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Transition metal-catalyzed enantioselective C–H functionalization has emerged as an efficient and powerful strategy to access various chiral molecules. Recently, this strategy has also provided a complementary pathway to the construction of P- and S-stereogenic compounds. In this short review, we summarize the development and applications of various catalytic systems: Pd(II)/mono-N-protected amino acids (MPAA), Pd(0)/trivalent phosphorus chiral ligands, chiral cyclopentadienyl-ligated metal catalysts [CpxM(III)] (M = Rh, Ir), half-sandwich d6 Ir(III) and Ru(II) with a chiral carboxylic acid (CCA) ligand, Ir(I)/chiral bidentate boryl ligand, and Ir(I)/chiral cation, for accessing these chiral compounds via enantioselective C–H functionalization. 1 Introduction2 Pd(II)/Mono-N-protected Amino Acids3 Pd(0)/Trivalent Phosphorus Chiral Ligands4 Chiral Cyclopentadienyl-Ligated Metal Catalysts [CpxM(III)] (M = Rh, Ir)5 Half-sandwich d6 Ir(III) and Ru(II) with a Chiral Carboxylic Acid (CCA) Ligand6 Ir(I)/Chiral Bidentate Boryl Ligand7 Ir(I)/Chiral Cation8 Conclusion and Outlook

The first cobalt-catalyzed ortho-C–H allylation and acyloxylation of [2,2]paracyclophanes are reported.

Recent advances in transition-metal-catalyzed enantioselective desymmetric C–H functionalization are summarized.

A review of recent advances in the construction of racemic and chiral ferrocene derivatives via 3d transition metal-catalyzed C–H activation.

A Cp*Rh-catalyzed solvent-switched tunable [4 + 1]/[4 + 3] cyclization of free 1-naphthylamines with propargyl carbonates is developed, providing dihydrobenzo[cd]indoles and dihydronaphtho[1,8-bc]azepines in moderate to good yields and broad range of functional groups.

The merging of C–H and C–C bond cleavage into one single chemical process remains a daunting challenge, especially in an asymmetric manner. Herein, a Pd(II)-catalyzed enantioselective tandem C–H/C–...

Transition-metal-catalyzed, coordination-assisted C(sp3)-H functionalization has revolutionized synthetic planning over the past few decades as the use of these directing groups has allowed for increased access to many strategic positions in organic molecules. Nonetheless, several challenges remain preeminent, such as the requirement for high temperatures, the difficulty in removing or converting directing groups, and, although many metals provide some reactivity, the difficulty in employing metals outside of palladium. This review aims to give a comprehensive overview of coordination-assisted, transition-metal-catalyzed, direct functionalization of nonactivated C(sp3)-H bonds by covering the literature since 2004 in order to demonstrate the current state-of-the-art methods as well as the current limitations. For clarity, this review has been divided into nine sections by the transition metal catalyst with subdivisions by the type of bond formation. Synthetic applications and reaction mechanism are discussed where appropriate.

The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd(II)-catalyzed thioether-directed alkenyl C-H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.

A cobalt-catalyzed oxidative [4+2] annulation of benz­amides with dihydrofuran was developed for the expeditious synthesis of tetrahydrofuro[2,3-c]isoquinolinones. Commercially available and inexpensive Co(OAc)2·4H2O was used as an efficient catalyst. Various functional groups were tolerated, affording the desired products in good yields with excellent regioselectivity and good diastereoselectivity under mild conditions.

The atroposelective synthesis of atropisomers with vicinal diaxes remains rare and challenging, due to the steric influence between the two axes and their unique topology. Herein, we disclose a single-step construction of atropisomers with vicinal C-C and C-N chiral diaxes by cyclopentadiene (Cp)-free cobalt-catalyzed intramolecular atroposelective C-H annulation, providing the desired diaxial atropisomers of unique structures with decent stereocontrols of both axes (up to99 % ee and 70 : 1 dr). The optically pure products bearing fluorophores show circular polarized luminescence (CPL) properties, being candidate materials for potential CPL applications. Atropisomerization experiments and density function theory (DFT) calculations are conducted to study the rotational barriers and rotation pathways of the diaxes.

