Small-molecule Catalysts Research Articles

A Sequential Umpolung/Enzymatic Dynamic Kinetic Resolution Strategy for the Synthesis of γ-Lactones.

Combining biological and small-molecule catalysts under a chemoenzymatic manifold presents a series of significant advantages to the synthetic community. We report herein the successful development of a two-step/single flask synthesis of γ-lactones through the merger of Umpolung catalysis with a ketoreductase-catalyzed dynamic kinetic resolution, reduction, and cyclization. This combined approach delivers highly enantio- and diastereoenriched heterocycles and demonstrates the feasibility of integrating NHC catalysis with enzymatic processes.

Autocatalytic chemical networks at the origin of metabolism.

Modern cells embody metabolic networks containing thousands of elements and form autocatalytic sets of molecules that produce copies of themselves. How the first self-sustaining metabolic networks arose at life's origin is a major open question. Autocatalytic sets smaller than metabolic networks were proposed as transitory intermediates at the origin of life, but evidence for their role in prebiotic evolution is lacking. Here, we identify reflexively autocatalytic food-generated networks (RAFs)—self-sustaining networks that collectively catalyse all their reactions—embedded within microbial metabolism. RAFs in the metabolism of ancient anaerobic autotrophs that live from H2 and CO2 provided with small-molecule catalysts generate acetyl-CoA as well as amino acids and bases, the monomeric components of protein and RNA, but amino acids and bases without organic catalysts do not generate metabolic RAFs. This suggests that RAFs identify attributes of biochemical origins conserved in metabolic networks. RAFs are consistent with an autotrophic origin of metabolism and furthermore indicate that autocatalytic chemical networks preceded proteins and RNA in evolution. RAFs uncover intermediate stages in the emergence of metabolic networks, narrowing the gaps between early Earth chemistry and life.

Polyketide Cyclizations for the Synthesis of Polyaromatics.

The folding and cyclization of poly-β-carbonyl chains controlled by the intricate enzymatic polyketide synthase machinery results in a remarkable diversity of aromatic natural products. Synthetic methods that allow for the preparation of highly reactive polyketide chains while governing their folding in ensuing cyclizations likewise lead to versatile divergent preparations of aromatic scaffolds valuable for numerous applications. Although biomimetic polyketide cyclizations have repeatedly been applied in the total synthesis of polyphenol natural products, their utility for the preparation of the broad range of polyaromatic architectures has yet to reach its full potential. This Minireview highlights some of the virtues of applying polyketide logic to the retrosynthetic analysis of polycyclic aromatic scaffolds, the increasing accessibility of precursors, and the potential of small-molecule catalysts for controlling polyketide cyclizations to provide polyaromatic scaffolds.

Mechanisms of peptide and phosphoester hydrolysis catalyzed by two promiscuous metalloenzymes (insulin degrading enzyme and glycerophosphodiesterase) and their synthetic analogues

AbstractThe hydrolysis of extremely stable peptide and phosphoester bonds by metalloenzymes is of great interest in biotechnology and industry. However, due to various shortcomings only a handful of these enzymes have been used for industrial applications. Therefore, in the last two decades intensive scientific efforts have been made in rational development of small molecules to imitate the activities of natural enzymes. Despite these efforts, their currently available synthetic analogues are inferior in terms of selectivity, catalytic rate, and turnover and the designing of efficient artificial metalloenzymes remains a distant goal. This is a challenging area of research that necessitates a rigorous integration between experiments and theory. The realization of this goal requires knowledge of the catalytic activities of both enzymes and their existing analogues and an effective fusion of that knowledge. This article reviews several studies in which a plethora of computational techniques have been successfully employed to investigate the functioning of two chemically promiscuous mono‐ and binuclear metalloenzymes (insulin degrading enzyme and glycerophosphodiesterase) and two synthetic analogues. These studies will help us derive fundamental principles of peptide and phosphoester hydrolysis and pave the way to design efficient small molecule catalysts for these reactions.This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis

