Enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles

Zishuo Zhang, Jintong Zhang, Quan Gao, Yu Zhou, Mingyu Yang, Haiqun Cao, Tingting Sun, Gen Luo () and Zhi-Chao Cao ()
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Zishuo Zhang: Anhui Agricultural University
Jintong Zhang: Anhui Agricultural University
Quan Gao: Anhui Agricultural University
Yu Zhou: Anhui University
Mingyu Yang: Shaanxi Normal University
Haiqun Cao: Anhui Agricultural University
Tingting Sun: Anhui Agricultural University
Gen Luo: Anhui University
Zhi-Chao Cao: Anhui Agricultural University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Nonpolar alkyl moieties, especially methyl group, are frequently used to modify bioactive molecules during lead optimization in medicinal chemistry. Thus transition-metal catalyzed alkylative cross-coupling reactions by using readily available and environmentally benign C–O electrophiles have been established as powerful tools to install alkyl groups, however, the C(sp3)–C(sp2) cross-coupling via asymmetric activation of aromatic C–O bond for the synthesis of alkylated chiral compounds remains elusive. Here, we unlock a C(sp3)–C(sp2) cross-coupling via enantioselective activation of aromatic C–O bond for the efficient synthesis of versatile axially chiral 2-alkyl-2’-hydroxyl-biaryl compounds. By employing a unique chiral N-heterocyclic carbene ligand, this transformation is accomplished via nickel catalysis with good enantiocontrol. Mechanistic studies indicate that bis-ligated nickel complexes might be formed as catalytically active species in the enantioselective alkylative cross-coupling. Moreover, further derivation experiments suggest this developed methodology holds great promise for complex molecule synthesis and asymmetric catalysis.

Date: 2022
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DOI: 10.1038/s41467-022-30693-x

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