Transition-metal-catalyzed enantioselective C-H functionalization has become a powerful strategy for the formation of C-C or C-X bonds, enabling the highly asymmetric synthesis of a wide range of enantioenriched compounds. Atropisomers are widely found in natural products and pharmaceutically relevant molecules, and have also found applications as privileged frameworks for chiral ligands and catalysts. Thus, research into asymmetric routes for the synthesis of atropisomers has garnered great interest in recent years. In this regard, transition-metal-catalyzed enantioselective C-H functionalization has emerged as an atom-economic and efficient strategy toward their synthesis. In this Perspective, the approaches for the synthesis of atropisomers by transition-metal-catalyzed asymmetric C-H functionalization reactions are summarized. The main focus here is on asymmetric catalysis via Pd, Rh, and Ir complexes, which have been the most frequently utilized catalysts among reported enantioselective C-H functionalization reactions. Finally, we discuss limitations on available protocols and give an outlook on possible future avenues of research.

Synthesis of Atropisomers by Transition-Metal-Catalyzed Asymmetric C-H Functionalization Reactions.

Recent Progress toward the Construction of Axially Chiral Molecules Catalyzed by an N-heterocyclic Carbene

In recent years, transition-metal-catalyzed enantioselective C–H bond functionalization has emerged as a powerful and attractive synthetic approach to access silicon-stereogenic centers, which continues to give impetus for the innovation of chiral organosilicon chemistry. This short review is aimed to summarize recent advances in the construction of silicon-stereogenic silanes via transition-metal-catalyzed enantioselective C–H functionalization. We have endeavored to highlight the great potential of this methodology and hope that this review will shed light on new perspectives, inspire further research in this emerging area.

Enantioselective C–H Functionalization toward Silicon-Stereogenic Silanes

The development of a straightforward strategy to obtain enantioenriched silicon-stereogenic benzosiloles remains a challenging yet appealing synthesis venture due to their potential future application in chiral electronic and optoelectronic devices. In this context, all of the existing methods rely on Rh-catalyzed systems and are somewhat limited in scope. Herein, we disclose the first Ni0 -catalyzed ring expansion process that enables the preparation of benzosiloles possessing tetraorganosilicon stereocenters in excellent yields and enantioselectivities. The presented catalysis strategy is further applied to the asymmetric synthesis of silicon-stereogenic bis-silicon-bridged π-extended systems. Preliminary studies reveal that such compounds exhibit fluorescence emission, Cotton effects and circularly polarized luminescence (CPL) activity.

Nickel(0)-Catalyzed Asymmetric Ring Expansion Toward Enantioenriched Silicon-Stereogenic Benzosiloles.

Axially chiral biaryls and heterobiaryls constitute the most represented subclass of atropisomers with prevalence in natural products, bioactive compounds, privileged chiral ligand/catalysts, and optically pure materials. Despite many ionic protocols for their construction, radical-based variants represent another highly desirable and intriguing strategy but are far less developed. Moreover, efficient synthesis of axially chiral heterobiaryl molecules, especially ones having multiple heteroatoms and other types of chiral elements, through radical routes remains extremely limited. We herein disclose the first catalytic asymmetric, metal-free construction of axially and centrally chiral heterobiaryls by Minisci reaction of 5-arylpyrimidines and α-amino acid-derived redox-active esters. This is enabled by the use of 4CzIPN as an organic photoredox catalyst in conjunction with a chiral phosphoric acid catalyst. The reaction achieved a variety of interesting 5-arylpyrimidines featuring the union of an axially chiral heterobiaryl and a centrally chiral α-branched amine with generally excellent regio-, diastereo-, and enantioselectivity (up to 82% yield; >19:1 dr; >99% ee). This finding also builds up a new platform for the development of desymmetrization methods via radical-involved atroposelective functionalization at heteroarene of prochiral heterobiaryls. 

Catalytic Asymmetric Construction of Axially and Centrally Chiral Heterobiaryls by Minisci Reaction

A Rh-catalyzed asymmetric synthesis of silicon-stereogenic dihydrodibenzosilines featuring axially chiral 6-membered bridged biaryls is demonstrated. In the presence of a RhI catalyst with a chiral diphosphine ligand, a wide range of dihydrodibenzosilines containing both silicon-central and axial chiralities are conveniently constructed in excellent enantioselectivities via dehydrogenative C(sp3 )-H silylation. Absolute configuration analysis by single-crystal X-ray structures revealed a novel silicon central-to-axial chirality relay phenomenon, which we believe will inspire further research in the field of asymmetric catalysis and chiroptical materials.

Catalytic Asymmetric Synthesis of Silicon-Stereogenic Dihydrodibenzosilines: Silicon Central-to-Axial Chirality Relay.

Despite a growing progress for the construction of chiral organosilicon compounds, the catalytic asymmetric synthesis of silicon-stereogenic silanols is less explored and remains a considerable challenge. Herein, we report the first enantioselective construction of silicon-stereogenic silanols via catalytic asymmetric hydrolytic oxidation of dihydrosilanes. This practical protocol features ambient reaction conditions, high atom economy, good functional-group compatibility, and cleaner manner with H2 as the only by-product, producing a wide range of valuable chiral silanols and bis-silanols in decent yields with excellent chemo- and stereoselectivity.

Synthesis of Si-Stereogenic Silanols by Catalytic Asymmetric Hydrolytic Oxidation.

An efficient electrochemical radical silyl-oxygenation of electron-deficient alkenes is demonstrated, which gives access to a variety of new highly functionalized silicon-containing molecules, including β-silyl-cyanohydrin derivatives in good yields with excellent chemo- and regio-selectivity. This electrochemical radical silylation process conducts under mild conditions without the use of transition metal catalyst or chemical oxidant and exhibits a wide scope of substrate silanes with high functional-group tolerance. The ability to access silyl radicals using electrochemical Si-H activation offers new perspectives for the synthesis of valuable organosilicon compounds in a sustainable and green manner.

Electrochemical Radical Silyl-Oxygenation of Activated Alkenes.

Despite a growing progress for the construction of chiral organosilicon compounds, the catalytic asymmetric synthesis of silicon-stereogenic silanols is less explored and remains a considerable challenge. Herein, we report the first enantioselective construction of silicon-stereogenic silanols via catalytic asymmetric hydrolytic oxidation of dihydrosilanes. This practical protocol features ambient reaction conditions, high atom economy, good functional-group compatibility, and cleaner manner with H2 as the only by-product, producing a wide range of valuable chiral silanols and bis-silanols in decent yields with excellent chemo- and stereoselectivity. 

Xujiang Zhu

Papers

Catalytic Asymmetric Synthesis of Silicon-Stereogenic Dihydrodibenzosilines: Silicon Central-to-Axial Chirality Relay.

Synthesis of Si-Stereogenic Silanols by Catalytic Asymmetric Hydrolytic Oxidation.

Electrochemical Radical Silyl-Oxygenation of Activated Alkenes.

Synthesis of Si‐Stereogenic Silanols by Catalytic Asymmetric Hydrolytic Oxidation