Congested C(sp3)-rich architectures enabled by iron-catalysed conjunctive alkylation.

Catalytic cross-coupling by transition metals has revolutionized the formation of C-C bonds in organic synthesis. However, the challenge of forming multiple alkyl-alkyl bonds in crowded environments remains largely unresolved. Here, we report the regioselective functionalization of olefins with sp3-hybridized organohalides and organozinc reagents using a simple (terpyridine)iron catalyst. Aliphatic groups of various sizes are successfully installed on either olefinic carbon, furnishing a diverse array of products with congested cores featuring C- or heteroatom-substituted stereocenters. The method enables access to valuable but synthetically challenging C(sp3)-rich molecules, including alicyclic compounds bearing multiple contiguous stereocenters through annulation cascades. Mechanistic and theoretical studies suggest a stepwise iron-mediated radical carbometallation pathway followed by outer-sphere C-C bond formation, which potentially opens the door to a broader scope of transformations and new chemical space.

Direct radical functionalization of native sugars.

Naturally occurring (native) sugars and carbohydrates contain numerous hydroxyl groups of similar reactivity1,2. Chemists, therefore, rely typically on laborious, multi-step protecting-group strategies3 to convert these renewable feedstocks into reagents (glycosyl donors) to make glycans. The direct transformation of native sugars to complex saccharides remains a notable challenge. Here we describe a photoinduced approach to achieve site- and stereoselective chemical glycosylation from widely available native sugar building blocks, which through homolytic (one-electron) chemistry bypasses unnecessary hydroxyl group masking and manipulation. This process is reminiscent of nature in its regiocontrolled generation of a transient glycosyl donor, followed by radical-based cross-coupling with electrophiles on activation with light. Through selective anomeric functionalization of mono- and oligosaccharides, this protecting-group-free 'cap and glycosylate' approach offers straightforward access to a wide array of metabolically robust glycosyl compounds. Owing to its biocompatibility, the method was extended to the direct post-translational glycosylation of proteins.

Electrochemical Synthesis of C(sp3)-Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds.

Alkylamines form the backbone of countless nitrogen-containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three-dimensional α-substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report the design of a catalyst-free electroreductive manifold that merges amines, carbonyl compounds and carbon-based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α-amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug-like scaffolds which are inaccessible by conventional means.

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes.

The construction of C(sp3)-C(sp3) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, we report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp3)-C(sp3) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (SH2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp3-hybridized carbon scaffolds.

Selective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (-CF2 H) Motifs.

An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.

Recent Advances in First-Row Transition Metal-Catalyzed Reductive Coupling Reactions for π-Bond Functionalization and C-Glycosylation.

