beta-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-atalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight

Chang, Xin1,2; Yang, Yuhong3,4,5; Shen, Chong1; Xue, Kun-Shan1; Wang, Zuo-Fei1; Cong, Hengjiang1; Tao, Hai-Yan1; Chung, Lung Wa3,4; Wang, Chun-Jiang1,2

2021-03-10

10.1021/jacs.0c12911

Journal of the American Chemical Society   影响因子和分区

0002-7863

1520-5126

The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various beta-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal C = C bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

SCI ; EI

英语

NI期刊

通讯

NSFC[21525207,21672096,21772147,21933003,220711186] ; Huibei Province NSF[2020CFA036] ; Guangdong Provincial Key Laboratory of Catalysis[2020B121201002] ; Shenzhen Municipal Science and Technology Innovation Committee[JCYJ20170817104736009] ; Shenzhen Peacock Program[KQTD20150717103157174]

Chemistry

Chemistry, Multidisciplinary

WOS:000629075900029

AMER CHEMICAL SOC

20211410176681

Catalysis ; Chemical activation ; Cycloaddition ; Density functional theory ; Enantioselectivity ; Metal working ; Olefins ; Organic polymers ; Polyols ; Stereochemistry ; Stereoselectivity ; Substrates ; Synthesis (chemical)

Metal Forming Practice:535.2.2 ; Chemistry:801 ; Physical Chemistry:801.4 ; Chemical Reactions:802.2 ; Organic Compounds:804.1 ; Organic Polymers:815.1.1 ; Probability Theory:922.1

Web of Science

1.Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China
2.Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Grubbs Inst, Dept Chem, Shenzhen 518055, Peoples R China
4.Southern Univ Sci & Technol, Guangdong Prov Key Lab Catalysis, Shenzhen 518055, Peoples R China
5.Harbin Inst Technol, Sch Chem & Chem Engn, Harbin 150001, Peoples R China

Chang, Xin,Yang, Yuhong,Shen, Chong,et al. beta-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-atalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight[J]. Journal of the American Chemical Society,2021,143(9):3519-3535.

Chang, Xin.,Yang, Yuhong.,Shen, Chong.,Xue, Kun-Shan.,Wang, Zuo-Fei.,...&Wang, Chun-Jiang.(2021).beta-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-atalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight.Journal of the American Chemical Society,143(9),3519-3535.

Chang, Xin,et al."beta-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-atalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight".Journal of the American Chemical Society 143.9(2021):3519-3535.