Nitrene-Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ-Aminomethyl-γ-Lactones.

Attaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral-at-ruthenium catalysts, chiral γ-aminomethyl-γ-lactones containing a quaternary carbon in γ-position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ-Aminomethyl-γ-lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ-lactams, 2-oxazolidinones, and tetrahydrofurans.

Trading Symmetry for Stereoinduction in Tetradentate, non-C2 -Symmetric Fe(II)-Complexes for Asymmetric Catalysis.

A series of stereogenic-at-metal iron complexes comprising a non-C2 -symmetric chiral topology is introduced and applied to asymmetric 3d-transition metal catalysis. The chiral iron(II) complexes are built from chiral tetradentate N4-ligands containing a proline-derived amino pyrrolidinyl backbone which controls the relative (cis-α coordination) and absolute metal-centered configuration (Λ vs. Δ). Two chloride ligands complement the octahedral coordination sphere. The modular composition of the tetradentate ligands facilitates the straightforward incorporation of different terminal coordinating heteroaromatic groups into the scaffold. The influence of various combinations was evaluated in an asymmetric ring contraction of isoxazoles to 2H-azirines revealing that a decrease of symmetry is beneficial for the stereoinduction to obtain chiral products in up to 99 % yield and with up to 92 % ee. Conveniently, iron catalysis is feasible under open flask conditions with the bench-stable dichloro complexes exhibiting high robustness towards oxidative or hydrolytic decomposition. The versatility of non-racemic 2H-azirines was subsequently showcased with the conversion into a variety of quaternary α-amino acid derivatives.

Chiral-at-Ruthenium Catalysts for Nitrene-Mediated Asymmetric C-H Functionalizations.

ConspectusAsymmetric transition metal catalysis is an indispensable tool used both in academia and industry for forging chiral molecules in an enantioselective fashion. Its advancement relies in large part on the design and discovery of new chiral catalysts. In contrast to conventional endeavors of generating chiral transition metal catalysts from carefully tailored chiral ligands, the development of chiral transition metal catalysts containing solely achiral ligands (chiral-at-metal catalysts) has been neglected. This Account presents our recent work on the synthesis and catalytic applications of a new class of C2-symmetric chiral-at-ruthenium catalysts. These octahedral ruthenium(II) complexes are constructed from two achiral bidentate N-(2-pyridyl)-substituted N-heterocyclic carbene (PyNHC) ligands and two monodentate acetonitriles, and the dicationic complexes are typically complemented with two hexafluorophosphate anions. The chirality of these complexes originates from the helical cis-arrangement of the bidentate ligands, thereby generating a stereogenic metal center as the exclusive stereocenter in these complexes. The strong σ donor and π acceptor properties of the PyNHC ligands provide a strong ligand field that ensures a high constitutional and configurational inertness of the helical Ru(PyNHC)2 core, while at the same time, the trans-effect exerted by the σ-donating NHC ligands results in high lability of the MeCN ligands and, therefore, provides high catalytic activity. As a result, this chiral-at-ruthenium catalyst scaffold combines formidable structural robustness with high catalytic activity in a unique fashion. Asymmetric nitrene C-H insertion constitutes an efficient strategy for accessing chiral amines. The direct conversion of C(sp3)-H bonds into amine functionality circumvents the need for using functionalized starting materials. Our C2-symmetric chiral-at-ruthenium complexes display exceptionally high catalytic activity and excellent stereocontrol for various asymmetric nitrene C(sp3)-H insertion reactions. The ruthenium nitrene species can be generated from nitrene precursors, such as organic azides and hydroxylamine derivatives, which undergo ring-closing C-H aminations to afford chiral cyclic pyrrolidines, ureas, and carbamates in high yields and with excellent enantioselectivities at low catalyst loadings. Mechanistically, the turnover-determining C-H insertion is proposed to proceed in a concerted or stepwise fashion, depending on the nature of intermediate ruthenium nitrenes (singlet or triplet). Computational studies revealed that the stereocontrol originates from a better steric fit in combination with favorable catalyst/substrate π-π stacking effects for aminations at benzylic C-H bonds. In addition, we also present our research for exploring novel reaction patterns and reactivities of intermediate transition metal nitrenes. First, we discovered a novel chiral-at-ruthenium-catalyzed 1,3-migratory nitrene C(sp3)-H insertion to convert azanyl esters into nonracemic α-amino acids. Second, we found a chiral-at-ruthenium-catalyzed intramolecular C(sp3)-H oxygenation, thereby allowing for the construction of chiral cyclic carbonates and lactones via nitrene chemistry. We expect that our research program on catalyst development and reaction discovery will inspire the creation of novel types of chiral-at-metal catalysts and drive the development of new applications for nitrene-mediated asymmetric C-H functionalization reactions.