The past decade has witnessed a rapid progress in asymmetric C-H activation. However, the enantioselective C-H alkoxylation and amination with alcohols and free amines remains elusive. Herein, we disclose the first enantioselective dehydrogenative C-H alkoxylation and amination enabled by a simple cobalt/salicyloxazoline (Salox) catalysis. The use of cheap and readily available cobalt(II) salts as catalysts and Saloxs as chiral ligands provides an efficient method to access P-stereogenic compounds in excellent enantioselectivities (up to99 % ee). The practicality of this protocol is demonstrated by gram-scale preparation and further derivatizations of the resulting P-stereogenic phosphinamides, which offering a flexible asymmetric alternative to access P-stereogenic mono- and diphosphine chiral ligands. Preliminary mechanistic studies on the enantioselective C-H alkoxylation reaction suggest that a cobalt(III/IV/II) catalytic cycle might be involved.

A catalytic 1,2-oxyhalogenation method that converts non-conjugated internal alkynes into tetrasubstituted alkenes with high regio- and stereoselectivity is described. Mechanistically, the reaction involves a Pd(II)/Pd(IV) catalytic cycle that begins with a directed oxypalladation step. The origin of regioselectivity is the preference for formation of a six-membered palladacycle intermediate, which is facilitated by a N,N-bidentate 2-(pyridin-2-yl)isopropyl (PIP) amide directing group. Selectivity for C(alkenyl)–X versus –N (X = halide) reductive elimination from the Pd(IV) center depends on the identity of the halide anion; bromide and iodide engage in C(alkenyl)–X formation, while intramolecular C(alkenyl)–N reductive elimination occurs with chloride to furnish a lactam product. DFT calculations shed light on the origins of this phenomenon.

Directing group (DG) assistance provides a good solution to the problems of reactivity and selectivity, two of the fundamental challenges in C(sp3)-H activation. However, the activation of unbiased methylene C(sp3)-H bonds remains challenging due to the high heterolytic bond dissociation energy and substantial steric hindrance. Two main strategies have been developed thus far, that is, use of a strongly coordinating bidentate DG pioneered by Daugulis and use of a weakly coordinating monodentate DG accelerated by pyridine-type ligands, as disclosed by Yu. The seminal work by Daugulis sparked significant interest in the application of the monoanionic bidentate auxiliary in aliphatic C-H activation reactions. Our research has focused on enabling the divergent functionalization and enantiotopic differentiation of unactivated methylene C-H bonds. Inspired by the structure of bidentate 8-aminoquinoline and the accelerating effect of the gem-dimethyl moiety in cyclometalations, we developed a strongly coordinating bidentate 2-(pyridine-yl)isopropyl (PIP) amine DG consisting of a pyridyl group, a gem-dimethyl moiety, and an amino group, which enabled the divergent functionalization of unactivated β-methylene C(sp3)-H bonds to forge C-O, C-N, C-C, and C-F bonds with palladium catalysts. The exclusive β-selectivity was ascribed to the preferential formation of kinetically favored [5,5]-bicyclic palladacycle intermediates. DFT calculations revealed that the well-designed gem-dimethyl group was responsible for the lowered energy and compressed bite angle of the key transition state related to C-H cleavage.More recently, the combination of PIP amine with axially chiral ligands was found to promote asymmetric functionalization of unbiased methylene C(sp3)-H bonds, a challenging research topic in the area of C-H activation that remains to be addressed. Two different types of axially chiral ligands, namely, non-C2-symmetric chiral phosphoric acids (CPAs) and 3,3'-disubstituted BINOLs, have been developed. The former enabled Pd(II)-catalyzed inter- and intramolecular arylation of unbiased methylene C(sp3)-H bonds with high enantioselectivity, whereas the latter promoted a series of asymmetric functionalization reactions, such as alkynylation, arylation, alkenylation/aza-Wacker cyclization, and intramolecular amidation. The unexpectedly high stereocontrol compared with other bidentate DGs might be attributable to steric communication between the ligand and gem-dimethyl moiety of PIP amine. Thus far, the combination of PIP amine DG with 3,3'-disubstituted BINOL ligands is arguably the most general strategy for asymmetric functionalization of unbiased methylene C(sp3)-H bonds. Finally, the ease of installation and removal of PIP under mild conditions and synthetic applications are described.