Computational studies on nonenzymatic pyroglutamylation mechanism of N-terminal glutamic acid residues in aqueous conditions*

Spontaneous cyclisation of glutamic acid (Glu) residues located at N-termini in peptides and proteins is called ‘pyroglutamylation’ and is assumed to be involved in several neurodegenerative diseases. Although it has long been believed that N-terminal Glu residues undergo pyroglutamylation enzymatically, it has recently been experimentally confirmed that nonenzymatic pyroglutamylation can proceed in some types of aqueous buffer. However, the detailed mechanism has not been proposed or investigated, and even whether some small-molecule catalysts are required for pyroglutamylation has not been clarified. Therefore, we investigated three types of pyroglutamylation mechanism of N-terminal Glu residues using quantum chemical calculations: in the absence of any catalysts, catalysed by one water molecule, and catalysed by two water molecules. All calculations were performed using N-terminal Glu residues capped with a methylamino group on the C-terminal as a model compound. Optimised energy minima and transition state geometries were obtained using the B3LYP density functional method. The pyroglutamylation mechanism is roughly divided into two steps: cyclisation and dehydration, and the calculated activation barrier was 108 and 107 kJ mol−1 in the two- and three-water-assisted pathways, respectively. The results of computational analysis suggest that water molecules can act as catalysts for pyroglutamylation. The calculated activation barrier of two-water-assisted pyroglutamylation was 108 kJ mol−1, and the results of computational analysis indicate that water molecules can act as catalysts for pyroglutamylation.

Synthesis of Enantioenriched Tetra-ortho-3,3′-substituted Biaryls by Small-Molecule-Catalyzed Noncanonical Polyketide Cyclizations

The arene-forming aldol condensation is a fundamental reaction in the biosynthesis of aromatic polyketides. Precisely controlled by the polyketide synthases, the highly reactive poly-β-carbonyl substrates are diverged into numerous aromatic natural products by selective cyclization reactions; a fascinating biosynthetic strategy that sparked our interest to investigate atroposelective aldol condensations. In this Account, we contextualize and highlight the ability of small-molecule catalysts to selectively convert noncanonical hexacarbonyl substrates in a double arene-forming aldol condensation resulting in the atroposelective synthesis of tetra-ortho-3,3′-substituted biaryls. The hexacarbonyl substrates were obtained by a fourfold ozonolysis enabling a late-stage introduction of all carbonyl functions in one step. Secondary amine catalysts capable of forming an extended hydrogen-bonding network triggered the noncanonical polyketide cyclization in order to form valuable biaryls in high yields and with stereocontrol of up to 98:2 er.1 Biosynthesis of Aromatic Polyketides2 Rotationally Restricted Aromatic Polyketides3 3,3′-Substituted Binaphthalenes in Catalysis4 Stereoselective Synthesis of Atropisomers5 Synthesis of Enantioenriched Tetra-ortho-3,3′-Substituted Biaryls by the Atroposelective Arene-Forming Aldol Condensation6 Conclusion

An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp3)-H bonds.

The ability to selectively functionalize ubiquitous C-H bonds streamlines the construction of complex molecular architectures from easily available precursors. Here we report enzyme catalysts derived from a cytochrome P450 that use a nitrene transfer mechanism for the enantioselective amination of primary, secondary and tertiary C(sp3)-H bonds. These fully genetically encoded enzymes are produced and function in bacteria, where they can be optimized by directed evolution for a broad spectrum of enantioselective C(sp3)-H amination reactions. These catalysts can aminate a variety of benzylic, allylic and aliphatic C-H bonds in excellent enantioselectivity with access to either antipode of product. Enantioselective amination of primary C(sp3)-H bonds in substrates that bear geminal dimethyl substituents furnished chiral amines that feature a quaternary stereocentre. Moreover, these enzymes enabled the enantioconvergent transformation of racemic substrates that possess a tertiary C(sp3)-H bond to afford products that bear a tetrasubstituted stereocentre, a process that has eluded small-molecule catalysts. Further engineering allowed for the enantioselective construction of methyl-ethyl stereocentres, which is notoriously challenging in asymmetric catalysis.