Metal Stereogenicity in Asymmetric Transition Metal Catalysis.

Chiral transition metal catalysts represent a powerful and economic tool for implementing stereocenters in organic synthesis, with the metal center providing a strong chemical activation upon its interaction with substrates or reagents, while the overall chirality of the metal complex achieves the desired stereoselectivity. Often, the overall chiral topology of the metal complex implements a stereogenic metal center, which is then involved in the origin of the asymmetric induction. This review provides a comprehensive survey of reported chiral transition metal catalysts in which the metal formally constitutes a stereocenter. A stereogenic metal center goes along with an overall chiral topology of the metal complex, regardless of whether the ligands are chiral or achiral. Implications for the catalyst design and mechanism of asymmetric induction are discussed for half-sandwich, tetracoordinated, pentacoordinated, and hexacoordinated chiral transition metal complexes containing a stereogenic metal center. The review distinguishes between chiral metal catalysts originating from the coordination to chiral ligands and those which are solely composed of optically inactive ligands (achiral or rapidly interconverting enantiomers) prior to complexation (dubbed "chiral-at-metal" catalysts).

Symmetry-breaking host-guest assembly in a hydrogen-bonded supramolecular system.

Bio-inspired self-assembly is invaluable to create well-defined giant structures from small molecular units. Owing to a large entropy loss in the self-assembly process, highly symmetric structures are typically obtained as thermodynamic products while formation of low symmetric assemblies is still challenging. In this study, we report the symmetry-breaking self-assembly of a defined C1-symmetric supramolecular structure from an Oh-symmetric hydrogen-bonded resorcin[4]arene capsule and C2-symmetric cationic bis-cyclometalated Ir complexes, carrying sterically demanding tertiary butyl (tBu) groups, on the basis of synergistic effects of weak binding forces. The flexible capsule framework shows a large structural change upon guest binding to form a distorted resorcin[4]arene hexameric capsule, providing an asymmetric cavity. Location of the chiral guest inside the anisotropic environment leads to modulation of its Electric Dipole (ED) and Magnetic Dipole (MD) transition moments in the excited state, causing an increased emission quantum yield, longer emission lifetime, and enhancement of the dissymmetry factor (glum) in the circularly polarized luminescence.

Nitrene-Mediated C-H Oxygenation: Catalytic Enantioselective Formation of Five-Membered Cyclic Organic Carbonates.

The synthesis of non-racemic 5-membered cyclic carbonates from abundant alcohols is reported. Conversion of the alcohol into an azanyl carbonate is followed by a chiral-at-ruthenium catalyzed cyclization to provide chiral cyclic carbonates in yields of up to 95 % and with up to 99 % ee. This new synthetic method is proposed to proceed through a nitrene-mediated intramolecular C(sp3 )-H oxygenation which includes an unusual 1,7-hydrogen atom transfer within a ruthenium nitrene intermediate. The method is applicable to the synthesis of non-racemic chiral mono-, di- and trisubstituted cyclic alkylene carbonates.

Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids.

