Photoinduced Cu(II)-Mediated Decarboxylative Thianthrenation of Aryl and Heteroaryl Carboxylic Acids.

Given that (hetero)aryl carboxylic acids are inexpensive materials available in a great variety from commercial and natural resources or synthesis, the strategies enabling their use as starting materials for preparing fine chemicals are highly sought after. Here we report a photoinduced Cu(II)-mediated protocol converting (hetero)aryl carboxylic acids into (hetero)aryl thianthrenium salts, high value-added building blocks that can undergo various subsequent transformations, creating an attractive two-step pathway for the divergent functionalization of these ubiquitous starting materials. The excellent compatibility of the method is shown by preparing a broad range of sterically and electronically varied (hetero)aryl thianthrenium salts, including derivatives of pharmaceuticals, such as ataluren, celecoxib, flavoxate, probenecid, repaglinide, and tamibarotene. The syntheses of 13C-labeled probenecid and bioisosteres of ataluren as well as the unconventional modifications of celecoxib and flavoxate, illustrate the synthetic potential of the strategy. Mechanistic studies are in line with a reaction occurring through a photoinduced ligand-to-metal charge transfer (LMCT) of Cu(II)-arylcarboxylates, enabling radical decarboxylative carbometallation to form arylcopper(II) intermediates that in turn react with thianthrene to form the product. Noteworthy, the susceptibility of aryl thianthrenium salts to photodegradation is overcome by a Cu(I)-driven salvage loop, which continuously intercepts the transiently formed radicals and regenerates the products.

Multi-Stimuli-Responsive Network of Multicatalytic Reactions using a Single Palladium/Platinum Catalyst.

Given her unrivalled proficiency in the synthesis of all molecules of life, nature has been an endless source of inspiration for developing new strategies in organic chemistry and catalysis. However, one feature that remains beyond chemists' grasp is her unique ability to adapt the productivity of metabolic processes in response to triggers that indicate the temporary need for specific metabolites. To demonstrate the remarkable potential of such stimuli-responsive systems, we present a metabolism-inspired network of multicatalytic processes capable of selectively synthesising a range of products from simple starting materials. Specifically, the network is built of four classes of distinct catalytic reactions - cross-couplings, substitutions, additions, and reductions, involving three organic starting materials - terminal alkyne, aryl iodide, and hydrosilane. All starting materials are either introduced sequentially or added to the system at the same time, with no continuous influx of reagents or efflux of products. All processes in the system are catalysed by a multifunctional heteronuclear PdII/PtII complex, whose performance can be controlled by specific additives and external stimuli. The reaction network exhibits a substantial degree of orthogonality between different pathways, enabling the controllable synthesis of ten distinct products with high efficiency and selectivity through simultaneous triggering and suppression mechanisms.

A Merger of Relay Catalysis with Dynamic Kinetic Resolution Enables Enantioselective ß-C(sp3)-H Arylation of Alcohols.

The conceptual merger of relay catalysis with dynamic kinetic resolution strategy is reported to enable regio- and enantioselective C(sp3)-H bond arylation of aliphatic alcohols, forming enantioenriched ß-aryl alcohols typically with >90 : 10 enantiomeric ratios (up to 98 : 2 er) and 36-74 % yields. The starting materials bearing neighbouring stereogenic centres can be converted to either diastereomer of the ß-aryl alcohol products, with >85 : 15 diastereomeric ratios determined by the catalysts. The reactions occur under mild conditions, ensuring broad compatibility, and involve readily available aryl bromides, an inorganic base, and commercial Ru- and Pd-complexes. Mechanistic experiments support the envisioned mechanism of the transformation occurring through a network of regio- and stereoselective processes operated by a coherent Ru/Pd-dual catalytic system.

Variable structure diversification by multicatalysis: the case of alcohols.