Kinetic Study of CO2 Hydration by Small-Molecule Catalysts with A Second Coordination Sphere that Mimic the Effect of the Thr-199 Residue of Carbonic Anhydrase.

Zinc complexes were synthesized as catalysts that mimic the ability of carbonic anhydrase (CA) for the CO2 hydration reaction (H2O + CO2 → H+ + HCO3−). For these complexes, a tris(2-pyridylmethyl)amine (TPA) ligand mimicking only the active site, and a 6-((bis(pyridin-2-ylmethyl)amino)methyl)pyridin-2-ol (TPA-OH) ligand mimicking the hydrogen-bonding network of the secondary coordination sphere of CA were used. Potentiometric pH titration was used to determine the deprotonation ability of the Zn complexes, and their pKa values were found to be 8.0 and 6.8, respectively. Stopped-flow spectrophotometry was used to confirm the CO2 hydration rate. The rate constants were measured to be 648.4 and 730.6 M−1s−1, respectively. The low pKa value was attributed to the hydrogen-bonding network of the secondary coordination sphere of the catalyst that mimics the behavior of CA, and this was found to increase the CO2 hydration rate of the catalyst.

Site-Selective Functionalization of (sp3 )C-H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium-Porphyrin Cofactor.

The selective functionalization of one C-H bond over others in nearly identical steric and electronic environments can facilitate the construction of complex molecules. We report site-selective functionalizations of C-H bonds, differentiated solely by remote substituents, catalyzed by artificial metalloenzymes (ArMs) that are generated from the combination of an evolvable P450 scaffold and an iridium-porphyrin cofactor. The generated systems catalyze the insertion of carbenes into the C-H bonds of a range of phthalan derivatives containing substituents that render the two methylene positions in each phthalan inequivalent. These reactions occur with site-selectivity ratios of up to 17.8:1 and, in most cases, with pairs of enzyme mutants that preferentially form each of the two constitutional isomers. This study demonstrates the potential of abiotic reactions catalyzed by metalloenzymes to functionalize C-H bonds with site selectivity that is difficult to achieve with small-molecule catalysts.

Enantiodivergent α-Amino C-H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s.

The introduction of fluoroalkyl groups into organic compounds can significantly alter pharmacological characteristics. One enabling but underexplored approach for the installation of fluoroalkyl groups is selective C( sp3)-H functionalization due to the ubiquity of C-H bonds in organic molecules. We have engineered heme enzymes that can insert fluoroalkyl carbene intermediates into α-amino C( sp3)-H bonds and enable enantiodivergent synthesis of fluoroalkyl-containing molecules. Using directed evolution, we engineered cytochrome P450 enzymes to catalyze this abiological reaction under mild conditions with total turnovers (TTN) up to 4070 and enantiomeric excess (ee) up to 99%. The iron-heme catalyst is fully genetically encoded and configurable by directed evolution so that just a few mutations to the enzyme completely inverted product enantioselectivity. These catalysts provide a powerful method for synthesis of chiral organofluorine molecules that is currently not possible with small-molecule catalysts.

Polymeric "Clickase" Accelerates the Copper Click Reaction of Small Molecules, Proteins, and Cells.

Recent work has shown that polymeric catalysts can mimic some of the remarkable features of metalloenzymes by binding substrates in proximity to a bound metal center. We report here an unexpected role for the polymer: multivalent, reversible, and adaptive binding to protein surfaces allowing for accelerated catalytic modification of proteins. The catalysts studied are a group of copper-containing single-chain polymeric nanoparticles (CuI-SCNP) that exhibit enzyme-like catalysis of the copper-mediated azide-alkyne cycloaddition reaction. The CuI-SCNP use a previously observed "uptake mode", binding small-molecule alkynes and azides inside a water-soluble amphiphilic polymer and proximal to copper catalytic sites, but with unprecedented rates. Remarkably, a combined experimental and computational study shows that the same CuI-SCNP perform a more efficient click reaction on modified protein surfaces and cell surface glycans than do small-molecule catalysts. The catalysis occurs through an "attach mode" where the SCNPs reversibly bind protein surfaces through multiple hydrophobic and electrostatic contacts. The results more broadly point to a wider capability for polymeric catalysts as artificial metalloenzymes, especially as it relates to bioapplications.