α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of unnatural amino acids is often desirable for modulating chemical, physical and pharmaceutical properties. Here we report a protocol for the economical and practical synthesis of optically active α-amino acids based on an unprecedented stereocontrolled 1,3-nitrogen shift. Our method employs abundant and easily accessible carboxylic acids as starting materials, which are first connected to a nitrogenation reagent, followed by a highly regio- and enantioselective ruthenium- or iron-catalysed C(sp3)-H amination. This straightforward method displays a very broad scope, providing rapid access to optically active α-amino acids with aryl, allyl, propargyl and alkyl side chains, and also permits stereocontrolled late-stage amination of carboxylic-acid-containing drugs and natural products.

Electrochemical Enantioselective Nucleophilic α-C(sp3)-H Alkenylation of 2-Acyl Imidazoles.

Merging electrochemistry with asymmetric catalysis promises to provide an environmentally friendly and efficient strategy for the construction of nonracemic chiral molecules. However, in practice, significant challenges arise from the instability or incompatibility of the chiral catalysts under the electrochemical conditions at the interface of electrode and solution. Herein, we report a catalytic asymmetric indirect electrolysis employing the combination of a redox mediator and a chiral-at-rhodium Lewis acid, which achieves a previously elusive enantioselective nucleophilic α-C(sp3)-H alkenylation of ketones. Specifically, 2-acyl imidazoles react with potassium alkenyl trifluoroborates in high yields (up to 94%) and with exceptional enantioselectivities (27 examples with ≥99% ee) without the need for any additional stoichiometric oxidants (overall 40 examples). The new indirect electrosynthesis can be scaled to gram quantities and was applied to the straightforward synthesis of intermediates of the natural product cryptophycin A and a cathepsin K inhibitor.

Improving the Configurational Stability of Chiral-at-Iron Catalysts Containing Two N-(2-Pyridyl)-Substituted N-Heterocyclic Carbene Ligands.

Recently, we introduced the first example of chiral-at-iron catalysts in which two achiral N-(2-pyridyl)-substituted N-heterocyclic carbene (NHC) ligands in addition to two labile acetonitriles are coordinated around a central iron, to generate a stereogenic metal center [Hong Y.Chiral-at-Iron Catalyst: Expanding the Chemical Space for Asymmetric Earth-Abundant Metal Catalysis. J. Am. Chem. Soc.2019, 141, 4569-4572]. A more facile synthesis of such chiral-at-iron catalysts was developed, which omits the use of expensive silver salts and an elaborate electrochemical setup. Configurational robustness was improved by replacing the imidazol-2-ylidene carbene moieties with benzimidazol-2-ylidenes. The π-acceptor properties of the altered NHCs were investigated by Ganter's 77Se NMR method. The obtained benzimidazol-2-ylidene chiral-at-iron complex is an excellent catalyst for an asymmetric hetero-Diels-Alder reaction under open-flask conditions.

Understanding the mechanism of direct visible-light-activated [2 + 2] cycloadditions mediated by Rh and Ir photocatalysts: combined computational and spectroscopic studies.

The mechanism of [2 + 2] cycloadditions activated by visible light and catalyzed by bis-cyclometalated Rh(iii) and Ir(iii) photocatalysts was investigated, combining density functional theory calculations and spectroscopic techniques. Experimental observations show that the Rh-based photocatalyst produces excellent yield and enantioselectivity whereas the Ir-photocatalyst yields racemates. Two different mechanistic features were found to compete with each other, namely the direct photoactivation of the catalyst-substrate complex and outer-sphere triplet energy transfer. Our integrated analysis suggests that the direct photocatalysis is the inner working of the Rh-catalyzed reaction, whereas the Ir catalyst serves as a triplet sensitizer that activates cycloaddition via an outer-sphere triplet excited state energy transfer mechanism.

Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation.

This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.

Bis-Cyclometalated Indazole and Benzimidazole Chiral-at-Iridium Complexes: Synthesis and Asymmetric Catalysis.