ConspectusEfficient construction of ubiquitous carbon-carbon bonds between two electrophiles has garnered interest in recent decades, particularly if it is mediated by nonprecious, first-row transition metals. Reductive coupling has advantages over traditional cross-coupling by obviating the need for stoichiometric air- and moisture-sensitive organometallic reagents. By harnessing transition metal-catalyzed reductive coupling as a powerful tool, intricate molecular architectures can be readily assembled through the installation of two C-C bonds across π systems (alkenes/alkynes) via reaction with two appropriate electrophiles. Despite advances in reductive alkene difunctionalization, there remains significant potential for the discovery of novel reaction pathways. In this regard, development of reductive protocols that enable the union of challenging alkyl/alkynyl electrophiles in high regio- and chemoselectivity remains a highly sought-after goal.Apart from π-bond functionalization, reductive coupling has found application in carbohydrate chemistry, particularly in the synthesis of valuable C-glycosyl compounds. In this vein, suitable glycosyl donors can be used to generate reactive glycosyl radical intermediates under reductive conditions. Through elaborately designed reactions, these intermediates can be trapped to furnish pharmaceutically relevant glycoconjugates. Consequently, diversification in C-glycosyl compound synthesis using first-row transition metal catalysis holds strong appeal.In this Account, we summarize our efforts in the development of first-row transition metal-catalyzed reductive coupling reactions for applications in alkene/alkyne functionalization and C-glycosylation. We will first discuss the nickel (Ni)-catalyzed reductive difunctionalization of alkenes, aided by an 8-aminoquinoline (AQ) directing auxiliary. Next, we highlight the Ni-catalyzed hydroalkylation of alkenyl amides tethered with a similar AQ-derived directing auxiliary. Lastly, we discuss an efficient synthesis of 1,3-enynes involving site- and stereoselective reductive coupling of terminal alkynes with alkynyl halides and NHPI esters.Beyond alkene dicarbofunctionalization, we extended the paradigm of transition metal-catalyzed reductive coupling toward the construction of C-glycosidic linkages in carbohydrates. By employing an earth-abundant iron (Fe)-based catalyst, we show that useful glycosyl radicals can be generated from glycosyl chlorides under reductive conditions. These intermediates can be captured in C-C bond formation to furnish valuable C-aryl, C-alkenyl, and C-alkynyl glycosyl compounds with high diastereoselectivity. Our Ni-catalyzed multicomponent union of glycosyl chlorides, aryl/alkyl iodides, and isobutyl chloroformate under reductive conditions led to the stereoselective synthesis of C-acyl glycosides. In addition to Fe and Ni, we discovered a Ti-catalyzed/Mn-promoted synthetic route to access C-alkyl and C-alkenyl glycosyl compounds, through the reaction of glycosyl chlorides with electron-deficient alkenes/alkynes. We further developed an electron donor-acceptor (EDA) photoactivation system leveraging decarboxylative and deaminative strategies for C-glycosylation under Ni catalysis. This approach has been demonstrated to selectively activate carboxyl and amino motifs to furnish glycopeptide conjugates. Finally, through two distinct catalytic transformations of bench-stable heteroaryl glycosyl sulfones, we achieved stereodivergent access to both α- and ß-anomers of C-aryl glycosides, one of which involves a Ni-catalyzed reductive coupling with aryl iodides.The findings presented in this Account are anticipated to have far-reaching implications beyond our research. We foresee that these results will pave the way for new transformations founded on the concept of reductive coupling, leading to the discovery of novel applications in the future.

Divergent and Selective Light Alkene Cross-Coupling.

Light olefins are abundantly manufactured in the petroleum industry and thus represent ideal starting materials for modern chemical synthesis. Selective and divergent transformations of feedstock light olefins to value-added chemicals are highly sought-after but remain challenging. Herein we report an exceptionally regioselective carbonickelation of light alkenes followed by in situ trapping with three types of nucleophiles, namely a reductant, base, or Grignard reagent. This protocol enables efficient 1,2-hydrofunctionalization, dicarbofunctionalization, and branched-selective Heck-type cross-coupling of light alkenes with aryl and alkenyl reagents to streamline access to diverse alkyl arenes and complex alkenes. Harnessing bulky N-heterocyclic carbene ligands with acenaphthyl backbones for nickel catalysts is crucial to attain high reactivity and selectivity. This strategy provides a rare, modular, and divergent platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes.

Modular and Practical 1,2-Aryl(Alkenyl) Heteroatom Functionalization of Alkenes through Iron/Photoredox Dual Catalysis.

Efficient methods for synthesizing 1,2-aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2-aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.

Geminal-atom catalysis for cross-coupling.

Single-atom catalysts (SACs) have well-defined active sites, making them of potential interest for organic synthesis1-4. However, the architecture of these mononuclear metal species stabilized on solid supports may not be optimal for catalysing complex molecular transformations owing to restricted spatial environment and electronic quantum states5,6. Here we report a class of heterogeneous geminal-atom catalysts (GACs), which pair single-atom sites in specific coordination and spatial proximity. Regularly separated nitrogen anchoring groups with delocalized π-bonding nature in a polymeric carbon nitride (PCN) host7 permit the coordination of Cu geminal sites with a ground-state separation of about 4 Å at high metal density8. The adaptable coordination of individual Cu sites in GACs enables a cooperative bridge-coupling pathway through dynamic Cu-Cu bonding for diverse C-X (X = C, N, O, S) cross-couplings with a low activation barrier. In situ characterization and quantum-theoretical studies show that such a dynamic process for cross-coupling is triggered by the adsorption of two different reactants at geminal metal sites, rendering homo-coupling unfeasible. These intrinsic advantages of GACs enable the assembly of heterocycles with several coordination sites, sterically congested scaffolds and pharmaceuticals with highly specific and stable activity. Scale-up experiments and translation to continuous flow suggest broad applicability for the manufacturing of fine chemicals.

Diversification of Glycosyl Compounds via Glycosyl Radicals.