Radical Biocatalysis: Using Non-Natural Single Electron Transfer Mechanisms to Access New Enzymatic Functions

Exploiting non-natural reaction mechanisms within native enzymes is an emerging strategy for expanding the synthetic capabilities of biocatalysts. When coupled with modern protein engineering techniques, this approach holds great promise for biocatalysis to address long-standing selectivity and reactivity challenges in chemical synthesis. Controlling the stereochemical outcome of reactions involving radical intermediates, for instance, could benefit from biocatalytic solutions because these reactions are often difficult to control by using existing small molecule catalysts. General strategies for catalyzing non-natural radical reactions within enzyme active sites are, however, undeveloped. In this account, we highlight three distinct strategies developed in our group that exploit non-natural single electron transfer mechanisms to unveil previously unknown radical biocatalytic functions. These strategies allow common oxidoreductases to be used to address the enduring synthetic challenge of asymmetric hydrogen atom transfer.1 Introduction2 Photoinduced Electron Transfer from NADPH3 Ground State Electron Transfer from Flavin Hydroquinone4 Enzymatic Redox Activation in NADPH-Dependent Oxidoreductases5 Conclusion

Biocatalytic Strategies towards [4+2] Cycloadditions.

Long sought after [4+2] cyclases have sprouted up in numerous biosynthetic pathways in recent years, raising hopes for biocatalytic solutions to cycloaddition catalysis, an important problem in chemical synthesis. In a few cases, detailed pictures of the inner workings of these catalysts have emerged, but intense efforts to gain deeper understanding are underway by means of crystallography and computational modelling. This Minireview aims to shed light on the catalytic strategies that this highly diverse family of enzymes employs to accelerate and direct the course of [4+2] cycloadditions with reference to small-molecule catalysts and designer enzymes. These catalytic strategies include oxidative or reductive triggers and lid-like movements of enzyme domains. A precise understanding of natural cycloaddition catalysts will be instrumental for customizing them for various synthetic applications.

Broadening the scope of Pd-catalyzed oscillatory carbonylation reactions: solvent, substrate, catalyst

On our way to producing all-polymeric self-oscillatory materials, we have expanded the horizons of oscillatory carbonylation reactions by searching for alternative substrates, solvents and even catalysts. In this paper, we demonstrate that pH oscillations in carbonylation reactions have the potential to occur in a broad range of aliphatic alcohol solutions when using either a small molecule substrate (phenylacetylene) or a polymeric substrate (pegylated alkyne) with either a small molecule catalyst (Pd-diacetate) or a non-leaching polymeric catalyst (Pd-polyacrylate). The alcohols studied are methanol, ethanol, 1-propanol, 1-butanol and 1-hexanol. In this carbonylation reaction an alcohol serves as both the solvent and as a reactant. The resulting oscillations suggest that carbonylation reactions have strong potential for the discovery and development of new oscillatory chemical systems. Replacing methanol, commonly used in oscillatory carbonylation processes, with ethanol is an important step in enhancing the biocompatibility of these systems. Furthermore, showing that oscillations in pH are feasible in ethanol solutions when polymeric substrate and polymeric catalyst are used supports the vision of employing oscillatory chemical reactions to build oscillatory materials.

