Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination Enabled by a Transient Chiral Auxiliary

Atroposelective synthesis of axially chiral biaryls by palladium-catalyzed C−H olefination, using tert-leucine as an inexpensive, catalytic, and transient chiral auxiliary, has been realized. This strategy provides a highly efficient and straightforward access to a broad range of enantioenriched biaryls in good yields (up to 98 %) with excellent enantioselectivities (95 to >99 % ee). Kinetic resolution of trisubstituted biaryls bearing sterically more demanding substituents is also operative, thus furnishing the optically active olefinated products with excellent selectivity (95 to >99 % ee, s-factor up to 600).     

Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C−H Allylation

The significance of stereoselective C−H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.     

Synthesis of Axially Chiral Biaryl-2-amines by PdII-Catalyzed Free-Amine-Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II-catalyzed atroposelective C−H olefination. A broad range of axially chiral biaryl-2-amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram-scale synthesis. The resulting axially chiral biaryl-2-amines also provide a platform for the synthesis of a set of chiral ligands.     

Palladium-Catalyzed Enantioselective C−H Olefination to Access Planar-Chiral Cyclophanes by Dynamic Kinetic Resolution

Planar-chiral cyclophanes have received increasing attention for drug discovery and catalyst design. However, the catalytically asymmetric synthesis of planar-chiral cyclophanes has been a longstanding challenge. We describe the first Pd(II)-catalyzed enantioselective C−H olefination of prochiral cyclophanes. The low rotational barrier of less hindered benzene ring in the substrates allows the reaction to proceed through a dynamic kinetic resolution. This approach exhibits broad substrate scope, providing the planar-chiral cyclophanes in high yields (up to 99 %) with excellent enantioselectivities (up to >99 % ee). The ansa chain length scope studies reveal that the chirality of the cyclophanes arises from the bond rotation constraint of the benzene ring around the macrocycle plane, rather than the C−N axis. The C−H activation approach is also applicable to the late-stage modification of bioactive molecules and pharmaceuticals.     

Late-Stage Peptide Macrocyclization by Palladium-Catalyzed Site-Selective C−H Olefination of Tryptophan

Transition-metal-catalyzed C−H activation has shown potential in the functionalization of peptides with expanded structural diversity. Herein, the development of late-stage peptide macrocyclization methods by palladium-catalyzed site-selective C(sp²)−H olefination of tryptophan residues at the C2 and C4 positions is reported. This strategy utilizes the peptide backbone as endogenous directing groups and provides access to peptide macrocycles with unique Trp–alkene crosslinks.     

Atroposelective Synthesis of C−N Vinylindole Atropisomers by Palladium-Catalyzed Asymmetric Hydroarylation of 1-Alkynylindoles

Transition-metal-catalyzed hydroarylation of unsymmetrical internal alkynes remains challenging because of the difficulty in controlling regioselectivity and stereoselectivity. Moreover, the enantioselective hydroarylation of alkynes using organoboron reagents has not been reported. Herein, we report for the first time that palladium compounds can catalyze the hydroarylation of 1-alkynylindoles with organoborons for the synthesis of chiral C−N atropisomers. A series of rarely reported vinylindole atropisomers was synthesized with excellent regio-, stereo- (Z-selectivity), and enantioselectivity under mild reaction conditions. The ready availability of organoborons and alkynes and the simplicity, high stereoselectivity, and good functional group tolerance of this catalytic system make it highly attractive.     

Sterically Controlled C−H Olefination of Heteroarenes

The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C−H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.     

Enantioselective Synthesis of N-N Atropisomers by Palladium-Catalyzed C−H Functionalization of Pyrroles

The catalytic asymmetric construction of N−N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon-carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium-catalyzed enantioselective C−H activation of pyrroles for the synthesis of N−N atropisomers is presented. Structurally diverse indole-pyrrole atropisomers possessing a chiral N−N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N−N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C−H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N−N atropisomers.     

