Recent advances in Rh(I)-catalyzed enantioselective C-H functionalization.

Chiral carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds are pervasive and very essential in natural products, bioactive molecules, and functional materials, and their catalytic construction has emerged as one of the hottest research fields in synthetic organic chemistry. The last decade has witnessed vigorous progress in Rh(I)-catalyzed asymmetric C-H functionalization as a complement to Rh(II) and Rh(III) catalysis. This review aims to provide the most comprehensive and up-to-date summary covering the recent advances in Rh(I)-catalyzed C-H activation for asymmetric functionalization. In addition to the development of diverse reactions, chiral ligand design and mechanistic investigation (inner-sphere mechanism, outer-sphere mechanism, and 1,4-Rh migration) will also be highlighted.

Toward in silico Catalyst Optimization.

In this minireview, we overview a computational pipeline developed within the framework of NCCR Catalysis that can be used to successfully reproduce the enantiomeric ratios of homogeneous catalytic reactions. At the core of this pipeline is the SCINE Molassembler module, a graph-based software that provides algorithms for molecular construction of all periodic table elements. With this pipeline, we are able to simultaneously functionalizenand generate ensembles of transition state conformers, which permits facile exploration of the influencenof various substituents on the overall enantiomeric ratio. This allows preconceived back-of-the-envelope designnmodels to be tested and subsequently refined by providing quick and reliable access to energetically low-lyingntransition states, which represents a key step in undertaking in silico catalyst optimization.

Swiss CAT+, a Data-driven Infrastructure for Accelerated Catalysts Discovery and Optimization.

The Catalysis Hub - Swiss CAT+ is a new infrastructure project funded by ETH-domain, co-headed by EPFL and ETHZ. It offers the scientific community a unique integrated technology platform combining automated and high-throughput experimentation with advanced computational data analysis to accelerate the discoveries in the field of sustainable catalytic technologies. Divided into two hubs of expertise, homogeneous catalysis at EPFL and heterogeneous catalysis at ETHZ, the platform is open to academic and private research groups. Following a multi-year investment plan, both hubs have acquired and developed several high-end robotic platforms devoted to the synthesis, characterization, and testing of large numbers of molecular and solid catalysts. The hardware is associated with a fully digitalized experimental workflow and a specific data management strategy to support closed-loop experimentation and advanced computational data analysis.

Reductive Asymmetric Aza-Mislow-Evans Rearrangement by 1,3,2-Diazaphospholene Catalysis.

1,3,2-diazaphospholene hydrides (DAP-H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus-enolate provides a potential platform for reductive α-functionalizations. In this respect, asymmetric C-heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2-diazaphospholene-catalyzed three-step cascade reaction of N-sulfinyl acrylamides comprised of conjugate reduction, [2,3]-sigmatropic aza-Mislow-Evans rearrangement and subsequent S-O bond cleavage. The obtained enantio-enriched α-hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo-defined P-bound N,O-ketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α-carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAP-H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow-Evans processes.

Catalytic Reduction of Oximes to Hydroxylamines: Current Methods, Challenges and Opportunities.

Catalytic reduction of oximes represents a direct efficient approach to synthesize valuable hydroxylamine derivatives. However this transformation presents significant challenges: oximes are hard to reduce and, if reactive, reductive cleavage of the weak N-O bond often leads to primary amine side products. The first suitable systems involved the use of platinum-based heterogeneous catalysts with hydrogen as reductant and stoichiometric amounts of a strong Brønsted acid. More recently metal-free and transition-metal-based homogeneous catalysts have been developed, which display the highest turnovers (up to 4000). In the asymmetric variants, the E/Z-geometry of the oxime double bond affects significantly the stereoselectivity, sometimes requiring extra synthetic efforts in substrate preparation. This minireview provides an overview of the advances and limitations in catalytic oxime to hydroxylamine reduction. Emphasis is put on highlighting and comparing the practical aspects of the existing methods, such as their reaction conditions and substrate scope. Additionally, future directions for improving this young research area are suggested.

Mapping Catalyst-Solvent Interplay in Competing Carboamination/Cyclopropanation Reactions.