Given that alcohol moieties are present in a great diversity of valuable fine chemicals from nature and synthesis, methods enabling their structure diversification are highly sought after. Catalysis proved to enable the development of new transformations that are beyond the inherent reactivity of alcohols. However, modifying the structure of alcohols at certain unbiased positions remains a major challenge or requires tedious multistep procedures. Recently, increased attention has been given to multicatalyis, which combines multiple reactions and catalysts within one system, creating room for discovering previously inaccessible reactivities or increasing the overall efficiency of multistep transformations. This feature article focuses on demonstrating various aspects of devising such multicatalytic systems that modify the structure of alcohol-containing compounds. Special attention is given to highlighting the challenges and advantages of multicatalysis, and in a broader context discussing how the field of catalysis may progress toward more complex systems.

Isoselective Hydroformylation of Propylene by Iodide-Assisted Palladium Catalysis.

Isobutanal is a high value bulk material that, in principle, could be produced with 100 % atom-economy by isoselective hydroformylation of propylene with syngas. However, leading industrial Rh- and Co-catalyzed hydroformylation methods preferentially form n-butanal over the iso-product, and methods offering isoselectivity remain underdeveloped. Here we report an iodide-assisted Pd-catalyzed hydroformylation of propylene that produces isobutanal with unprecedented levels of selectivity. The method involves PdI2 , simple alkyl monophosphines, such as tricyclohexylphosphine, and common green solvents, enabling the title reaction to occur with isoselectivity in up to 50 : 1 iso/n product ratios under industrially relevant conditions (80-120 °C). The catalytic and preliminary mechanistic experiments indicate a key role of the iodide anions in both the catalytic activity and the isoselectivity.

Teaching natural enzymes new radical tricks.

Cytochromes P450 were engineered to conduct abiotic, stereoselective radical reactions.

Enantioselective α-Arylation of Primary Alcohols under Sequential One-Pot Catalysis.

Secondary benzylic alcohols and diarylmethanols are common structural motifs of biologically active and medicinally relevant compounds. Here we report their enantioselective synthesis by α-arylation of primary aliphatic and benzylic alcohols under sequential catalysis integrating a Ru-catalyzed hydrogen transfer oxidation and a Ru-catalyzed nucleophilic addition. The method can be applied to various alcohols and aryl nucleophiles tolerating a range of functional groups, including secondary alcohols, ketones, alkenes, esters, NH amides, tertiary amines, aryl halides, and heterocycles.

Multicatalytic Approach to One-Pot Stereoselective Synthesis of Secondary Benzylic Alcohols.

One-pot procedures bear the potential to rapidly build up molecular complexity without isolation and purification of consecutive intermediates. Here, we report multicatalytic protocols that convert alkenes, unsaturated aliphatic alcohols, and aryl boronic acids into secondary benzylic alcohols with high stereoselectivities (typically >95:5 er) under sequential catalysis that integrates alkene cross-metathesis, isomerization, and nucleophilic addition. Prochiral allylic alcohols can be converted to any stereoisomer of the product with high stereoselectivity (>98:2 er, >20:1 dr).

Binuclear Pd(I)-Pd(I) Catalysis Assisted by Iodide Ligands for Selective Hydroformylation of Alkenes and Alkynes.

Since its discovery in 1938, hydroformylation has been thoroughly investigated and broadly applied in industry (>107 metric ton yearly). However, the ability to precisely control its regioselectivity with well-established Rh- or Co-catalysts has thus far proven elusive, thereby limiting access to many synthetically valuable aldehydes. Pd-catalysts represent an appealing alternative, yet their use remains sparse due to undesired side-processes. Here, we report a highly selective and exceptionally active catalyst system that is driven by a novel activation strategy and features a unique Pd(I)-Pd(I) mechanism, involving an iodide-assisted binuclear step to release the product. This method enables ß-selective hydroformylation of a large range of alkenes and alkynes, including sensitive starting materials. Its utility is demonstrated in the synthesis of antiobesity drug Rimonabant and anti-HIV agent PNU-32945. In a broader context, the new mechanistic understanding enables the development of other carbonylation reactions of high importance to chemical industry.

Effector responsive hydroformylation catalysis.