Herein, the first Cp*Co(III)-catalyzed C-H allylation of ferrocene thioamides with allyl carbonates has been developed. This reaction is compatible with a wide range of functional groups, providing various allylated ferrocene derivatives in up to 90% yields. In addition, the C-H allylation protocol is also compatible with the use of vinylcyclopropanes as allylating reagents by merging C-H and C-C activation into one catalytic system. Mechanistic studies revealed that the thiocarbonyl-directing group plays a vital role in C-H activation.

γ-Lactam containing α,β-contiguous stereogenic centers stands out as a pivotal motif in various bioactive compounds, while its efficient synthesis still needs to be enhanced. Herein, an asymmetric C-H activation strategy for accessing α,β-stereospecific γ-lactams in good yields (≤79%) with high enantio- and diastereoselectivities (≤96% ee and >20:1 dr) was described, which serves as an effective supplement to the existing strategies.

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure. However, the lack of an efficient strategy for the synthesis of structurally diverse chiral peptoids has hampered the studies. Herein, we report the efficient synthesis of a wide variety of N-aryl peptoid atropisomers in good yields with excellent enantioselectivities (up to 99% yield and 99% ee) by palladium-catalyzed asymmetric C–H alkynylation. The inexpensive and commercially available l-pyroglutamic acid was used as an efficient chiral ligand. The exceptional compatibility of the C–H alkynylation with various peptoid oligomers renders this procedure valuable for peptoid modifications. Computational studies suggested that the amino acid ligand distortion controls the enantioselectivity in the Pd/l-pGlu-catalyzed C–H bond activation step., The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure.

Palladium-catalyzed asymmetric functionalization of unbiased methylene C(sp3)-H bonds is a long-standing challenge. Here, we report a Pd(ii)-catalyzed highly enantioselective arylation of unbiased methylene C(sp3)-H bonds enabled by a strongly coordinating bidentate 2-pyridinylisopropyl (PIP) directing group and an easily accessible 3,3'-F2-BINOL chiral ligand. The use of aryl iodides with the combination of 3,3'-F2-BINOL was beneficial for high enantiocontrol. A range of aliphatic amides and aryl iodides were tolerated, providing the desired arylated products in high enantioselectivities (up to 96% ee). The PIP directing group could be removed under mild conditions without erosion of enantiopurity.

Herein, we report a Pd(II)-catalyzed asymmetric intramolecular arylation of unbiased methylene C(sp3)–H bonds using 2-pyridylisopropyl (PIP) as a directing group and readily accessible 3,3′-F2-BINOL as a chiral ligand. The reaction provided a straightforward and efficient strategy to access various chiral benzo-fused six-membered heterocyclic compounds with excellent yields (up to 99%) and enantioselectivities (up to 97%). The PIP directing group could be removed under mild conditions without the loss of enantiopurity.

The asymmetric formal synthesis of (−)-tetrazomine is described. Key features of the synthesis include the efficient synthesis of (2S,3R)-3-hydroxypipecolic acid via a Pd(II)-catalyzed methylene C(sp3)–H acetoxylation, the stereoselective construction of the tetrahydroisoquinoline skeleton via Pd(II)-catalyzed C(sp3)–H monoarylation and Pictet–Spengler reactions, and a Cu(I)-catalyzed exo-selective asymmetric [C + NC + CC] coupling reaction to build the chiral pyrrolidine scaffold.