Group 9 metals, in particular RhIII complexes with cyclopentadienyl ligands, are competent C-H activation catalysts. Recently, a Cp*RhIII -catalyzed reaction of alkenes with N-enoxyphthalimides showed divergent outcome based on the solvent, with carboamination favored in methanol and cyclopropanation in 2,2,2-trifluoroethanol (TFE). Here, we create selectivity and activity maps capable of unravelling the catalyst-solvent interplay on the outcome of these competing reactions by analyzing 42 cyclopentadienyl metal catalysts, CpX MIII (M=Co, Rh, Ir). These maps not only can be used to rationalize previously reported experimental results, but also capably predict the behavior of untested catalyst/solvent combinations as well as aid in identifying experimental protocols that simultaneously optimize both catalytic activity and selectivity (solutions in the Pareto front). In this regard, we demonstrate how and why the experimentally employed Cp*RhIII catalyst represents an ideal choice to invoke a solvent-induced change in reactivity. Additionally, the maps reveal the degree to which even perceived minor changes in the solvent (e. g., replacing methanol with ethanol) influence the ratio of carboamination and cyclopropanation products. Overall, the selectivity and activity maps presented here provide a generalizable tool to create global pictures of anticipated reaction outcome that can be used to develop new experimental protocols spanning metal, ligand, and solvent space.

Catalytic Enantioselective Functionalizations of C-H Bonds by Chiral Iridium Complexes.

The development of catalytic enantioselective transformations, enabling the construction of complex molecular scaffolds from simple precursors, has been a long-standing challenge in organic synthesis. Recent achievements in transition-metal catalyzed enantioselective functionalizations of carbon-hydrogen (C-H) bonds represent a promising pathway toward this goal. Over the last two decades, iridium catalysis has evolved as a valuable tool enabling the stereocontrolled synthesis of chiral molecules via C-H activation. The development of iridium-based systems with various chiral ligand classes, as well as studies of their reaction mechanisms, has resulted in dynamic progress in this area. This review aims to present a comprehensive picture of the enantioselective functionalizations of C-H bonds by chiral iridium complexes with emphasis on the mechanisms of the C-H activation step.

Crossed Regio- and Enantioselective Iron-Catalyzed [4+2]-Cycloadditions of Unactivated Dienes.

The cyclohexene motif is ubiquitous in nature and specialty chemicals. A straightforward selective access to chiral cyclohexenes from unactivated dienes and dienophiles is not feasible by classical Diels-Alder reaction and constitutes an unsolved synthetic challenge. We report a mild and enantioselective iron-catalyzed cross-[4+2]-cycloaddition of unactivated dienes providing access to chiral 1,3-substituted vinyl-cyclohexenes. The development of bis-dihydroisoquinoline ligands was vital to obtain iron complexes that display high reactivities and excellent chemo-, regio- and enantioselectivities towards the targeted cyclohexenes. A range of diene substrates is well accommodated including feedstocks like butadiene, isoprene and myrcene. The structures of different iron complexes are mapped by X-ray crystallographic analysis and linked to their performance.

1,3,2-Diazaphospholene-Catalyzed Reductive Cyclizations of Organohalides.

1,3,2-diazaphospholenes hydrides (DAP-Hs) are highly nucleophilic organic hydrides serving as main-group catalysts for a range of attractive transformations. DAP hydrides can act as stoichiometric hydrogen atom transfer agents in radical reactions. Herein, we report a DAP-catalyzed reductive radical cyclization of a broad range of aryl and alkyl halides under mild conditions. The pivotal DAP catalyst turnover was achieved by a DBU-assisted σ-bond metathesis between the formed DAP halide and HBpin, which rapidly regenerates DAP-H. The transformation is significantly accelerated by irradiation with visible light. Mechanistic investigations indicate that visible light irradiation leads to the formation of DAP dimers, which are in equilibrium with DAP radicals and accelerate the cyclization. The direct use of (DAP)2 enabled a catalytic protocol in the absence of light.

Atropo-Enantioselective Oxidation-Enabled Iridium(III)-Catalyzed C-H Arylations with Aryl Boronic Esters.

Atropo-enantioselective biaryl coupling through C-H bond functionalization is an emerging technology allowing direct construction of axially chiral molecules. This approach is largely limited to electrophilic coupling partners. We report a highly atropo-enantioselective C-H arylation of tetralone derivatives paired with aryl boronic esters as nucleophilic components. The transformation is catalyzed by chiral cyclopentadienyl (Cpx ) iridium(III) complexes and enabled by oxidatively enhanced reductive elimination from high-valent cyclometalated Ir-species.

Cobalt(III)-Catalyzed Enantioselective Intermolecular Carboamination by C-H Functionalization.

