Zhong‐Liang Li

The radical-involved 1,2-difunctionalization of alkenes has developed into a robust tool for preparation of complex organic molecules. Despite significant advances in this area, the catalytic asymmetric version still remains a challenging task mainly due to the difficulty in the stereocontrol of the highly reactive radical intermediates. Recently, owing to the good single-electron transfer ability and coordination with chiral ligands of copper catalysts, remarkable achievements in radical-involved asymmetric alkene difunctionalization have been made via synergistic combination of copper and chiral ligands. This tutorial review highlights the recent progress in copper-catalysed radical-involved asymmetric 1,2-difunctionalization of alkenes and the mechanistic scenarios governing the stereocontrol, with an emphasis on utilization of chiral ligands.

ConspectusAsymmetric functionalization of alkyl radicals represents a robust yet underdeveloped method for efficient construction and decoration of carbon skeletons in chiral organic molecules. In this field, we have been inspired by the excellent redox, alkyl radical trapping, and Lewis acidic properties of copper to develop several catalytic modes for asymmetric reactions involving alkyl radicals. At the beginning, we discovered tandem radical hydrotrifluoromethylation of unactivated alkenes and enantioselective alkoxylation of remote C(sp3)–H bonds by copper/chiral phosphate relay catalysis. This success has stimulated us to develop an asymmetric three-component 1,2-dicarbofunctionalization of 1,1-diarylalkenes using a similar strategy via radical intermediates. Meanwhile, we also discovered a copper/chiral secondary amine cooperative catalyst for asymmetric radical intramolecular cyclopropanation of alkenes using α-aldehyde methylene groups as C1 sources. The trapping of alkyl radical intermediates by CuII species during the reaction was essential for the chemoselectivity toward cyclopropanation.Encouraged by the efficient enantiocontrol with chiral phosphate and the effective trapping of alkyl radicals with CuII species, we then sought to develop copper/chiral phosphate as a single-electron-transfer catalyst for asymmetric reactions involving alkyl radicals. Subsequently, we successfully achieved a series of highly enantioselective 1,2-aminofluoroalkylation, -aminoarylation, -diamination, -aminosilylation, and -oxytrifluoromethylation of unactivated alkenes. The key for high enantioinduction was believed to be the effective trapping of alkyl radicals by CuII/chiral phosphate complexes. Besides, an achiral pyridine ligand was found to be indispensable for achieving high enantioselectivity, presumably via stabilization of CuIII species in the 1,2-alkoxytrifluoromethylation reaction. This discovery reminded us of tuning the redox properties and chemoreactivity of copper centers with an ancillary ligand. As a result, we subsequently identified cinchona alkaloid-derived sulfonamides as novel neutral-anionic hybrid ligands for simultaneous chemo- and enantiocontrol. We thus accomplished highly enantioselective 1,2-iminoxytrifluoromethylation of unactivated alkenes under the catalysis of copper/cinchona alkaloid-derived sulfonamide ligand, affording trifluoromethylated isoxazolines in high enantiomeric excess. Our copper-catalyzed asymmetric reactions with alkyl radicals provide expedient access to a diverse range of valuable chiral molecules with broad application potential in areas of organic synthesis, medicine, agrochemical, and material sciences.

A novel radical 1,2-formylfunctionalization of alkenes involving 1,2(4,5)-formyl migration triggered by addition of various carbon- and heteroatom-centered radicals to alkenes has been developed for the first time, thus providing straightforward access to diverse β-functionalized aldehydes with good efficiency, remarkable selectivity, and excellent functional group tolerance. Analogous transformations mediated by a keto-carbonyl migration have also been effected under similar conditions. This method was used to access ring systems including various benzannulated nine-, ten-, and eleven-membered rings, complex 6-5(6,7)-6(5) fused rings, and bridged rings with diverse functionalities.

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8-11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.