Contributions of methionine to recognition of trimethyllysine in aromatic cage of PHD domains: implications of polarizability,hydrophobicity, and charge on binding

Recognition of trimethyllysine (Kme3) by reader proteins is an important regulator of gene expression. This recognition event is mediated by an aromatic cage made up of 2–4 aromatic residues in the reader proteins that bind Kme3 via cation–π interactions. A small subset of reader proteins contain a methionine (Met) residue in place of an aromatic sidechain in the binding pocket. The unique role of sulfur in molecular recognition has been demonstrated in a number of noncovalent interactions recently, including interactions of thiols, thioethers, and sulfoxides with aromatic rings. However, the interaction of a thioether with an ammonium ion has not previously been investigated and the role of Met in binding Kme3 has not yet been explored. Herein, we systematically vary the Met in two reader proteins, DIDO1 and TAF3, and the ligand, Kme3 or its neutral analog tert-butyl norleucine (tBuNle), to determine the role of Met in the recognition of the cationic Kme3. Our studies demonstrate that Met contributes to binding via dispersion forces, with about an equal contribution to binding Kme3 and tBuNle, indicating that electrostatic interactions do not play a role. During the course of these studies, we also discovered that DIDO1 exhibits equivalent binding to tBuNle and Kme3 through a change in the mechanism of binding.

A conserved methionine in a trimethyllysine (Kme3) reader protein interacts via dispersion forces rather than ion-dipole interactions or the hydrophobic effect. Differences in selectivity for Kme3 versus its neutral analog were also discovered.     

A new type of noncovalent surface–π stacking interaction occurring on peroxide-modified titania nanosheets driven by vertical π-state polarization

Noncovalent π stacking of aromatic molecules is a universal form of noncovalent interactions normally occurring on planar structures (such as aromatic molecules and graphene) based on sp²-hybridized atoms. Here we reveal a new type of noncovalent surface–π stacking unusually occurring between aromatic groups and peroxide-modified titania (PMT) nanosheets, which can drive versatile aromatic adsorptions. We experimentally explore the underlying electronic-level origin by probing the perturbed changes of unoccupied Ti 3d states with near-edge X-ray absorption fine structures (NEXAFS), and find that aromatic groups can vertically attract π electrons in the surface peroxo-Ti states and increase their delocalization regions. Our discovery updates the concept of noncovalent π-stacking interactions by extending the substrates from carbon-based structures to a transition metal oxide, and presents an approach to exploit the surface chemistry of nanomaterials based on noncovalent interactions.

A new type of noncovalent surface–π stacking interaction occurring on a transition metal oxide, titania, is reported, which is different from the traditional forms on sp²-hybridized planar structures like graphene.     

Increasing protein stability by engineering the n → π* interaction at the β-turn

Abundant n → π* interactions between adjacent backbone carbonyl groups, identified by statistical analysis of protein structures, are predicted to play an important role in dictating the structure of proteins. However, experimentally testing the prediction in proteins has been challenging due to the weak nature of this interaction. By amplifying the strength of the n → π* interaction via amino acid substitution and thioamide incorporation at a solvent exposed β-turn within the GB1 proteins and Pin 1 WW domain, we demonstrate that an n → π* interaction increases the structural stability of proteins by restricting the ϕ torsion angle. Our results also suggest that amino acid side-chain identity and its rotameric conformation play an important and decisive role in dictating the strength of an n → π* interaction.

Amino acid residues adopt a right-handed α-helical conformation with increasing strength of the n → π* interaction. We also demonstrate a direct consequence of n → π* interactions on enhancing the structural stability of proteins.     

Crystallographic characterization of the metal–organic framework Fe2(bdp)3 upon reductive cation insertion

