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.
This tutorial review highlights the recent progress in copper-catalysed radical asymmetric 1,2-difunctionalization of alkenes.
Recently, with the boosted development of radical chemistry, enantioselective functionalization of C(sp
)-H bonds via a radical pathway has witnessed a renaissance. In principle, two distinct ...catalytic modes, distinguished by the steps in which the stereochemistry is determined (the radical formation step or the radical functionalization step), can be devised. This Perspective discusses the state-of-the-art in the area of catalytic enantioselective C(sp
)-H functionalization involving radical intermediates as well as future challenges and opportunities.
Radical‐involved enantioselective oxidative C−H bond functionalization by a hydrogen‐atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched ...products, while asymmetric C(sp3)−H bond amination remains a formidable challenge. To address this problem, described herein is a dual CuI/chiral phosphoric acid (CPA) catalytic system for radical‐involved enantioselective intramolecular C(sp3)−H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4‐methoxy‐NHPI (NHPI=N‐hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.
Radical control: The first radical‐involved intramolecular enantioselective oxidative C−H amination of not only allylic substrates, but also benzylic substrates, by a hydrogen atom transfer process with a CuI/chiral phosphoric acid catalytic system is reported. Critical to the success is the use of 4‐methoxy‐PINO as a stable and chemoselective hydrogen or.
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A copper‐catalyzed asymmetric radical oxytrifluoromethylation of alkenyl oxime and Togni's reagent has been successfully developed, thereby providing straightforward access to CF3‐containing ...isoxazolines bearing α‐tertiary stereocenters with excellent yield and enantioselectivity. The key to success is the rational design of cinchona‐alkaloid‐based sulfonamides as neutral/anionic hybrid ligands to effectively control the stereochemistry in copper‐catalyzed reactions involving free alkyl radical species. The utility of this method is illustrated by efficient transformation of the products into useful chiral CF3‐containing 1,3‐aminoalcohols.
Powerful hybrid ligand: Cinchona‐alkaloid‐based sulfonamides were designed as effective hybrid ligands for copper, which enabled catalytic asymmetric radical oxytrifluoromethylation of alkenyl oximes to give CF3‐containing isoxazolines bearing α‐tertiary stereocenters with excellent yield and enantioselectivity.
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Reported is a novel two‐step ring‐expansion strategy for expeditious synthesis of all ring sizes of synthetically challenging (hetero)aryl‐fused medium‐sized lactams from readily available ...5–8‐membered cyclic ketones. This step‐economic approach features a remote radical (hetero)aryl migration from C to N under visible‐light conditions. Broad substrate scope, good functional‐group tolerance, high efficiency, and mild reaction conditions make this procedure very attractive. In addition, this method also provides expedient access to 13–15‐membered macrolactams upon an additional one‐step manipulation. Mechanistic studies indicate that the reaction involves an amidyl radical and is promoted by acid.
Growth rings: A two‐step ring‐expansion strategy for expedient synthesis of all ring sizes of synthetically challenging (hetero)aryl‐fused medium‐sized lactams from readily available 5–8‐membered cyclic ketones has been developed. The key step involves an uncommon remote radical (hetero)aryl migration from C to N by C−C bond cleavage under irradiation with visible light.
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Conspectus Asymmetric 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.
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In contrast to the wealth of asymmetric transformations for generating central chirality from alkyl radicals, the enantiocontrol over the allenyl radicals for forging axial chirality represents an ...uncharted domain. The challenge arises from the unique elongated linear configuration of the allenyl radicals that necessitates the stereo‐differentiation of remote motifs away from the radical reaction site. We herein describe a copper‐catalyzed asymmetric radical 1,4‐carboalkynylation of 1,3‐enynes via the coupling of allenyl radicals with terminal alkynes, providing diverse synthetically challenging tetrasubstituted chiral allenes. A chiral N,N,P‐ligand is crucial for both the reaction initiation and the enantiocontrol over the highly reactive allenyl radicals. The reaction features a broad substrate scope, covering a variety of (hetero)aryl and alkyl alkynes and 1,3‐enynes as well as radical precursors with excellent functional group tolerance.
A copper‐catalyzed asymmetric radical 1,4‐carboalkynylation of 1,3‐enynes is realized, providing diverse tetrasubstituted chiral allenes. The utilization of the copper/chiral N,N,P‐ligand is crucial for the enantiocontrol over the allenyl radicals, which is difficult due to their elongated linear configuration that necessitates the stereo‐differentiation of remote motifs away from the reaction site.
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The mitomycins, a family of bioactive natural products, feature a compact 6/5/5‐fused polycyclic ring structure densely decorated with highly reactive and/or fragile quinone, amino ketal, and ...aziridine as well as carbamate moieties. It is this striking feature that has defeated numerous synthetic attempts towards these apparently small molecules, rendering them one of the most formidable targets for total synthesis. We herein report the first enantioselective synthesis of (+)‐mitomycin K, a representative of G series mitomycins. The key step of this synthesis is an enantioselective oxidative cyclization catalyzed by a palladium/(+)‐sparteine system that had previously been developed by our group. The robustness of this method bodes well for further applications in the asymmetric total synthesis of natural products, particularly those with characteristic 6/5/5‐fused pyrroloindole skeletons.
Finally enantioselective: Decades after its initial isolation, the first enantioselective synthesis of mitomycin K has been enabled by an asymmetric palladium‐catalyzed oxidative tandem cyclization that quickly forged the ring skeleton with high enantioselectivity. Subsequent multistep manipulations provided (+)‐mitomycin K with 97 % ee.
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We describe a photoinduced copper‐catalyzed asymmetric radical decarboxylative alkynylation of bench‐stable N‐hydroxyphthalimide(NHP)‐type esters of racemic alkyl carboxylic acids with terminal ...alkynes, which provides a flexible platform for the construction of chiral C(sp3)−C(sp) bonds. Critical to the success of this process are not only the use of the copper catalyst as a dual photo‐ and cross‐coupling catalyst but also tuning of the NHP‐type esters to inhibit the facile homodimerization of the alkyl radical and terminal alkyne, respectively. Owing to the use of stable and easily available NHP‐type esters, the reaction features a broader substrate scope compared with reactions using the alkyl halide counterparts, covering (hetero)benzyl‐, allyl‐, and aminocarbonyl‐substituted carboxylic acid derivatives, and (hetero)aryl and alkyl as well as silyl alkynes, thus providing a vital complementary approach to the previously reported method.
Two in one: A photoinduced asymmetric radical decarboxylative alkynylation of bench‐stable racemic carboxylic acid derivatives with easily available terminal alkynes provides expedient access to diverse enantioenriched alkynes. The chiral copper catalyst serves as a dual photo‐ and cross‐coupling catalyst to achieve stereocontrol over the highly reactive prochiral alkyl radical intermediates.
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The copper‐catalyzed enantioconvergent radical C(sp3)−C(sp2) cross‐coupling of tertiary α‐bromo‐β‐lactams with organoboronate esters could provide the synthetically valuable α‐quaternary β‐lactams. ...The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N‐ligand catalyst to forge the sterically congested chiral C(sp3)−C(sp2) bond via a single‐electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross‐coupling reactions.
Copper‐catalyzed enantioconvergent radical C(sp3)−C(sp2) cross‐coupling of tertiary alkyl bromides with organoboronate esters is developed to access synthetically valuable α‐quaternary chiral β‐lactams. The success of this work relies on the utilization of chiral N,N,N‐ligands to forge the sterically congested C(sp3)−C(sp2) bonds.
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