A new class of bis-cyclometalated iridium(III) catalysts containing two inert cyclometalated 6-tert-butyl-2-phenyl-2H-indazole bidentate ligands or two inert cyclometalated 5-tert-butyl-1-methyl-2-phenylbenzimidazoles is introduced. The coordination sphere is complemented by two labile acetonitriles, and a hexafluorophosphate ion serves as a counterion for the monocationic complexes. Single enantiomers of the chiral-at-iridium complexes (>99% er) are obtained through a chiral-auxiliary-mediated approach using a monofluorinated salicyloxazoline and are investigated as catalysts in the enantioselective conjugate addition of indole to an α,ß-unsaturated 2-acyl imidazole and an asymmetric Nazarov cyclization.

Chiral-at-Iron Catalyst for Highly Enantioselective and Diastereoselective Hetero-Diels-Alder Reaction.

This study demonstrates that chiral-at-iron complexes, in which all coordinated ligands are achiral and the overall chirality the consequence of a stereogenic iron center, are capable of catalyzing asymmetric transformations with very high enantioselectivities. The catalyst is based on a previously reported design (J. Am. Chem. Soc. 2017, 139, 4322), in which iron(II) is surrounded by two configurationally inert achiral bidentate N-(2-pyridyl)-substituted N-heterocyclic carbenes in a C2 -symmetric fashion and complemented by two labile acetonitriles. By replacing mesityl with more bulky 2,6-diisopropylphenyl substituents at the NHC ligands, the steric hindrance at the catalytic site was increased, thereby providing a markedly improved asymmetric induction. The new chiral-at-iron catalyst was applied to the inverse electron demand hetero-Diels-Alder reaction between ß,γ-unsaturated α-ketoester and enol ethers provide 3,4-dihydro-2H-pyrans in high yields with excellent diastereoselectivities (up to 99 : 1 dr) and excellent enantioselectivities (up to 98 % ee). Other electron rich dienophiles are also suitable as demonstrated for a reaction with a vinyl azide.

Efficient Amination of Activated and Non-Activated C(sp3 )-H Bonds with a Simple Iron-Phenanthroline Catalyst.

A readily available catalyst consisting of iron dichloride in combination with 1,10-phenanthroline catalyzes the ring-closing C-H amination of N-benzoyloxyurea to form imidazolidin-2-ones in high yields. The C-H amination reaction is very general and applicable to benzylic, allylic, propargylic, and completely non-activated aliphatic C(sp3 )-H bonds, and it also works for C(sp2 )-H bonds. The surprisingly simple method can be performed under open flask conditions.

Ruthenium Pybox-Catalyzed Enantioselective Intramolecular C-H Amination of Sulfamoyl Azides en Route to Chiral Vicinal Diamines.

Enantioselective C(sp3)-H aminations allow an efficient access to nonracemic chiral amines. This work reports the catalytic asymmetric synthesis of chiral 1,2,5-thiadiazolidine-1,1-dioxides by an enantioselective ring-closing 1,5-C-H amination of sulfamoyl azides. The reaction is catalyzed by a recently introduced simple chiral ruthenium bis(oxazoline) (pybox) complex ( Angew. Chem. Int. Ed. 2020, 59, 12395) and provides cyclic 5-membered sulfamide products in up to 98% yield and up to 98% ee if the C-H bond is in a benzylic position. Mechanistic experiments support a stepwise mechanism in which an intermediate ruthenium nitrenoid species initiates a 1,5-hydrogen atom transfer followed by an immediate radical rebound. The cyclic sulfamide products are suitable intermediates for the synthesis of chiral vicinal diamines as has been verified for a representative example.

Asymmetric Ring-Closing Aminooxygenation of Alkenes en Route to 2-Amino-1,3-Diols with Vicinal Stereocenters.

