The first-row transition-metal-catalyzed asymmetric C(sp3)–C cross-coupling represents a powerful approach in the expedient synthesis of enantioenriched molecules. Recently, a series of chiral ...copper catalysts have been designed to promote a variety of asymmetric radical C(sp3)–C cross-coupling reactions with high efficiency and enantioselectivity. The key to success is the design of chiral ligands to initiate the reaction and achieve enantiocontrol over the highly reactive prochiral alkyl radical species. This Perspective will discuss the impressive advances and provide an outlook on the direction of further development.
Transition‐metal catalyzed enantioconvergent cross‐coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α‐disubstituted amino acids. However, the construction ...of chiral C−N bonds between tertiary‐carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper‐catalyzed enantioconvergent radical C−N cross‐coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N‐ligand with a long spreading side arm. An array of α,α‐disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α‐fully substituted amine building blocks.
A copper‐catalyzed enantioconvergent radical C−N cross‐coupling of tertiary alkyl halides with sulfoximines (as ammonia surrogates) was realized by employing a chiral anionic N,N,N‐ligand with a long spreading side arm under mild conditions. An array of valuable α,α‐disubstituted amino acids could be furnished with good efficiency (up to 95 % yield) and enantioselectivity (up to >99 % ee).
A copper-catalyzed intermolecular three-component asymmetric radical 1,2-carboalkynylation of alkenes has been developed, providing straightforward access to diverse chiral alkynes from readily ...available alkyl halides and terminal alkynes. The utilization of a cinchona alkaloid-derived multidentate N,N,P-ligand is crucial for the efficient radical generation from mildly oxidative precursors by copper and the effective inhibition of the undesired Glaser coupling side reaction. The substrate scope is broad, covering (hetero)aryl-, alkynyl-, and aminocarbonyl-substituted alkenes, (hetero)aryl and alkyl as well as silyl alkynes, and tertiary to primary alkyl radical precursors with excellent functional group compatibility. Facile transformations of the obtained chiral alkynes have also been demonstrated, highlighting the excellent complementarity of this protocol to direct 1,2-dicarbofunctionalization reactions with C(sp 2/sp 3)-based reagents.
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•Trifluoromethylation of alkenes has long been the interest of synthetic chemists.•This digest focuses on racemic amino- and azidotrifluoromethylation of alkenes.•Recent breakthrough ...on asymmetric aminotrifluoromethylation was highlighted.
Trifluoromethylation of alkenes has long been the interest of synthetic chemists. It is not only because of the great importance of F-containing compounds, but also on account of the pleasure of cracking the challenges in methodology development in this field. In particular, amino- and azidotrifluoromethylation of alkenes have recently been developing in a fast speed. This digest mainly deals with this advancement in racemic copper- and photocatalyzed amino- and azidotrifluoromethylation of alkenes while giving special highlight on our recent breakthrough on the copper-catalyzed asymmetric aminotrifluoromethylation reaction.
We have described a copper-catalyzed radical 1,2-carbotrifluoromethylselenolation of alkenes using the readily available alkyl halides and (Me
N)SeCF
salt. Critical to the success is the use of a ...proline-based N,N,P-ligand to enhance the reducing capability of copper for easy conversion of diverse alkyl halides to the corresponding radicals via a single-electron transfer process. The reaction features a broad substrate scope, including various mono-, di-, and trisubstituted alkenes with many functional groups.
The copper-catalyzed enantioselective intermolecular radical 1,2-carboamination of alkenes with readily accessible alkyl halides is an appealing strategy for producing chiral amine scaffolds. The ...challenge arises from the easily occurring atom transfer radical addition between alkyl halides and alkenes and the issue of enantiocontrol. We herein describe a radical alkene 1,2-carboamination with sulfoximines in a highly chemo- and enantioselective manner. The key to the success of this process is the conceptual design of a counterion/highly sterically demanded ligand coeffect to promote the ligand exchange of copper(I) with sulfoximines and forge chiral C–N bonds between alkyl radicals and the chiral copper(II) complex. The reaction covers alkenes bearing distinct electronic properties, such as aryl-, heteroaryl-, carbonyl-, and aminocarbonyl-substituted ones, and various radical precursors, including alkyl chlorides, bromides, iodides, and the CF3 source. Facile transformations deliver many chiral amine building blocks of interest in organic synthesis and related areas.
The development of a general catalytic method for the direct and stereoselective construction of cyclopropanes bearing highly congested vicinal all-carbon quaternary stereocenters remains a ...formidable challenge in chemical synthesis. Here, we report an intramolecular radical cyclopropanation of unactivated alkenes with simple α-methylene group of aldehydes as C1 source via a Cu(I)/secondary amine cooperative catalyst, which enables the single-step construction of bicyclo3.1.0hexane skeletons with excellent efficiency, broad substrate scope covering various terminal, internal alkenes as well as diverse (hetero)aromatic, alkenyl, alkyl-substituted geminal alkenes. Moreover, this reaction has been successfully realized to an asymmetric transformation, providing an attractive approach for the construction of enantioenriched bicyclo3.1.0hexanes bearing two crucial vicinal all-carbon quaternary stereocenters with good to excellent enantioselectivity. The utility of this method is illustrated by facile transformations of the products into various useful chiral synthetic intermediates. Preliminary mechanistic studies support a stepwise radical process for this formal 2 + 1 cycloaddition.
α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The ...enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)–N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C–N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenriched N-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon–heteroatom formation strategy.
Chiral amines are commonly used in the pharmaceutical and agrochemical industries
. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods
. Although ...the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version
. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.
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