Noble−Metal Substitution in Hemoproteins: An Emerging Strategy for Abiological Catalysis

Enzymes have evolved to catalyze a range of biochemical transformations with high efficiencies and unparalleled selectivities, including stereoselectivities, regioselectivities, chemoselectivities, and substrate selectivities, while typically operating under mild aqueous conditions. These properties have motivated extensive research to identify or create enzymes with reactivity that complements or even surpasses the reactivity of small-molecule catalysts for chemical reactions. One of the limitations preventing the wider use of enzymes in chemical synthesis, however, is the narrow range of bond constructions catalyzed by native enzymes. One strategy to overcome this limitation is to create artificial metalloenzymes (ArMs) that combine the molecular recognition of nature with the reactivity discovered by chemists. This Account describes a new approach for generating ArMs by the formal replacement of the natural iron found in the porphyrin IX (PIX) of hemoproteins with noble metals. Analytical techniques coupled with studies of chemical reactivity have demonstrated that expression of apomyoglobins and apocytochrome P450s (for which "apo-" denotes the cofactor-free protein) followed by reconstitution with metal-PIX cofactors in vitro creates proteins with little perturbation of the native structure, suggesting that the cofactors likely reside within the native active site. By means of this metal substitution strategy, a large number of ArMs have been constructed that contain varying metalloporphyrins and mutations of the protein. The studies discussed in this Account encompass the use of ArMs containing noble metals to catalyze a range of abiological transformations with high chemoselectivity, enantioselectivity, diastereoselectivity, and regioselectivity. These transformations include intramolecular and intermolecular insertion of carbenes into C-H, N-H, and S-H bonds, cyclopropanation of vinylarenes and of internal and nonconjugated alkenes, and intramolecular insertions of nitrenes into C-H bonds. The rates of intramolecular insertions into C-H bonds catalyzed by thermophilic P450 enzymes reconstituted with an Ir(Me)-PIX cofactor are now comparable to the rates of reactions catalyzed by native enzymes and, to date, 1000 times greater than those of any previously reported ArM. This reactivity also encompasses the selective intermolecular insertion of the carbene from ethyl diazoacetate into C-H bonds over dimerization of the carbene to form alkenes, a class of carbene insertion or selectivity not reported to occur with small-molecule catalysts. These combined results highlight the potential of well-designed ArMs to catalyze abiological transformations that have been challenging to achieve with any type of catalyst. The metal substitution strategy described herein should complement the reactivity of native enzymes and expand the scope of enzyme-catalyzed reactions.

The importance of synthetic chemistry in the pharmaceutical industry.

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.

Synthetic innovation in drug development

Organic Chemistry Chemical synthesis plays a key role in pharmaceutical research and development. Campos et al. review some of the advantages that have come from recent innovations in synthetic methods. In particular, they highlight small-molecule catalysts stimulated by visible light, enzymes engineered for versatility beyond their intrinsic function, and bio-orthogonal reactions to selectively modify proteins for conjugation. High-throughput techniques are also poised to accelerate methods optimization from small-scale discovery to large-scale production, and complementary machine-learning approaches are just coming into focus. Science , this issue p. [eaat0805][1] [1]: /lookup/doi/10.1126/science.aat0805

Chemoselective methylene oxidation in aromatic molecules.

Despite significant progress in the development of site-selective aliphatic C–H oxidations over the past decade, the ability to oxidize strong methylene C–H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Herein we report a simple manganese small molecule catalyst Mn(CF3–PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic, and biaryl moieties. Late stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C–H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.

Peptide-Based Catalysts Reach the Outer Sphere through Remote Desymmetrization and Atroposelectivity.