Glycosyl radical functionalization is one of the central topics in synthetic carbohydrate chemistry. Recent advances in metal-catalyzed cross-coupling chemistry and metallaphotoredox catalysis provided powerful platforms for glycosyl radical diversification. In particular, the discovery of new glycosyl radical precursors in conjunction with these advanced reaction technologies have significantly expanded the space for glycosyl compound synthesis. In this Review, we highlight the most recent progress in this area starting from 2021, and the reports included will be categorized based on different reaction types for better clarity.

N-Heterocyclic carbenes as privileged ligands for nickel-catalysed alkene functionalisation.

Alkene functionalisation is a powerful strategy that has enabled access to a wide array of compounds including valuable pharmaceuticals and agrochemicals. The reactivity of the alkene π-bond has allowed incorporation of a diverse range of atoms and functional groups through a wide variety of reaction pathways. N-Heterocyclic carbenes (NHCs) are a class of persistent carbenes that are widely employed as ancillary ligands due to their ability to act as strong σ-donors compared to widely-applied conventional phosphine-based ligands. NHCs are also unique as their molecular bulk provides steric influence for regio- and stereo-control in many alkene functionalisation reactions, illustrated by the examples covered in this review. A combination of the unique reactivity of NHC ligands and nickel's characteristics has facilitated the design of reaction pathways that show distinct selectivity and reactivity, including the activation of bonds previously considered "inert", such as C-H bonds, the C-O bond of ethers and esters, and the C-N bonds of amides. This review summarises the advancements in Ni(NHC) catalysed alkene functionalisation up to 2022, covering the following major reaction classes: Heck-type reactions, hydrofunctionalisation and dicarbofunctionalisation.

Catalytically active atomically thin cuprate with periodic Cu single sites.

Rational design and synthesis of catalytically active two-dimensional (2D) materials with an abundance of atomically precise active sites in their basal planes remains a great challenge. Here, we report a ligand exchange strategy to exfoliate bulk [Cu4(OH)6][O3S(CH2)4SO3] cuprate crystals into atomically thin 2D cuprate layers ([Cu2(OH)3]+). The basal plane of 2D cuprate layers contains periodic arrays of accessible unsaturated Cu(II) single sites (2D-CuSSs), which are found to promote efficient oxidative Chan-Lam coupling. Our mechanistic studies reveal that the reactions proceed via coordinatively unsaturated CuO4(II) single sites with the formation of Cu(I) species in the rate-limiting step, as corroborated by both operando experimental and theoretical studies. The robust stability of 2D-CuSSs in both batch and continuous flow reactions, coupled with their recyclability and good performance in complex molecule derivatization, render 2D-CuSSs attractive catalyst candidates for broad utility in fine chemical synthesis.

Stereoselective C-Aryl Glycosylation by Catalytic Cross-Coupling of Heteroaryl Glycosyl Sulfones.

Stereoselective C-glycosylation reactions are increasingly gaining attention in carbohydrate chemistry because they enable glycosyl precursors, readily accessible as anomeric mixtures, to converge to a single diastereomeric product. However, controlling the stereochemical outcome through transition-metal catalysis remains challenging, and methods that leverage bench-stable heteroaryl glycosyl sulfone donors to facilitate glycosylation are rare. Herein, we show two complementary nonprecious metal catalytic systems, based on iron or nickel, which are capable of promoting efficient C-C coupling between heteroaryl glycosyl sulfones and aromatic nucleophiles or electrophiles through distinct mechanisms and modes of activation. Diverse C-aryl glycosides were secured with excellent selectivity, scope, and functional-group compatibility, and reliable access to both α and ß isomers was possible for key sugar residues.

A Photoinduced, Nickel-Catalyzed Reaction for the Stereoselective Assembly of C-Linked Glycosides and Glycopeptides.

C-Alkyl glycosides and glycoproteins exist in natural products and are prized for their role as carbohydrate mimics in drug design. However, a practical strategy that merges glycosyl donors with readily accessible reagents, derived from abundant carboxylic acid and amine feedstocks, is yet to be conceived. Herein, we show that a nickel catalyst promotes C-C coupling between glycosyl halides and aliphatic acids or primary amines (converted into redox-active electrophiles in one step), in the presence of Hantzsch ester and LiI (or Et3 N) under blue LED illumination to deliver C-alkyl glycosides with high diastereoselectivity. Mechanistic studies support the photoinduced formation of alkyl radicals that react with a glycosyl nickel species generated in situ to facilitate cross-coupling. Through this manifold, innate CO2 H and NH2 motifs embedded within amino acids and oligopeptides are selectively capped and functionalized to afford glycopeptide conjugates through late-stage glycosylation.

Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre.

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.

Catalytic Multicomponent Synthesis of C-Acyl Glycosides by Consecutive Cross-Electrophile Couplings.

C-Acyl glycosides are versatile intermediates to natural products and medicinally relevant entities. Conventional cross-coupling strategies to secure these molecules often relied on two-component manifolds in which a glycosyl precursor is coupled with an acyl donor (pre-synthesized or generated in situ) under transition metal or dual catalysis to forge a C-C bond. Here, we disclose a three-component Ni-catalyzed reductive regime that facilitates the chemoselective union of glycosyl halides, organoiodides and commercially available isobutyl chloroformate as a CO surrogate. The method tolerates multiple functionalities and the resulting products are obtained in high diastereoselectivities. Theoretical calculations provide a mechanistic rationale for the unexpectedly high chemoselectivity of sequential cross-electrophile couplings. This approach enables the expeditious assembly of difficult-to-synthesize C-acyl glycosides, as well as late-stage keto-glycosylation of oligopeptides.

Addressing the quantitative conversion bottleneck in single-atom catalysis.

Single-atom catalysts (SACs) offer many advantages, such as atom economy and high chemoselectivity; however, their practical application in liquid-phase heterogeneous catalysis is hampered by the productivity bottleneck as well as catalyst leaching. Flow chemistry is a well-established method to increase the conversion rate of catalytic processes, however, SAC-catalysed flow chemistry in packed-bed type flow reactor is disadvantaged by low turnover number and poor stability. In this study, we demonstrate the use of fuel cell-type flow stacks enabled exceptionally high quantitative conversion in single atom-catalyzed reactions, as exemplified by the use of Pt SAC-on-MoS2/graphite felt catalysts incorporated in flow cell. A turnover frequency of approximately 8000 h-1 that corresponds to an aniline productivity of 5.8 g h-1 is achieved with a bench-top flow module (nominal reservoir volume of 1 cm3), with a Pt1-MoS2 catalyst loading of 1.5 g (3.2 mg of Pt). X-ray absorption fine structure spectroscopy combined with density functional theory calculations provide insights into stability and reactivity of single atom Pt supported in a pyramidal fashion on MoS2. Our study highlights the quantitative conversion bottleneck in SAC-mediated fine chemicals production can be overcome using flow chemistry.

Stereoselective Synthesis of Trisubstituted Alkenes by Nickel-Catalyzed Benzylation and Alkene Isomerization.

Catalytic strategies that provide stereoselective access to highly substituted alkenes from abundant monosubstituted substrates are exceedingly sought-after but rare. Here, we show that a N-heterocyclic carbene-NiI catalytic species mediates efficient union of electronically polarized terminal olefins with benzyl chlorides, in the presence of trimethylsilyl triflate and trimethylamine additives, to generate trisubstituted boron- and arene-containing trans alkenes in excellent regio- and stereoselectivities. Control experiments provide evidence for a mechanism involving branched-selective Heck-type benzylation that overrides substrate control, followed by trans-selective 1,3-hydrogen shift. The method represents a significant addition to the toolbox of reactions for the concise synthesis of unsaturated biologically active compounds.

Single-Atom Catalysis: From Simple Reactions to the Synthesis of Complex Molecules.

To date, the scope of single-atom catalysts (SAC) in liquid-phase transformations is rather limited owing to stability issues and the inability to activate complex substances. This calls for a better design of the catalyst support that can provide a dynamic coordination environment needed for catalytic action, and yet retain robustness against leaching or aggregation. In addition, the chemical orthogonality of SAC is useful for designing tandem or multicomponent reactions, in which side reactions common to metal nanoparticles are suppressed. In this review, the intrinsic mechanism will be highlighted that controls reaction efficiency and selectivity in SAC-catalyzed pathways, as well as the structural dynamism of SAC under complex liquid-phase conditions. These mechanistic insights are helpful for the development of next-generation SAC systems for the synthesis of high-value pharmaceuticals through late-stage functionalization, sequential and multicomponent strategies.