Herein, we report a supramolecular rhodium complex that can form dimeric or monomeric Rh-species catalytically active in hydroformylation, depending on the binding of effectors within the integrated DIM-receptor. X-ray crystal structures, in situ (high-pressure (HP)) spectroscopy studies, and molecular modelling studies show that in the absence of effectors, the preferred Rh-species formed is the dimer, of which two ligands coordinate to two rhodium metals. Importantly, upon binding guest molecules, -effectors-, to the DIM-receptor under hydroformylation conditions, the monomeric Rh-active species is formed, as evidenced by a combination of in situ HP NMR and IR spectroscopy studies and molecular modelling. As the monomeric complex has different catalytic properties from the dimeric complex, we effectively generate a catalytic system of which the properties respond to the presence of effectors, reminiscent of how the properties of proteins are regulated in nature. Indeed, catalytic and kinetic experiments show that both the selectivity and activity of this supramolecular catalytic system can be influenced in the hydroformylation of 1-octene using acetate as an effector that shift the equilibrium from the dimeric to monomeric species.

The Influence of Binding Site Geometry on Anion-Binding Selectivity: A Case Study of Macrocyclic Receptors Built on the Azulene Skeleton.

An understanding of host-guest noncovalent interactions lies at the very heart of supramolecular chemistry. Often a minute change to the structure of a host molecule's binding site can have a dramatic impact on a prospective host-guest binding event, changing the relative selectivity for potential guest molecules. With the overall goal of aiding the rational design of selective and effective receptors for anions, we have studied the influence of small perturbations in binding site geometry for a series of five closely related 20-membered macrocyclic tetra-amide receptors, constructed from two building blocks from a pool of azulene-5,7-bisamide, azulene-1,3-bisamide, and dipicolinic bisamide units. The solid-state structures revealed that the conformational preferences of the free receptors are driven by the inherent preferences of the building blocks, yet in some cases the macrocyclic topology is able to over-ride these to promote pre-organized conformations favorable for anion binding. The solid-state structures of the chloride complexes of these receptors revealed that although all the receptors can adapt to binding to the challenging small Cl- guest with all the NH groups, only receptors containing azulene-5,7-bisamide units form short and linear, and therefore strong, hydrogen-bonding interactions. These conclusions are further supported by studies in solution. Although all the receptors showed high affinities toward a series of anions (H2 PO4- , PhCO2- , Cl- , and Br- ), even in a highly competitive polar medium (DMSO/25 % MeOH), only receptors containing azulene-5,7-bisamide units exhibited non-inherent selectivity for Cl- over PhCO2- , breaking the Hofmeister trend of selectivity. The data presented herein highlight the privileged properties of the azulene-5,7-bisamide building block for binding to chloride anions and provide guidelines for the construction of selective and efficient anion receptors with prospective practical applications.

Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes.

Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. We postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, >70:1 dr, >75% yield, and ∼10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Together, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.

Chemoselective, Enzymatic C-H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor.

Cytochrome P450 enzymes have been engineered to catalyze abiological C-H bond amination reactions, but the yields of these reactions have been limited by low chemoselectivity for the amination of C-H bonds over competing reduction of the azide substrate to a sulfonamide. Here we report that P450s derived from a thermophilic organism and containing an iridium porphyrin cofactor (Ir(Me)-PIX) in place of the heme catalyze enantioselective intramolecular C-H bond amination reactions of sulfonyl azides. These reactions occur with chemoselectivity for insertion of the nitrene units into C-H bonds over reduction of the azides to the sulfonamides that is higher and with substrate scope that is broader than those of enzymes containing iron porphyrins. The products from C-H amination are formed in up to 98% yield and ∼300 TON. In one case, the enantiomeric excess reaches 95:5 er, and the reactions can occur with divergent site selectivity. The chemoselectivity for C-H bond amination is greater than 20:1 in all cases. Variants of the Ir(Me)-PIX CYP119 displaying these properties were identified rapidly by evaluating CYP119 mutants containing Ir(Me)-PIX in cell lysates, rather than as purified enzymes. This study sets the stage to discover suitable enzymes to catalyze challenging C-H amination reactions.