Precisely locating extra-framework cations in anionic metal–organic framework compounds remains a long-standing, yet crucial, challenge for elucidating structure–performance relationships in functional materials. Single-crystal X-ray diffraction is one of the most powerful approaches for this task, but single crystals of frameworks often degrade when subjected to post-synthetic metalation or reduction. Here, we demonstrate the growth of sizable single crystals of the robust metal–organic framework Fe₂(bdp)₃ (bdp²⁻ = benzene-1,4-dipyrazolate) and employ single-crystal-to-single-crystal chemical reductions to access the solvated framework materials A₂Fe₂(bdp)₃·yTHF (A = Li⁺, Na⁺, K⁺). X-ray diffraction analysis of the sodium and potassium congeners reveals that the cations are located near the center of the triangular framework channels and are stabilized by weak cation–π interactions with the framework ligands. Freeze-drying with benzene enables isolation of activated single crystals of Na_0.5Fe₂(bdp)₃ and Li₂Fe₂(bdp)₃ and the first structural characterization of activated metal–organic frameworks wherein extra-framework alkali metal cations are also structurally located. Comparison of the solvated and activated sodium-containing structures reveals that the cation positions differ in the two materials, likely due to cation migration that occurs upon solvent removal to maximize stabilizing cation–π interactions. Hydrogen adsorption data indicate that these cation–framework interactions are sufficient to diminish the effective cationic charge, leading to little or no enhancement in gas uptake relative to Fe₂(bdp)₃. In contrast, Mg_0.85Fe₂(bdp)₃ exhibits enhanced H₂ affinity and capacity over the non-reduced parent material. This observation shows that increasing the charge density of the pore-residing cation serves to compensate for charge dampening effects resulting from cation–framework interactions and thereby promotes stronger cation–H₂ interactions.

Single-crystal X-ray diffraction reveals structural influences on gas adsorption properties in anionic metal–organic frameworks.     

Donor–acceptor–acceptor-type near-infrared fluorophores that contain dithienophosphole oxide and boryl groups: effect of the boryl group on the nonradiative decay

The use of donor–π–acceptor (D–π–A) skeletons is an effective strategy for the design of fluorophores with red-shifted emission. In particular, the use of amino and boryl moieties as the electron-donating and -accepting groups, respectively, can produce dyes that exhibit high fluorescence and solvatochromism. Herein, we introduce a dithienophosphole P-oxide scaffold as an acceptor–spacer to produce a boryl- and amino-substituted donor–acceptor–acceptor (D–A–A) π-system. The thus obtained fluorophores exhibit emission in the near-infrared (NIR) region, while maintaining high fluorescence quantum yields even in polar solvents (e.g. λ_em = 704 nm and Φ_F = 0.69 in CH₃CN). A comparison of these compounds with their formyl- or cyano-substituted counterparts demonstrated the importance of the boryl group for generating intense emission. The differences among these electron-accepting substituents were examined in detail using theoretical calculations, which revealed the crucial role of the boryl group in lowering the nonradiative decay rate constant by decreasing the non-adiabatic coupling in the internal conversion process. The D–A–A framework was further fine-tuned to improve the photostability. One of these D–A–A dyes was successfully used in bioimaging to visualize the blood vessels of Japanese medaka larvae and mouse brain.

Combination of electron-accepting diarylboryl terminal groups and dithienophosphole oxide spacers with electron-donating triarylamine moieties produces donor–acceptor–acceptor type π-systems, which exhibit emissions in the near-infrared region.     

2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases

Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., K_i = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.

Metallo-β-lactamases (MBLs) are major culprits of resistance to carbapenems in bacteria. A series of thiazolidines are potent MBL inhibitors, restoring the activity of carbapenems. Metal binding and sulphur–π interactions are key to inhibition.     

Origin of rate enhancement and asynchronicity in iminium catalyzed Diels–Alder reactions

The Diels–Alder reactions between cyclopentadiene and various α,β-unsaturated aldehyde, imine, and iminium dienophiles were quantum chemically studied using a combined density functional theory and coupled-cluster theory approach. Simple iminium catalysts accelerate the Diels–Alder reactions by lowering the reaction barrier up to 20 kcal mol⁻¹ compared to the parent aldehyde and imine reactions. Our detailed activation strain and Kohn–Sham molecular orbital analyses reveal that the iminium catalysts enhance the reactivity by reducing the steric (Pauli) repulsion between the diene and dienophile, which originates from both a more asynchronous reaction mode and a more significant polarization of the π-system away from the incoming diene compared to aldehyde and imine analogs. Notably, we establish that the driving force behind the asynchronicity of the herein studied Diels–Alder reactions is the relief of destabilizing steric (Pauli) repulsion and not the orbital interaction between the terminal carbon of the dienophile and the diene, which is the widely accepted rationale.

Quantum chemical activation strain analyses revealed that iminium catalysts accelerate Diels–Alder reactions by reducing the Pauli repulsion between reactants.     