7-Deoxycylindrospermopsin is a member of cylindrospermopsin marine alkaloid containing a cyclic guanidine group. Herein, we present a concise formal total synthesis of (±)-7-deoxycylindrospermopsin in 14 steps from commercailly available 4-methoxypyridine. Key features of our synthetic route include the elaboration of densely functionalized piperidine via 1,4-addition of propargylindium to enone, Sonogashira coupling to attach the pyrimidine moiety, and intramolecular conjugate addition of guanidine with alkyne to form C ring. The synthesis of its 8-epi isomer was also achieved following the same synthetic strategy.

Indole 2,5-diketopiperazines (DKPs) are an important type of metabolic cyclic dipeptides containing a tryptophan (Trp) unit possessing a range of interesting biological activities. The intriguing structural features and divergent activities have stimulated tremendous efforts towards their efficient synthesis. Herein, we report the development of a unified strategy for the synthesis of three Trp-containing DKPs, namely tryprostatin A, and maremycins A and B, via a sequential C–H activation strategy. The key Trp skeletons were synthesized from the inexpensive, readily available alanine via a Pd(ii)-catalyzed β-methyl C(sp3)–H monoarylation. A subsequent C2-selective prenylation of the resulting 6-OMe-Trp by Pd/norbornene-promoted C–H activation led to the total synthesis of tryprostatin A in 12 linear steps from alanine with 25% overall yield. Meanwhile, total syntheses of maremycins A and B were successfully accomplished using a sequential Pd-catalyzed methylene C(sp3)–H methylation as the key step in 15 linear steps from alanine., Indole 2,5-diketopiperazines (DKPs) are an important type of metabolic cyclic dipeptides containing a tryptophan (Trp) unit possessing a range of interesting biological activities.

The asymmetric synthesis of chiral benzo-ring containing compounds through enantioselective intramolecular arylation of unbiased methylene C(sp3)-H bonds was reported. Judicious choice of non-C2-symmetric chiral phosphoric acid (CPA) ligand is crucial for the high reactivity and enantioselectivity. The slight decrease in enantioselectivity at the late stage of the reaction was attributed to the hydrolysis of CPA ligands to the corresponding BINOL.

Directing group assistance provided a paradigm for controlling site-selectivity in transition metal-catalyzed C–H functionalization reactions. However, the kinetically and thermodynamically favored formation of 5-membered metallacycles has greatly hampered the selective activation of remote C(sp3)–H bonds via larger-membered metallacycles. Recent development to achieve remote C(sp3)–H functionalization via the C–H metallation process largely relies on employing specific substrates without accessible proximal C–H bonds. Encouragingly, recent advances in this field have enabled the selective functionalization of remote aliphatic C–H bonds in the presence of equally accessible proximal ones by taking advantage of the switch of the regiodetermining step, ring strain of metallacycles, multiple non-covalent interactions, and favourable reductive elimination from larger-membered metallacycles. In this review, we summarize these advancements according to the strategies used, hoping to facilitate further efforts to achieve site- and even enantioselective functionalization of remote C(sp3)–H bonds., Recent advances in site-selective functionalization of remote aliphatic C–H bonds in organometallic pathways are summarized.

Herein, we report a Pd(II)-catalyzed nitrooxylation of unactivated methyl C(sp3)-H bonds using commercial available and easily manageable tert-butyl nitrite as the precursor of ONO2 radical under aerobic conditions. Environmentally benign molecular oxygen is used to initiate the generation of active radical reactant; it is also used as the terminal oxidant. A broad range of nitrooxylated aliphatic carboxamides were prepared in moderate to good yields under mild conditions.

Previous methods on Co

Bingfeng Shi (professor and vice dean of the Department of Chemistry at Zhejiang University) and Francoise Colobert (professor at the University of Strasbourg) discuss dynamic kinetic resolution via C–H functionalization as a strategy for controlling the C–N atropisomeric axis of preformed C–N bonds.

Francoise Colobert (professor at the University of Strasbourg) and Bingfeng Shi (professor and vice dean of the Department of Chemistry at Zhejiang University) introduce a new method of generating C–N atropisomeric compounds and discuss the challenges associated with the efficiency and stereoinduction during this coupling of two sterically hindered precursors.