ConspectusNature’s catalytic machinery has provided endless inspiration for chemists. While the enzymatic ideal has yet to be fully realized, the field has made tremendous strides toward synthetic, small-molecule catalysts for a wide array of transformations, often drawing upon biological concepts in their design. One strategy that has been particularly influenced by enzymology is peptide catalysis, wherein oligopeptides are implemented as chiral catalysts in synthetically relevant reactions. The fundamental goal has been to mimic enzymatic active sites by taking advantage of secondary structures that allow for multifunctional activation of substrates within a framework of significantly reduced molecular complexity.Our group has now been studying peptide-based catalysis for over two decades. At the outset, there were many reasons to be concerned that general contributions might not be possible. Precedents existed, including the Juliá–Colonna epoxidations mediated by helical oligopeptides, among others. However, we sought to explore whether peptide catalysts could find broad applications in organic synthesis despite what was expected to be their principal liability: conformational flexibility. Over time, we have been able to identify peptidic catalysts for a variety of site- and enantioselective transformations ranging from hydroxyl group and arene functionalizations to redox and C–C bond forming reactions. The peptides often exhibited excellent catalytic activities, in many cases enabling never-before-seen patterns of selectivity. Recent studies even suggest that, in certain situations, the conformational flexibility of these catalysts may be advantageous for asymmetric induction.In the course of our studies, opportunities to employ peptide-based catalysis to solve long-standing and stereochemically intriguing problems in asymmetric synthesis presented themselves. For example, we have found that peptides provide exceptional enantiotopic group differentiation in catalytic desymmetrization reactions. Early results with symmetrical polyol substrates, such as myo-inositols and glycerols, eventually spurred the development of remote desymmetrizations of diarylmethanes, in which the enantiotopic groups are separated from the prochiral center by ∼6 Å and from one another by nearly 1 nm. Various hydroxyl group functionalizations and electrophilic brominations, as well as C–C, C–O, and C–N cross-coupling reactions using peptidic ligands on copper(I) have now been developed within this reaction archetype. Additionally, the preponderance of axially chiral, atropisomeric compounds as ligands, organocatalysts, and pharmacophores encouraged us to employ peptides as atroposelective catalysts. We have developed peptide-catalyzed brominations of pharmaceutically relevant biaryl, non-biaryl, and hetero-biaryl atropisomers that take advantage of dynamic kinetic resolution schemes. These projects have vastly expanded the reach of our original hypotheses and raised new questions about peptide-based catalysts and the extent to which they might mimic enzymes.Herein, we recount the development and optimization of these stereochemically complex reactions, with a particular focus on structural and mechanistic aspects of the peptide-based catalysts that make them well-suited for their respective functions. The ability of these peptides to address important yet fundamentally challenging issues in asymmetric catalysis, combined with their modularity and ease-of-synthesis, make them primed for future use in organic synthesis.

Macromolecular Engineering of the Outer Coordination Sphere of [2Fe-2S] Metallopolymers to Enhance Catalytic Activity for H2 Production.

Small-molecule catalysts inspired by the active sites of [FeFe]-hydrogenase enzymes have long struggled to achieve fast rates of hydrogen evolution, long-term stability, water solubility, and oxygen compatibility. We profoundly improved on these deficiencies by grafting polymers from a metalloinitiator containing a [2Fe-2S] moiety to form water-soluble poly(2-dimethylamino)ethyl methacrylate metallopolymers (PDMAEMA-g-[2Fe-2S]) using atom transfer radical polymerization (ATRP). This study illustrates the critical role of the polymer composition in enhancing hydrogen evolution and aerobic stability by comparing the catalytic activity of PDMAEMA-g-[2Fe-2S] with a nonionic water-soluble metallopolymer based on poly(oligo(ethylene glycol) methacrylate) prepared via ATRP (POEGMA-g-[2Fe-2S]) with the same [2Fe-2S] metalloinitiator. Additionally, the tunability of catalyst activity is demonstrated by the synthesis of metallocopolymers incorporating the 2-(dimethylamino)ethyl methacrylate (DMAEMA) and oligo(ethylene glycol) methacrylate (OEGMA) monomers. Electrochemical investigations into these metallo(co)polymers show that PDMAEMA-g-[2Fe-2S] retains complete aerobic stability with catalytic current densities in excess of 20 mA·cm-2, while POEGMA-g-[2Fe-2S] fails to reach 1 mA·cm-2 current density even with the application of high overpotentials (η > 0.8 V) and loses all activity in the presence of oxygen. Random copolymers of the two monomers polymerized with the same [2Fe-2S] initiator showed intermediate activity in terms of current density, overpotential, and aerobic stability.