Understanding the unique reactivity patterns of nickel/JoSPOphos manifold in the nickel-catalyzed enantioselective C–H cyclization of imidazoles

The 3d transition metal-catalyzed enantioselective C–H functionalization provides a sustainable strategy for the construction of chiral molecules. A better understanding of the catalytic nature of the reactions and the factors controlling the enantioselectivity is important for rational design of more efficient systems. Herein, the mechanisms of Ni-catalyzed enantioselective C–H cyclization of imidazoles are investigated by density functional theory (DFT) calculations. Both the π-allyl nickel(ii)-promoted σ-complex-assisted metathesis (σ-CAM) and the nickel(0)-catalyzed oxidative addition (OA) mechanisms are disfavored. In addition to the typically proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism, the reaction can also proceed via an unconventional σ-CAM mechanism that involves hydrogen transfer from the JoSPOphos ligand to the alkene through P–H oxidative addition/migratory insertion, C(sp²)–H activation via σ-CAM, and C–C reductive elimination. Importantly, computational results based on this new mechanism can indeed reproduce the experimentally observed enantioselectivities. Further, the catalytic activity of the π-allyl nickel(ii) complex can be rationalized by the regeneration of the active nickel(0) catalyst via a stepwise hydrogen transfer, which was confirmed by experimental studies. The calculations reveal several significant roles of the secondary phosphine oxide (SPO) unit in JoSPOphos during the reaction. The improved mechanistic understanding will enable design of novel enantioselective C–H transformations.

Several unique reactivity patterns of the Ni/JoSPOphos manifold, including facile hydrogen transfer via the two-step oxidative addition/migratory insertion and C(sp²)–H activation via an unconventional σ-CAM mechanism, were disclosed in this work.     

Activating intramolecular singlet exciton fission by altering π-bridge flexibility in perylene diimide trimers for organic solar cells

In this study, two analogous perylene diimide (PDI) trimers, whose structures show rotatable single bond π-bridge connection (twisted) vs. rigid/fused π-bridge connection (planar), were synthesized and investigated. We show via time resolved spectroscopic measurements how the π-bridge connections in A–π–D–π–A–π–D–π–A multichromophoric PDI systems strongly affect the triplet yield and triplet formation rate. In the planar compound, with stronger intramolecular charge transfer (ICT) character, triplet formation occurs via conventional intersystem crossing. However, clear evidence of efficient and fast intramolecular singlet exciton fission (iSEF) is observed in the twisted trimer compound with weaker ICT character. Multiexciton triplet generation and separation occur in the twisted (flexible-bridged) PDI trimer, where weak coupling among the units is observed as a result of the degenerate double triplet and quintet states, obtained by quantum chemical calculations. The high triplet yield and fast iSEF observed in the twisted compound are due not only to enthalpic viability but also to the significant entropic gain allowed by its trimeric structure. Our results represent a significant step forward in structure–property understanding, and may direct the design of new efficient iSEF materials.

We show via time resolved spectroscopy that triplet formation proceeds via intersystem crossing in a rigid-bridged perylene diimide trimer and via efficient and fast intramolecular singlet exciton fission in the analogous flexible-bridged trimer.     

Rationalizing the diverse reactivity of [1.1.1]propellane through σ–π-delocalization

[1.1.1]Propellane is the ubiquitous precursor to bicyclo[1.1.1]pentanes (BCPs), motifs of high value in pharmaceutical and materials research. The classical Lewis representation of this molecule places an inter-bridgehead C–C bond along its central axis; ‘strain relief’-driven cleavage of this bond is commonly thought to enable reactions with nucleophiles, radicals and electrophiles. We propose that this broad reactivity profile instead derives from σ–π-delocalization of electron density in [1.1.1]propellane. Using ab initio and DFT calculations, we show that its reactions with anions and radicals are facilitated by increased delocalization of electron density over the propellane cage during addition, while reactions with cations involve charge transfer that relieves repulsion inside the cage. These results provide a unified framework to rationalize experimental observations of propellane reactivity, opening up opportunities for the exploration of new chemistry of [1.1.1]propellane and related strained systems that are useful building blocks in organic synthesis.

A unified framework that explains the reactivity of [1.1.1]propellane through electron delocalization.     

Efficient and organic host–guest room-temperature phosphorescence: tunable triplet–singlet crossing and theoretical calculations for molecular packing

Organic host–guest doped materials exhibiting the room temperature phosphorescence (RTP) phenomenon have attracted considerable attention. However, it is still challenging to investigate their corresponding luminescence mechanism, because for host–guest systems, it is very difficult to obtain single crystals compared to single-component or co-crystal component materials. Herein, we developed a series of organic doped materials with triphenylamine (TPA) as the host and TPA derivatives with different electron-donating groups as guests. The doped materials showed strong fluorescence, thermally activated delayed fluorescence (τ: 39–47 ms), and efficient room temperature phosphorescence (Φ_phos: 7.3–9.1%; τ: 170–262 ms). The intensity ratio between the delayed fluorescence and phosphorescence was tuned by the guest species and concentration. Molecular dynamics simulations were used to simulate the molecular conformation of guest molecules in the host matrix and the interaction between the host and guest molecules. Therefore, the photophysical properties were calculated using the QM/MM model. This work provides a new concept for the study of molecular packing of guest molecules in the host matrix.