High-valent cyclopentadienyl cobalt catalysis is a versatile tool for sustainable C-H bond functionalizations. To harness the full potential of this strategy, control of the stereoselectivity of these processes is necessary. Herein, we report highly enantioselective intermolecular carboaminations of alkenes through C-H activation of N-phenoxyamides catalyzed by CoIII -complexes equipped with chiral cyclopentadienyl (Cpx ) ligands. The method converts widely available acrylates as well as bicyclic olefins into attractive enantioenriched isotyrosine derivatives as well as elaborated amino-substituted bicyclic scaffolds under very mild conditions. The outlined reactivity is unique to the Cpx CoIII complexes and is complementary to the reactivity of 4d- and 5d- precious-metal catalysts.

Chiral Cyclopentadienyl Ligands: Design, Syntheses, and Applications in Asymmetric Catalysis.

The creation of new chiral ligands capable of providing high stereocontrol in metal-catalyzed reactions is crucial in modern organic synthesis. The production of bioactive molecules as single enantiomers is increasingly required, and asymmetric catalysis with metal complexes constitutes one of the most efficient synthetic strategies to access optically active compounds. Herein we offer a historical overview on the development of chiral derivatives of the ubiquitous cyclopentadienyl ligand (CpX ), and detail their successful application in a broad range of metal-catalyzed transformations. Those include the functionalization of challenging C-H bonds and beyond, giving access to an extensive catalogue of valuable chiral molecules. A critical comparison of the existing ligand families, their design, synthesis, and complexation to different metals is also provided. In addition, future research directions are discussed to further enhance the performance and application of CpX ligands in enantioselective catalysis.

Iridium-Catalyzed Acid-Assisted Hydrogenation of Oximes to Hydroxylamines.

We found that cyclometalated cyclopentadienyl iridium(III) complexes are uniquely efficient catalysts in homogeneous hydrogenation of oximes to hydroxylamine products. A stable iridium C,N-chelation is crucial, with alkoxy-substituted aryl ketimine ligands providing the best catalytic performance. Several Ir-complexes were mapped by X-ray crystal analysis in order to collect steric parameters that might guide a rational design of even more active catalysts. A broad range of oximes and oxime ethers were activated with stoichiometric amounts of methanesulfonic acid and reduced at room temperature, remarkably without cleavage of the fragile N-O bond. The exquisite functional group compatibility of our hydrogenation system was further demonstrated by additive tests. Experimental mechanistic investigations support an ionic hydrogenation platform, and suggest a role for the Brønsted acid beyond a proton source. Our studies provide deep understanding of this novel acidic hydrogenation and may facilitate its improvement and application to other challenging substrates.

Enantioselective Iron-Catalyzed Cross-[4+4]-Cycloaddition of 1,3-Dienes Provides Chiral Cyclooctadienes.

Chiral cyclooctadienes are a frequently occurring scaffold in natural products and specialty chemicals, and are used as ligands in asymmetric catalysis. Accessing substituted cyclooctadienes in an efficient asymmetric fashion has been notoriously challenging. We report an iron-catalyzed enantioselective cross-[4+4]-cycloaddition of 1,3-dienes to form substituted cyclooctadienes under very mild conditions. A highly tailored chiral α-diimine iron complex is key for the success of the transformation providing a balanced performance between reactivity, excellent cross-selectivity and very high enantioselectivity. Steric maps of the complexes help accounting for the observed selectivity. The developed method allows rapid and atom-economic access to novel differently functionalized cyclooctadienes in very high yields and enantioselectivities.

Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C-H Arylation of Heteroarenes.

Atropisomeric (hetero)biaryls are motifs with increasing significance in ligands, natural products, and biologically active molecules. The straightforward construction of the stereogenic axis by efficient C-H functionalization methods is extremely rare and challenging. An intermolecular and highly enantioselective C-H arylation of relevant heteroarenes providing an efficient access to atropisomeric (hetero)biaryls is reported. The use of a Pd(0) complex equipped with H8-BINAPO as a chiral ligand enables the direct functionalization of a broad range of 1,2,3-triazoles and pyrazoles in excellent yields and selectivities of up to 97.5:2.5 er. The method also allows for an atroposelective double C-H arylation for the construction of two stereogenic axes with >99.5:0.5 er.

Modular Chiral N-Heterocyclic Carbene Ligands for the Nickel-Catalyzed Enantioselective C-H Functionalization of Heterocycles.