A ring-closing aminooxygenation of alkenes with N-benzoyloxycarbamates occurs with very high diastereoselectivity (typically >20:1 d.r.) and very high enantioselectivity (up to 99% ee). The reaction is catalyzed by a recently developed chiral-at-metal ruthenium complex at catalyst loadings of 0.5-1.0 mol %. The reaction is proposed to proceed through a ruthenium nitrenoid intermediate that depending on the nature of the substrate undergoes either an aminooxygenation (1,2-disubstituted alkenes) or stops at the stage of the aziridination (trisubstituted alkenes), which can then be ring opened with benzoic acid. The resulting chiral cyclic carbamates can be hydrolyzed under basic conditions to provide versatile chiral 2-amino-1,3-diols with vicinal stereocenters.

Intramolecular C(sp3 )-H Bond Oxygenation by Transition-Metal Acylnitrenoids.

This study demonstrates for the first time that easily accessible transition-metal acylnitrenoids can be used for controlled direct C(sp3 )-H oxygenations. Specifically, a ruthenium catalyst activates N-benzoyloxycarbamates as nitrene precursors towards regioselective intramolecular C-H oxygenations to provide cyclic carbonates, hydroxylated carbamates, or 1,2-diols. The method can be applied to the chemoselective C-H oxygenation of benzylic, allylic, and propargylic C(sp3 )-H bonds. The reaction can be performed in an enantioselective fashion and switched in a catalyst-controlled fashion between C-H oxygenation and C-H amination. This work provides a new reaction mode for the regiocontrolled and stereocontrolled conversion of C(sp3 )-H into C(sp3 )-O bonds.

Atroposelective Synthesis of Axially Chiral N-Arylpyrroles by Chiral-at-Rhodium Catalysis.

A transformation of fluxional into configurationally stable axially chiral N-arylpyrroles was achieved with a highly atroposelective electrophilic aromatic substitution catalyzed by a chiral-at-metal rhodium Lewis acid. Specifically, N-arylpyrroles were alkylated with N-acryloyl-1H-pyrazole electrophiles in up to 93 % yield and with up to >99.5 % ee, and follow-up conversions reveal the synthetic utility of this new method. DFT calculations elucidate the origins of the observed excellent atroposelectivity.

Asymmetric catalysis with a chiral-at-osmium complex.

The first example of a chiral osmium catalyst is reported in which the overall chirality originates exclusively from a stereogenic metal center (metal-centered chirality) with all coordinating ligands being achiral. The non-C2-symmetric chiral-at-metal complex contains two cyclometalated 7-methyl-1,7-phenanthrolinium heterocycles which can be described as two chelating pyridylidene remote N-heterocyclic carbene (rNHC) ligands. The octahedral coordination sphere is completed with one CO and one acetonitrile ligand. A monodentate chiral oxazoline ligand is used as a chiral auxiliary ligand to obtain enantiomerically pure chiral-at-osmium complexes (>99 : 1 e.r.). Finally, it is demonstrated that the developed chiral-at-osmium complex is suitable for ring-closing enantioselective C(sp3)-H aminations, including the first example of catalytic enantioselective cyclizations of azidoformates to chiral 2-oxazolidinones.

Complementing Pyridine-2,6-bis(oxazoline) with Cyclometalated N-Heterocyclic Carbene for Asymmetric Ruthenium Catalysis.

A strategy for expanding the utility of chiral pyridine-2,6-bis(oxazoline) (pybox) ligands for asymmetric transition metal catalysis is introduced by adding a bidentate ligand to modulate the electronic properties and asymmetric induction. Specifically, a ruthenium(II) pybox fragment is combined with a cyclometalated N-heterocyclic carbene (NHC) ligand to generate catalysts for enantioselective transition metal nitrenoid chemistry, including ring contraction to chiral 2H-azirines (up to 97 % ee with 2000 TON) and enantioselective C(sp3 )-H aminations (up to 97 % ee with 50 TON).