Molecular dynamics simulations were used to simulate the molecular conformation and interaction between hosts and guests. This work provides a new concept for the study of molecular packing for the investigation of the luminescence mechanism.     

A hierarchical assembly strategy for near-infrared photothermal conversion: unconventional heterogeneous metalla[2]catenanes

Herein, we report a hierarchical assembly strategy for constructing heterogeneous half-sandwich organometallic D–A (D = π-donor, A = π-acceptor) interlocked structures, and their application in near-infrared (NIR) photothermal conversion. Thienothiophene and diketopyrrolopyrrole groups were selected as the D and A units, leading to two homogeneous metalla[2]catenanes with D–D–D–D and A–A–A–A stacks, respectively. By the ordered secondary assembly of homogeneous metalla[2]catenanes, two unprecedented heterogeneous D–A metalla[2]catenanes comprising an unusual mixed D–A–D–D and unconventional D–A–A–A stacks were realized by the combination of multiple noncovalent interactions, as all demonstrated by a detailed X-ray crystallographic study. Benefiting from the mixed D–A stacking modes, NIR absorption of heterogeneous D–A metalla[2]catenanes is significantly enhanced in contrast to homogeneous metalla[2]catenanes. Thanks to the enhanced NIR absorption and the fluorescence quenching effect from half-sandwich organometallic fragments, heterogeneous D–A metalla[2]catenanes displayed high-performance NIR photothermal conversion properties (η = 27.3%).

Herein, we report a hierarchical assembly strategy for constructing heterogeneous half-sandwich organometallic D–A (D = π-donor, A = π-acceptor) interlocked structures, and their application in near-infrared (NIR) photothermal conversion.     

Direct metal–carbon bonding in symmetric bis(C–H) agostic nickel(i) complexes

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C–H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C–H activation processes and thus are of critical importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d⁹ Ni(i) complexes with symmetric bis(C–H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand–metal donation occurs directly along the C–Ni bond axis, reflecting a novel mode of bis-agostic bonding.

Symmetric Ni(i) agostic complexes reveal an unusual mode of bonding that is dominated by direct carbon-to-metal charge transfer.     

Long-lived triplet charge-separated state in naphthalenediimide based donor–acceptor systems

1,4,5,8-Naphthalenediimides (NDIs) are widely used motifs to design multichromophoric architectures due to their ease of functionalisation, their high oxidative power and the stability of their radical anion. The NDI building block can be incorporated in supramolecular systems by either core or imide functionalization. We report on the charge-transfer dynamics of a series of electron donor–acceptor dyads consisting of a NDI chromophore with one or two donors linked at the axial, imide position. Photo-population of the core-centred π–π* state is followed by ultrafast electron transfer from the electron donor to the NDI. Due to a solvent dependent singlet–triplet equilibrium inherent to the NDI core, both singlet and triplet charge-separated states are populated. We demonstrate that long-lived charge separation in the triplet state can be achieved by controlling the mutual orientation of the donor–acceptor sub-units. By extending this study to a supramolecular NDI-based cage, we also show that the triplet charge-separation yield can be increased by tuning the environment.

Ultrafast electron transfer from singlet and triplet excited states in equilibrium results in the population of both singlet and triplet charge-separated states.     

Nickel-catalyzed C–O/N–H,C–S/N–H,and C–CN/N–H annulation of aromatic amides with alkynes: C–O,C–S,and C–CN activation

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones. The use of a base is essential for the reaction to proceed. The reaction proceeds, even in the absence of a ligand, and under mild reaction conditions (40 °C). An electron-donating group on the aromatic ring facilitates the reaction. The reaction was also applicable to carbamate (C–O bond activation), methylthio (C–S bond activation), and cyano (C–CN bond activation) groups as leaving groups.

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones.     