N-Heterocyclic carbenes (NHCs) are the ligands of choice in a large variety of transformations entailing different transition metals. However, the number and variety of chiral NHCs suitable as stereo-controlling ligands in asymmetric catalysis remains limited. Herein we highlight the introduction of a modular NHC ligand family, consisting of a chiral version of the widely used IPr ligand. These chiral NHC ligands were applied in the nickel-catalyzed enantioselective C-H functionalization of N-heterocycles. Nickel-NHC catalysis unlocked the stereoselective C-H annulation of 2- and 4-pyridones, delivering fused bicyclic compounds found in many biologically active compounds. Applying a bulky, yet flexible ligand scaffold enabled the highly enantioselective C-H functionalization of pyridones under mild conditions. The introduction of a bulky chiral SIPr analogue enabled the nickel-catalyzed enantioselective C-H functionalization of indoles, yielding valuable tetrahydropyridoindoles. Additionally, pyrrolopyridines, pyrrolopyrimidines and pyrroles were efficiently functionalized, delivering chiral annulated azoles.

Enantioselective Cpx RhIII -Catalyzed Carboaminations of Acrylates.

Enantioselective carboaminations of olefins constitute an attractive strategy for a rapid increase in molecular complexity from readily available starting materials. Reported here is an intermolecular asymmetric carboamination of acrylates using rhodium(III)-catalyzed alkenyl C-H activations of N-enoxysuccinimides to generate the nitrogen and carbon portion for the transfer. A rhodium complex equipped with a tailored bulky trisubstituted chiral Cpx ligand ensures carboamination chemoselectivity as well high levels of enantioinduction. The transformation operates under mild reaction conditions at ambient temperatures and provides access to a variety of α-amino esters in good yields and excellent enantiomeric ratios of >99.5:0.5.

A Chiral Naphthyridine Diimine Ligand Enables Nickel-Catalyzed Asymmetric Alkylidenecyclopropanations.

A novel class of chiral naphthyridine diimine ligands (NDI*) readily accessible from C2 -symmetric 2,6-di-(1-arylethyl)anilines is described. The utility of these ligands, particularly one with fluorinated aryl side arms, is demonstrated by a reductive Ni-catalyzed enantioselective alkylidene transfer reaction from 1,1-dichloroalkenes to olefins. This transformation provides direct access to a broad range of synthetically valuable alkylidenecyclopropanes in high yields and enantioselectivities.

Chiral Cyclopentadienyl Cobalt(III) Complexes Enable Highly Enantioselective 3d-Metal-Catalyzed C-H Functionalizations.

The synthesis of a set of cobalt(III)-complexes equipped with trisubstituted chiral cyclopentadienyl ligands is reported, and their steric and electronic parameters are mapped. The application potential of these complexes for asymmetric C-H functionalizations with 3d-metals is shown by the synthesis of dihydroisoquinolones from N-chlorobenzamides with a broad range of alkenes. The transformation proceeds with excellent enantioselectivities of up to 99.5:0.5 er and high regioselectivities. The observed values outperform the best rhodium(III)-based methods for this reaction type. Moreover, challenging substrates such as alkyl alkenes also react with high regio- and enantioselectivities.

Divergent Synthesis of Densely Substituted Arenes and Pyridines via Cyclotrimerization Reactions of Alkynyl Triazenes.

Densely substituted fused aromatic triazenes can be prepared by [2 + 2 + 2] cyclotrimerization reactions of 1-alkynyl triazenes. The Cp*Ru-catalyzed cyclization proceeds well with both simple alkynyl triazenes and tethered 1-diynyl triazenes. Attractively, the methodology can be extended to pyridine synthesis by replacing an alkyne with a nitrile. The reaction is regioselective and yields the sterically more hindered product. The triazene group precisely installed on the synthesized aryl and pyridyl ring is a highly versatile moiety, which is effortlessly converted into the most important and frequently used functional aryl substituents, including fluorides. It is also suited for intramolecular transformations to afford a variety of valuable heterocycles. The coordination chemistry of alkynyl triazenes and Cp*RuCl was studied and led to the structural characterization of a Cp*RuCl(η2-alkyne) complex, a Cp*RuCl(η4-cyclobutadiene) complex, and an unusual dinuclear Ru complex with a bridging tetramethylfulvene ligand. Complexes of this type are potentially involved in catalyst deactivation pathways.