Synergetic iridium and amine catalysis enables asymmetric [4+2] cycloadditions of vinyl aminoalcohols with carbonyls

Mao-Mao Zhang,Liang-Qiu Lu,Ya-Ni Wang,Wen-Jing Xiao,Bao-Cheng Wang,Xiao-Wang Chen

doi:10.1038/s41467-019-10674-3

Abstract

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles. However, within the field of palladium catalysis, compared with the well-developed normal electron-demand cycloadditions with electrophilic dipolarophiles, a general strategy for inverse electron-demand ones with nucleophilic dipolarophiles remains elusive, due to the inherent linear selectivity in the key palladium-catalyzed intermolecular allylations. Herein, based on the switched regioselectivity of iridium-catalyzed allylations, we achieved two asymmetric [4+2] cycloadditions of vinyl aminoalcohols with aldehydes and β,γ-unsaturated ketones through synergetic iridium and amine catalysis. The activation of vinyl aminoalcohols by iridium catalysts and carbonyls by amine catalysts provide a foundation for the subsequent asymmetric [4+2] cycloadditions of the resulting iridium-containing 1,4-dipoles and (di)enamine dipolarophiles. The former provides a straightforward route to a diverse set of enantio-enriched hydroquinolines bearing chiral quaternary stereocenters, and the later represent an enantio- and diastereodivergent synthesis of chiral hydroquinolines.

Highlights

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles
Among the continuing and productive efforts, catalytic asymmetric cycloadditions via transition metal (TM)-containing dipolar intermediates have been determined to be powerful tools for this purpose[3,4,5]. Within this realm of palladium catalysis, many impressive advancements have been made regarding cycloadditions of Pd-containing dipolar intermediates with electrophilic dipolarophiles (Fig. 1a, path a: normal electron-demand cycloadditions)[6,7,8,9,10,11,12], the inherent linear selectivity of Pd-catalyzed intermolecular allylic alkylation (AA) reactions renders the development of a general strategy for the coupling of such intermediates with nucleophilic dipolarophiles a formidable task (Fig. 1a, path b: inverse electron-demand cycloaddition)[13,14]
Recent studies have indicated that iridium catalysis is compatible with many other catalysis modes, significantly expanding the scope of Ir-catalyzed asymmetric allylic alkylation (AAA) reactions[41]

Summary

Introduction

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles. Among the continuing and productive efforts, catalytic asymmetric cycloadditions via transition metal (TM)-containing dipolar intermediates have been determined to be powerful tools for this purpose[3,4,5] Within this realm of palladium catalysis, many impressive advancements have been made regarding cycloadditions of Pd-containing dipolar intermediates with electrophilic dipolarophiles (Fig. 1a, path a: normal electron-demand cycloadditions)[6,7,8,9,10,11,12], the inherent linear selectivity of Pd-catalyzed intermolecular allylic alkylation (AA) reactions renders the development of a general strategy for the coupling of such intermediates with nucleophilic dipolarophiles a formidable task (Fig. 1a, path b: inverse electron-demand cycloaddition)[13,14]. Active quinolinones and tetrahydroquinolines were produced in good yields and with high diastereoselectivity and enantioselectivity

Methods

Results

Conclusion