The enantioconvergent cross-coupling of racemic alkyl halides represents a powerful tool for the synthesis of enantioenriched molecules. In this regard, the first-row transition metal catalysis provides a suitable mechanism for stereoconvergence by converting racemic alkyl halides to prochiral radical intermediates owing to their good single-electron transfer ability. In contrast to the noble development of chiral nickel catalyst, copper-catalyzed enantioconvergent radical cross-coupling of alkyl halides is less studied. Besides the enantiocontrol issue, the major challenge arises from the weak reducing capability of copper that slows the reaction initiation. Recently, significant efforts have been dedicated to basic research aimed at developing chiral ligands for copper-catalyzed enantioconvergent radical cross-coupling of racemic alkyl halides. This perspective will discuss the advances in this burgeoning area with particular emphasis on the strategic chiral anionic ligand design to tune the reducing capability of copper for the reaction initiation under thermal conditions from our research group.

Ligand Development for Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Racemic Alkyl Halides.

Photocatalysis opens up a new window for carbonyl chemistry. Despite a multitude of photochemical reactions of carbonyl compounds, visible light-induced catalytic asymmetric transformations remain elusive and pose a formidable challenge. Accordingly, the development of simple, efficient, and economic catalytic systems is the ideal pursuit for chemists. Herein, we report an enantioselective radical photoaddition to ketones through a Lewis acid-enabled photoredox catalysis wherein the in situ formed chiral N,N'-dioxide/Sc(III)-ketone complex serves as a temporary photocatalyst to trigger single-electron transfer oxidation of silanes for the generation of nucleophilic radical species, including primary, secondary, and tertiary alkyl radicals, giving various enantioenriched aza-heterocycle-based tertiary alcohols in good to excellent yields and enantioselectivities. The results of electron paramagnetic resonance (EPR) and high-resolution mass spectrum (HRMS) measurements provided favorable evidence for the stereocontrolled radical addition process involved in this reaction.

Enantioselective Radical Addition to Ketones through Lewis Acid-Enabled Photoredox Catalysis.

http://sioc-journal.cn/Jwk_yjhx/EN/article/downloadArticleFile.do?attachType=PDF&id=349078

Asymmetric Photocatalytic Synthesis of Enantioenriched Azaarene Derivatives

The emergence of modern photocatalysis, characterized by mildness and selectivity, has significantly spurred innovative late-stage C-H functionalization approaches that make use of low energy photons as a controllable energy source. Compared to traditional late-stage functionalization strategies, photocatalysis paves the way toward complementary and/or previously unattainable regio- and chemoselectivities. Merging the compelling benefits of photocatalysis with the late-stage functionalization workflow offers a potentially unmatched arsenal to tackle drug development campaigns and beyond. This Review highlights the photocatalytic late-stage C-H functionalization strategies of small-molecule drugs, agrochemicals, and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted to identifying, describing, and comparing the main mechanistic scenarios. The Review draws a critical comparison between established ionic chemistry and photocatalyzed radical-based manifolds. The Review aims to establish the current state-of-the-art and illustrate the key unsolved challenges to be addressed in the future. The authors aim to introduce the general readership to the main approaches toward photocatalytic late-stage C-H functionalization, and specialist practitioners to the critical evaluation of the current methodologies, potential for improvement, and future uncharted directions.

Photocatalytic Late-Stage C-H Functionalization.

The potential of electron donor–acceptor (EDA) complex photochemistry has recently been recognized in visible-light-induced photocatalyst-free radical reactions. The design of catalytic asymmetric reactions driven by EDA complexes remains a substantial challenge, and existing examples are limited to sole activation modes with aminocatalysts or phase-transfer catalysts. Herein, we demonstrate that chiral bifunctional hydrogen-bonding catalysis can realize the asymmetric reaction of an EDA complex via dual activation modes and afford vicinal tertiary stereocenters at the β,γ-positions of pyridines in high yields with good enantio- and diastereoselectivities. Mechanistic studies suggest that the crucial success factor for this transformation is the use of chiral phosphoric acid (CPA), which not only accelerates the in situ formation of EDA aggregates between redox-active esters (RAEs) and Hantzsch esters (HEs) but also provides proper substrate activation and asymmetric induction. 

Enantioselective Hydroalkylation of Alkenylpyridines Enabled by Merging Photoactive Electron Donor–Acceptor Complexes with Chiral Bifunctional Organocatalysis

Ming-Yu Ngai

Papers

Asymmetric Photocatalysis Enabled by Chiral Organocatalysts