ...transition metals are also capable of catalyzing these reactions. C–H activation reactions can be further divided into ones where the C–H activation occurs with a low-valent metal and those where the activation occurs with a high-valent metal. This review will summarize advances in the area of high-valent Co(III)- and Ni(II)-catalyzed C–H activation with particular emphasis paid to how these catalysts compare their second- and third-row congeners.
Graphical abstract
The synthesis of pyridines from readily available α,β-unsaturated oximes and alkynes under mild conditions and low temperatures using Rh(III) catalysis has been developed. It was found that the use ...of sterically different ligands allows for complementary selectivities to be achieved.
Artificial metalloenzymes have received increasing attention over the last decade as a possible solution to unaddressed challenges in synthetic organic chemistry. Whereas traditional transition‐metal ...catalysts typically only take advantage of the first coordination sphere to control reactivity and selectivity, artificial metalloenzymes can modulate both the first and second coordination spheres. This difference can manifest itself in reactivity profiles that can be truly unique to artificial metalloenzymes. This Review summarizes attempts to modulate the second coordination sphere of artificial metalloenzymes by using genetic modifications of the protein sequence. In doing so, successful attempts and creative solutions to address the challenges encountered are highlighted.
The second row also matters: In contrast to traditional transition‐metal catalysts, artificial metalloenzymes can modulate both the first and second coordination spheres, and thus result in novel reactivities. This Review discusses attempts to modulate the second coordination sphere of artificial metalloenzymes through genetic modifications of the protein sequence.
Enzymes provide an exquisitely tailored chiral environment to foster high catalytic activities and selectivities, but their native structures are optimized for very specific biochemical ...transformations. Designing a protein to accommodate a non-native transition metal complex can broaden the scope of enzymatic transformations while raising the activity and selectivity of small-molecule catalysis. Here, we report the creation of a bifunctional artificial metalloenzyme in which a glutamic acid or aspartic acid residue engineered into streptavidin acts in concert with a docked biotinylated rhodium(III) complex to enable catalytic asymmetric carbon-hydrogen (C-H) activation. The coupling of benzamides and alkenes to access dihydroisoquinolones proceeds with up to nearly a 100-fold rate acceleration compared with the activity of the isolated rhodium complex and enantiomeric ratios as high as 93:7.
The coupling of O-pivaloyl benzhydroxamic acids with donor/acceptor diazo compounds provides isoindolones in high yield. The reaction tolerates a broad range of benzhydroxamic acids and diazo ...compounds, including substituted 2,2,2-trifluorodiazoethanes. Mechanistic experiments suggested that C–H activation is turnover-limiting and irreversible and that insertion of the diazo compound favors electron-deficient substrates.
We have developed a method for preparing pyridones from the coupling reaction of acrylamides and alkynes with either stoichometric Cu(OAc)
or catalytic Cu(OAc)
and air as oxidants. In the course of ...these studies, it was found that a larger ligand, 1,3-di-tert-butylcyclopentadienyl (termed Cp
) results in higher degrees of regioselectivity in the alkyne insertion event. The transformation tolerates a broad variety of alkynes and acrylamides. Furthermore, Cp
and Cp* demonstrate similar catalytic activity. This similarity allows for mechanistic studies to be undertaken which suggest a difference in mechanism between this reaction and the previously studied benzamide system.
Flavin-dependent “ene”-reductases can generate stabilized alkyl radicals when irradiated with visible light; however, they are not known to form unstabilized radicals. Here, we report an ...enantioselective radical cyclization using alkyl iodides as precursors to unstabilized nucleophilic radicals. Evidence suggests this species is accessed by photoexcitation of a charge-transfer complex that forms between flavin and substrate within the protein active site. Stereoselective delivery of a hydrogen atom from the flavin semiquinone to the prochiral radical formed after cyclization provides high levels of enantioselectivity across a variety of substrates. Overall, this transformation demonstrates that photoenzymatic catalysis can address long-standing selectivity challenges in the radical literature.
Conspectus Enzymes are desired catalysts for chemical synthesis, because they can be engineered to provide unparalleled levels of efficiency and selectivity. Yet, despite the astonishing array of ...reactions catalyzed by natural enzymes, many reactivity patterns found in small molecule catalysts have no counterpart in the living world. With a detailed understanding of the mechanisms utilized by small molecule catalysts, we can identify existing enzymes with the potential to catalyze reactions that are currently unknown in nature. Over the past eight years, our group has demonstrated that flavin-dependent “ene”-reductases (EREDs) can catalyze various radical-mediated reactions with unparalleled levels of selectivity, solving long-standing challenges in asymmetric synthesis. This Account presents our development of EREDs as general catalysts for asymmetric radical reactions. While we have developed multiple mechanisms for generating radicals within protein active sites, this account will focus on examples where flavin mononucleotide hydroquinone (FMNhq) serves as an electron transfer radical initiator. While our initial mechanistic hypotheses were rooted in electron-transfer-based radical initiation mechanisms commonly used by synthetic organic chemists, we ultimately uncovered emergent mechanisms of radical initiation that are unique to the protein active site. We will begin by covering intramolecular reactions and discussing how the protein activates the substrate for reduction by altering the redox-potential of alkyl halides and templating the charge transfer complex between the substrate and flavin-cofactor. Protein engineering has been used to modify the fundamental photophysics of these reactions, highlighting the opportunity to tune these systems further by using directed evolution. This section highlights the range of coupling partners and radical termination mechanisms available to intramolecular reactions. The next section will focus on intermolecular reactions and the role of enzyme-templated ternary charge transfer complexes among the cofactor, alkyl halide, and coupling partner in gating electron transfer to ensure that it only occurs when both substrates are bound within the protein active site. We will highlight the synthetic applications available to this activation mode, including olefin hydroalkylation, carbohydroxylation, arene functionalization, and nitronate alkylation. This section also discusses how the protein can favor mechanistic steps that are elusive in solution for the asymmetric reductive coupling of alkyl halides and nitroalkanes. We are aware of several recent EREDs-catalyzed photoenzymatic transformations from other groups. We will discuss results from these papers in the context of understanding the nuances of radical initiation with various substrates. These biocatalytic asymmetric radical reactions often complement the state-of-the-art small-molecule-catalyzed reactions, making EREDs a valuable addition to a chemist’s synthetic toolbox. Moreover, the underlying principles studied with these systems are potentially operative with other cofactor-dependent proteins, opening the door to different types of enzyme-catalyzed radical reactions. We anticipate that this Account will serve as a guide and inspire broad interest in repurposing existing enzymes to access new transformations.
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