Fluorescent supramolecular polymers of barbiturate dyes with thiophene-cored twisted π-systems

Because supramolecular polymerization of emissive π-conjugated molecules depends strongly on π–π stacking interaction, the formation of well-defined one-dimensional nanostructures often results in a decrease or only a small increase of emission efficiency. This is also true for our barbiturate-based supramolecular polymers wherein hydrogen-bonded rosettes of barbiturates stack quasi-one-dimensionally through π–π stacking interaction. Herein we report supramolecular polymerization-induced emission of two regioisomeric 2,3-diphenylthiophene derivatives functionalized with barbituric acid and tri(dodecyloxy)benzyl wedge units. In CHCl₃, both compounds are molecularly dissolved and accordingly poorly emissive due to a torsion-induced non-radiative decay. In methylcyclohexane-rich conditions, these barbiturates self-assemble to form crystalline nanofibers and exhibit strongly enhanced emission through supramolecular polymerization driven by hydrogen-bonding. Our structural analysis suggests that the barbiturates form a tape-like hydrogen-bonding motif, which is rationalized by considering that the twisted geometries of 2,3-diphenylthiophene cores prevend the competing rosettes from stacking into columnar supramolecular polymers. We also found that a small difference in the molecular polarity originating from the substitutional position of the thiophene core influences interchain association of the supramolecular polymers, affording different luminescent soft materials, gel and nanosheet.

Two barbiturate dyes with regioisomeric thiophene-cored twisted π-systems show strongly enhanced emission through supramolecular polymerization. The supramolecular polymers thus formed exhibit distinct emission colors and degree of agglomeration.     

Total synthesis of endiandric acid J and beilcyclone A from cyclooctatetraene

The endiandric acids are classic targets in natural product synthesis. The spectacular 8π/6π-electrocylisation/intramolecular Diels–Alder (8π/6π/IMDA) reaction cascade at the heart of their biosynthesis has inspired practitioners and students of pericyclic chemistry for nearly forty years. All previous synthetic approaches have sought to prepare a linear tetraene and thereby initiate the cascade. In this communication we demonstrate the use of cyclooctatetraene to rapidly intercept the 8π/6π/IMDA cascade at the cyclooctatriene stage. Endiandric acid J and beilcyclone A are prepared for the first time in six and five steps, respectively. The strategy features a tactical overall anti-vicinal difunctionalisation of cyclooctatetraene through S_N2′ alkylation of cyclooctatetraene oxide followed by an intriguing tandem Claisen rearrangement/6π-electrocyclisation from the corresponding vinyl ether. This rapidly constructs an advanced bicyclo[4.2.0]octadiene aldehyde intermediate. Olefinations and intramolecular Diels–Alder cycloadditions complete the syntheses. This establishes a short and efficient new path to the endiandric acid natural products. DFT modelling predicts thermal racemisation of bicyclo[4.2.0]octadiene intermediates, dashing hopes of enantioselective synthesis.

A new strategy to the endiandric acid natural products is demonstrated by intercepting the 8π/6π/IMDA pericyclic cascade through a tactical anti-vicinal difunctionalisation of cyclooctatetraene.     

Impact of the macrocyclic structure and dynamic solvent effect on the reactivity of a localised singlet diradicaloid with π-single bonding character

Localised singlet diradicals are key intermediates in bond homolysis processes. Generally, these highly reactive species undergo radical–radical coupling reaction immediately after their generation. Therefore, their short-lived character hampers experimental investigations of their nature. In this study, we implemented the new concept of “stretch effect” to access a kinetically stabilised singlet diradicaloid. To this end, a macrocyclic structure was computationally designed to enable the experimental examination of a singlet diradicaloid with π-single bonding character. The kinetically stabilised diradicaloid exhibited a low carbon–carbon coupling reaction rate of 6.4 × 10³ s⁻¹ (155.9 μs), approximately 11 and 1000 times slower than those of the first generation of macrocyclic system (7.0 × 10⁴ s⁻¹, 14.2 μs) and the parent system lacking the macrocycle (5 × 10⁶ s⁻¹, 200 ns) at 293 K in benzene, respectively. In addition, a significant dynamic solvent effect was observed for the first time in intramolecular radical–radical coupling reactions in viscous solvents such as glycerin triacetate. This theoretical and experimental study demonstrates that the stretch effect and solvent viscosity play important roles in retarding the σ-bond formation process, thus enabling a thorough examination of the nature of the singlet diradicaloid and paving the way toward a deeper understanding of reactive intermediates.

An extremely long-lived localised singlet diradical with π-single bonding character is found in a macrocyclic structure that retards the radical–radical coupling reaction by the “stretch and solvent-dynamic effects”.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls

Construction of C–C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C–C bonds in a tricomponent process.

α-Branched carboxylic acids and other carbonyls are readily accessed by a metal- and base-free deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls via boron enolates, resulting in a tricomponent coupling with unconventional electrophiles.