Formal enantioconvergent substitution of alkyl halides via catalytic asymmetric photoredox radical coupling

• Published in: Nature communications Vol. 9; no. 1; pp. 2445 - 9
• Main Authors: Li, Jiangtao, Kong, Manman, Qiao, Baokun, Lee, Richmond, Zhao, Xiaowei, Jiang, Zhiyong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-06-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/77/883; 639/638/77/889; 639/638/77/890; Amino acids; Aromatic compounds; Asymmetry; Carbon; Catalysis; Catalysts; Chemical reactions; Coupling (molecular); Cross coupling; Enantiomers; Halides; Humanities and Social Sciences; Ketones; Light; Molecular chains; multidisciplinary; Nucleophiles; Organic chemistry; Phosphoric acid; Radicals; Science; Science (multidisciplinary); Stereochemistry; Substitution reactions
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04885-3

Classic nucleophilic substitution reactions (S
N
1 and S
N
2) are not generally amenable to the enantioselective variants that use simple and racemic alkyl halide electrophiles. The merging of transition metal catalysis and radical chemistry with organometallic nucleophiles is a versatile method for addressing this limitation. Here, we report that visible light-driven catalytic asymmetric photoredox radical coupling can act as a complementary and generic strategy for the enantioconvergent formal substitution of alkyl haldies with readily available and bench-stable organic molecules. Single-electron reductive debrominations of racemic α-bromoketones generate achiral alkyl radicals that can participate in asymmetric C
sp3
–C
sp3
bonds forming cross-coupling reactions with α-amino radicals derived from
N
-aryl amino acids. A wide range of valuable enantiomerically pure β
2
- and β
2,2
-amino ketones were obtained in satisfactory yields with good-to-excellent enantioselectivities by using chiral phosphoric acid catalysts to control the stereochemistry and chemoselectivity. Fluoro-hetero-quaternary and full-carbon quaternary stereocenters that are challenging to prepare were successfully constructed.
Enantioselective substitution reactions of racemic alkyl halides are inherently limited by the specificity of their stereochemical course (S
N
1 or S
N
2). Here, the authors report a radical coupling strategy for the enantioselective aminoalkylation of α-bromoketones for modular, highly enantioselective C
sp3
−C
sp3
bond formation.