Conspectus 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-C 2-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.
Transition metal‐catalyzed enantioselective functionalization of C−H bond, the most abundant functionality in organic molecules, has emerged as an expedient synthetic approach to streamline the ...synthesis of complex chiral molecules. Despite significant progress, traditional directing group‐enabled strategies require additional steps for the installation and removal of directing groups from the target molecule. The recently developed asymmetric C−H functionalization using chiral transient directing groups (cTDGs) offers a promising alternative that can circumvent this obstacle and therefore simplify the process. In this Minireview, we briefly discuss the advent and recent advances of this emerging concept, with an emphasis on discussing the creation of various stereogenic centers and the developments of cTDGs. Applications in natural product synthesis and ligand derivatizations are also discussed. We hope this Minireview will highlight the great potential of this strategy and help to inspire further endeavors.
Chiral transient directing group (cTDG) strategies give rise to fundamentally new concepts in asymmetric C−H activation and enable the synthesis of chiral molecules without the need of pre‐installation and removal of directing groups. This Minireview provides an overview of recent advances in cTDG for the construction of chiral compounds with different types of chirality.
Improving the reactivity and selectivity is a long pursuing goal in C—H functionalization reactions. In line with this goal, a well‐designed bidentate 2‐(pyridine‐yl)isopropyl amine (PIP amine) ...directing group was developed by our group to achieve the activation of unbiased methylene C(sp3)–H activation, which also found its broad applications in C—H activation reactions catalyzed by base metals, such as Cu, Ni, Co and Fe, to form various C—C and C—X bonds. Moreover, PIP amine has also been applied in the strategic step toward the total synthesis of aeruginosin marine natural products. Its highly tunable structure has triggered the design of a series of chiral auxiliaries for diastereoselective C—H activation. More recently, Pd(II)‐catalyzed enantioselective functionalization of unbiased methylene C(sp3)–H bonds enabled by the cooperative effects between PIP amine and chiral ligands with axially chiral binaphthyl scaffold has also been realized. In this account, we briefly summaries the journey of developing PIP amine for C—H activation, from controlling the reactivity and regioselectivity to stereoselectivity.
The journey of developing PIP amine auxiliary for C—H activation, from controlling the reactivity and regioselectivity to stereoselectivity.
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).
No attachements: The title reaction employs tert‐leucine as a transient chiral auxiliary and provides efficient access to enantioenriched biaryls in good yields (up to 98 %) with excellent enantioselectivities (up 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 (up to >99 % ee, s‐factor up to 600).
The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C−H activation. Herein, we ...reported the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C−H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.
The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C−H activation. Herein, the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C−H olefination is reported. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee).
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 to >99 % 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.
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 with decent stereocontrols (up to >99 % ee and 70/1 dr) was reported. Atropisomerization experiments and DFT calculations are done to study the rotational barriers and pathways of the diaxes.
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(sp
)-H bonds
larger-membered metallacycles. Recent development to achieve remote C(sp
)-H functionalization
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(sp
)-H bonds.
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 atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the ...construction of axially chiral styrenes through PdII‐catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in CoIII‐catalyzed enantioselective C(sp3)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity‐determining step.
Axially chiral styrenes were constructed through a PdII‐catalyzed atroposelective C−H olefination with a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity. Carboxylic acid derivatives of these axially chiral styrenes showed superior enantiocontrol compared to the biaryl counterparts in CoIII‐catalyzed enantioselective C(sp3)−H amidation of ferrocenes.
Biaryl atropisomers are of great importance in natural products, pharmaceuticals, and asymmteric synthesis. The efficient synthesis of these chiral scaffolds with full enantiocontrol and high ...diversity remains challenging. Reported herein is a Pd‐catalyzed atroposelective C−H allylation with tert‐leucine as an efficient catalytic chiral transient auxiliary. A wide range of enantioenriched biaryl aldehydes were prepared in synthetically useful yields with excellent enantioselectivity (up to >99 % ee) through β‐O elimination. The reaction could be carried out on a gram scale without erosion of the ee value. A variety of axially chiral carboxylic acids could be obtained with high enantiopurity. The resulting axially chiral biaryl aldehydes and carboxylic acids might be used in asymmetric synthesis as chiral ligands and/or organocatalysts.
A Pd‐catalyzed atroposelective C−H allylation with allylic surrogates is reported. tert‐Leucine was identified as an efficient catalytic transient chiral auxiliary. A range of enantioenriched biaryls were prepared in synthetically useful yields with enantioselectivities up to >99 % ee through β‐O elimination. The reaction could be scaled up and the products could be further converted into enantiomerically pure axially chiral carboxylic acids.
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