Azulene-Based Macrocyclic Receptors for Recognition and Sensing of Phosphate Anions.

Herein we report the synthesis and detailed studies of the anion-binding properties of two 20-membered macrocyclic tetramide receptors: one symmetrical, containing two identical azulene-based bisamide units, the other a hybrid, containing a dipicolinic bisamide unit and an azulene-based bisamide unit. Analysis of the crystal structures of the macrocyclic receptors revealed their preference for adopting similar well-preorganized bent-sheet conformations, both as free receptors and in their complexes with anions. Studies of the optical properties of both receptors revealed abilities to selectively sense phosphate anions (H2 PO4- , HP2 O73- ), allowing for naked-eye detection of the presence of these guests in DMSO. Binding studies in solution confirmed that the receptors bind strongly to a series of anions even in highly demanding media, such as mixtures of DMSO with water or with methanol. Comparison of the anion affinity of linear analogues with that of the macrocyclic receptors evidenced the importance of macrocyclic topology. Quantitative analysis revealed that the macrocyclic receptors are selective for H2 PO4- over other anions. The affinity to H2 PO4- seen for the symmetrical receptor, containing two azulene-based subunits, is much higher than for the hybrid macrocycle containing both the azulene-based and pyridine-derived subunits. This highlights that the azulene-based building block serves efficiently as both a binding site and a structure-preorganizing motif.

Abiological catalysis by artificial haem proteins containing noble metals in place of iron.

Enzymes that contain metal ions--that is, metalloenzymes--possess the reactivity of a transition metal centre and the potential of molecular evolution to modulate the reactivity and substrate-selectivity of the system. By exploiting substrate promiscuity and protein engineering, the scope of reactions catalysed by native metalloenzymes has been expanded recently to include abiological transformations. However, this strategy is limited by the inherent reactivity of metal centres in native metalloenzymes. To overcome this limitation, artificial metalloproteins have been created by incorporating complete, noble-metal complexes within proteins lacking native metal sites. The interactions of the substrate with the protein in these systems are, however, distinct from those with the native protein because the metal complex occupies the substrate binding site. At the intersection of these approaches lies a third strategy, in which the native metal of a metalloenzyme is replaced with an abiological metal with reactivity different from that of the metal in a native protein. This strategy could create artificial enzymes for abiological catalysis within the natural substrate binding site of an enzyme that can be subjected to directed evolution. Here we report the formal replacement of iron in Fe-porphyrin IX (Fe-PIX) proteins with abiological, noble metals to create enzymes that catalyse reactions not catalysed by native Fe-enzymes or other metalloenzymes. In particular, we prepared modified myoglobins containing an Ir(Me) site that catalyse the functionalization of C-H bonds to form C-C bonds by carbene insertion and add carbenes to both ß-substituted vinylarenes and unactivated aliphatic α-olefins. We conducted directed evolution of the Ir(Me)-myoglobin and generated mutants that form either enantiomer of the products of C-H insertion and catalyse the enantio- and diastereoselective cyclopropanation of unactivated olefins. The presented method of preparing artificial haem proteins containing abiological metal porphyrins sets the stage for the generation of artificial enzymes from innumerable combinations of PIX-protein scaffolds and unnatural metal cofactors to catalyse a wide range of abiological transformations.

Beyond classical reactivity patterns: hydroformylation of vinyl and allyl arenes to valuable ß- and γ-aldehyde intermediates using supramolecular catalysis.