Iodane-Guided ortho C−H Allylation

A metal-free C−H allylation strategy is described to access diverse functionalized ortho-allyl-iodoarenes. The method employs hypervalent (diacetoxy)iodoarenes and proceeds through the iodane-guided “iodonio-Claisen” allyl transfer. The use of allylsilanes bearing electron-withdrawing functional groups unlocks the functionalization of a broad range of substrates, including electron-neutral and electron-poor rings. The resulting ortho-allylated iodoarenes are versatile building blocks, with examples of downstream transformation including a concise synthesis of the experimental antimitotic core of Dosabulin. DFT calculations shed additional light on the reaction mechanism, with notable aspects including the aromatic character of the transition-state structure for the [3,3] sigmatropic rearrangement, as well as the highly stereoconvergent nature of the trans-product formation.     

Combined Dynamic Kinetic Resolution and C−H Functionalization for Facile Synthesis of Non-Biaryl-Atropisomer-Type Axially Chiral Organosilanes

Although asymmetric C−H functionalization has been available for the synthesis of structurally diverse molecules, catalytic dynamic kinetic resolution (DKR) approaches to change racemic stereogenic axes remain synthetic challenges in this field. Here, a concise palladium-catalyzed DKR was combined with C−H functionalization involving olefination and alkynylation for the highly efficient synthesis of non-biaryl-atropisomer-type (NBA) axially chiral oragnosilanes. The chemistry proceeded through two different and distinct DKR: first, an atroposelective C−H olefination or alkynylation produced axially chiral vinylsilanes or alkynylsilanes as a new family of non-biaryl atropisomers (NBA), and second, the extension of this DKR strategy to twofold o,o′-C−H functionalization led to the multifunctional axially chiral organosilicon compounds with up to >99 % ee.     

Palladium-Catalyzed Synthesis of Benzophenanthrosilines by C−H/C−H Coupling through 1,4-Palladium Migration/Alkene Stereoisomerization

A new and efficient synthesis of 8H-benzo[e]phenanthro[1,10-bc]silines from 2-((2-(arylethynyl)aryl)silyl)aryl triflates under palladium catalysis has been developed. The reaction mechanism was experimentally investigated and a catalytic cycle involving C−H/C−H coupling through a new mode of 1,4-palladium migration with concomitant alkene stereoisomerization is proposed.     

Amine-Directed Palladium-Catalyzed C−H Halogenation of Phenylalanine Derivatives

An efficient primary-amine-directed, palladium-catalyzed C−H halogenation (X=I, Br, Cl) of phenylalanine derivatives is reported on a range of quaternary amino acid (AA) derivatives thanks to suitable conditions employing trifluoroacetic acid as additive. The extension of this original native functionality-directed ortho-selective halogenation was even demonstrated with the more challenging native phenylalanine as tertiary AA.     

RhIII-Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Rh^III-catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.     

Gold-Catalyzed C−H Functionalization Polycondensation for the Synthesis of Aromatic Polymers

Homogeneous gold (Au) complexes have demonstrated tremendous utility in modern organic chemistry; however, their application for the synthesis of polymers remains rare. Herein, we demonstrate the first catalytic application of Au complexes toward the polycondensation of alkyne-containing comonomers and heteroarene nucleophiles. Polymerization occurs through successive intermolecular hydroarylation reactions to produce high molecular weight aromatic copolymers with 1,1-disubstituted alkene backbone linkages. Clear correlations between the rate and degree of polymerization (DP) were established based on catalyst structure and counterion pairing, thus enabling polymerization reactions that proceeded with remarkable efficiency, high reactivity, and exceptional DPs. The reactivity is broad in scope, enabling the copolymerization of highly functionalized aromatic and aliphatic monomers. These results highlight the untapped utility of Au catalysis in providing access to new macromolecular constructs.     

Enantioselective Silylation of Aliphatic C−H Bonds for the Synthesis of Silicon-Stereogenic Dihydrobenzosiloles

A rhodium(I)-catalyzed enantioselective silylation of aliphatic C−H bonds for the synthesis of silicon-stereogenic dihydrobenzosiloles is demonstrated. This reaction involves a highly enantioselective intramolecular C(sp³)−H silylation of dihydrosilanes, followed by a stereospecific intermolecular alkene hydrosilylation leading to the asymmetrically tetrasubstituted silanes. A wide range of dihydrosilanes and alkenes displaying various functional groups are compatible with this process, giving access to a variety of highly functionalized silicon-stereogenic dihydrobenzosiloles in good to excellent yields and enantioselectivities.     

Enantioconvergent Palladium-Catalyzed Alkylation of Tertiary Allylic C−H Bonds

Enantioconvergent catalysis enables the conversion of racemic molecules into a single enantiomer in perfect yield and is considered an ideal approach for asymmetric synthesis. Despite remarkable advances in this field, enantioconvergent transformations of inert tertiary C−H bonds remain largely unexplored due to the high bond dissociation energy and the surrounding steric repulsion that pose unparalleled constraints on bond cleavage and formation. Here, we report an enantioconvergent Pd-catalyzed alkylation of racemic tertiary allylic C−H bonds of α-alkenes, providing a unique approach to access a broad range of enantioenriched γ,δ-unsaturated carbonyl compounds featuring quaternary carbon stereocenters. Mechanistic studies reveal that a stereoablative event occurs through the rate-limiting cleavage of tertiary allylic C−H bonds to generate σ-allyl-Pd species, and the achieved E/Z-selectivity of σ-allyl-Pd species effectively regulates the diastereoselectivity via a nucleophile coordination-enabled S_N2′-allylation pathway.     

Synthesis of Axially Chiral Biaryls through Cobalt(II)-Catalyzed Atroposelective C−H Arylation

Highly efficient synthesis of axially chiral biaryl amines through cobalt-catalyzed atroposelective C−H arylation using easily accessible cobalt(II) salt and salicyloxazoline ligand has been reported. This methodology provides a straightforward and sustainable access to a broad range of enantioenriched biaryl-2-amines in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). The synthetic utility of the unprecedented method is highlighted by its scalability and diverse transformations.     

Chiral Phosphoric Acid Catalyzed Atroposelective C−H Amination of Arenes

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C−H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C–N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C–N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.     

Palladium-Catalyzed Cascade C−H Functionalization/Asymmetric Allylation Reaction of Aryl α-Diazoamides and Allenes: Lewis Acid Makes a Difference

A Pd-catalyzed cascade C−H functionalization/asymmetric allylation reaction with aryl α-diazoamides and allenes has been developed. The reaction provides an efficient approach to construct chiral 3,3-disubstituted oxindole derivatives in high levels of yield and enantioselectivity (up to 93 % ee). Notably, the chromium complex works as Lewis acid to facilitate the formation of palladium carbene and to enhance acidity of carboxylic acid, allowing for higher stereochemical control and efficiency.     

Palladium-Catalyzed Enantioselective Isodesmic C−H Iodination of Phenylacetic Weinreb Amides

Isodesmic reactions represent mild alternatives to other chemical transformations that require harsh oxidizing agents or highly reactive intermediates. However, enantioselective isodesmic C−H functionalization is unknown and enantioselective direct iodination of inert C−H bond is very rare. Rapid synthesis of chiral aromatic iodides is of significant importance for synthetic chemistry. Herein, we report an unprecedented highly enantioselective isodesmic C−H functionalization to access chiral iodinated phenylacetic Weinreb amides via desymmetrization and kinetic resolution with Pd^II catalysis. Importantly, further transformations of the enantioenriched products are readily available at the iodinated or the Weinreb amide position, paving the way of related studies for synthetic and medicinal chemists.