In this study, we report on properties of a series of rhodium complexes of bisphosphine and bisphosphite L1-L7 ligands, which are equipped with an integral anion binding site (the DIM pocket), and their application in the regioselective hydroformylation of vinyl and allyl arenes bearing an anionic group. In principle, the binding site of the ligand is used to preorganize a substrate molecule through noncovalent interactions with its anionic group to promote otherwise unfavorable reaction pathways. We demonstrate that this strategy allows for unprecedented reversal of selectivity to form otherwise disfavored ß-aldehyde products in the hydroformylation of vinyl 2- and 3-carboxyarenes, with chemo- and regioselectivity up to 100%. The catalyst has a wide substrate scope, including the most challenging substrates with internal double bonds. Coordination studies of the catalysts under catalytically relevant conditions reveal the formation of the hydridobiscarbonyl rhodium complexes [Rh(Ln)(CO)2H]. The titration studies confirm that the rhodium complexes can bind anionic species in the DIM binding site of the ligand. Furthermore, kinetic studies and in situ spectroscopic investigations for the most active catalyst give insight into the operational mode of the system, and reveal that the catalytically active species are involved in complex equilibria with unusual dormant (reversibly inactivated) species. In principle, this involves the competitive inhibition of the recognition center by product binding, as well as the inhibition of the metal center via reversible coordination of either a substrate or a product molecule. Despite the inhibition effects, the substrate preorganization gives rise to very high activities and efficiencies (TON > 18,000 and TOF > 6000 mol mol(-1) h(-1)), which are adequate for commercial applications.

Scalable and chromatography-free synthesis of 2-(2-formylalkyl)arenecarboxylic acid derivatives through the supramolecularly controlled hydroformylation of vinylarene-2-carboxylic acids.

This protocol describes how to prepare 2-(2-formylalkyl)-arenecarboxylic acid derivatives, common building blocks for the synthesis of various valuable chemicals (e.g., anti-obesity and Alzheimer's disease treatment pharmaceuticals), by using the fully regioselective hydroformylation of vinyl arene derivatives. This catalytic reaction proceeds cleanly with 100% regioselectivity and chemoselectivity. The procedure is reliably scalable and can be efficiently conducted on a multigram scale. The analytically pure product is easily isolated with a nearly quantitative yield by using a simple acid-base extraction workup and avoids any tedious chromatography. This protocol details the synthesis of a bisphosphite ligand (L1) that is a pivotal element of the catalytic system used, Rh(acac)(CO)2 with ligand L1, starting from commercial building blocks. The protocol also describes a general procedure for the preparative hydroformylation of vinylarene-2-carboxylic acid derivatives to 2-formylalkylarene products, providing a representative example for the hydroformylation of 2-vinylbenzoic acid (1a) to 2-(3-oxopropane)-benzoic acid (2a). The synthesis of L1 (six chemical reactions) uses 2-nitrophenylhydrazine, 4-benzyloxybenzoylchloride and (S)-binol, and takes 5-7 working days. The actual hydroformylation reaction of each vinyl arene derivative takes ∼4 h of active effort over a period of 1-3 d.

Precise supramolecular control of selectivity in the Rh-catalyzed hydroformylation of terminal and internal alkenes.

In this study, we report a series of DIMPhos ligands L1-L3, bidentate phosphorus ligands equipped with an integral anion binding site (the DIM pocket). Coordination studies show that these ligands bind to a rhodium center in a bidentate fashion. Experiments under hydroformylation conditions confirm the formation of the mononuclear hydridobiscarbonyl rhodium complexes that are generally assumed to be active in hydroformylation. The metal complexes formed still strongly bind the anionic species in the binding site of the ligand, without affecting the metal coordination sphere. These bifunctional properties of DIMPhos are further demonstrated by the crystal structure of the rhodium complex with acetate anion bound in the binding site of the ligand. The catalytic studies demonstrate that substrate preorganization by binding in the DIM pocket of the ligand results in unprecedented selectivities in hydroformylation of terminal and internal alkenes functionalized with an anionic group. Remarkably, the selectivity controlling anionic group can be even 10 bonds away from the reactive double bond, demonstrating the potential of this supramolecular approach. Control experiments confirm the crucial role of the anion binding for the selectivity. DFT studies on the decisive intermediates reveal that the anion binding in the DIM pocket restricts the rotational freedom of the reactive double bound. As a consequence, the pathway to the undesired product is strongly hindered, whereas that for the desired product is lowered in energy. Detailed kinetic studies, together with the in situ spectroscopic measurements and isotope-labeling studies, support this mode of operation and reveal that these supramolecular systems follow enzymatic-type Michaelis-Menten kinetics, with competitive product inhibition.