Enantioselective Strategies for The Synthesis of N−N Atropisomers

Abstract

Axially chiral compounds have been always considered a laboratory curiosity with rare prospects of being applied in asymmetric synthesis. Things have changed very quickly in the last twenty years when it was understood the important role and the enormous impact that these compounds have in medicinal, biological and material chemistry. The asymmetric synthesis of atropisomers became a rapidly expanding field and recent reports on the development of N−N atropisomers strongly prove how this research field is a hot topic open to new challenges and frontiers of asymmetric synthesis. This review focuses on the recent advances in the enantioselective synthesis of N−N atropisomers highlighting the strategies and breakthroughs to obtain this novel and stimulating atropisomeric framework.

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…A variety of heterobiaryl scaffolds and nonbiaryl scaffolds have been characterized as distinct atropisomers, synthesized enantioselectively, and have found application in the above-mentioned fields. Heterobiaryl atropisomers feature the incorporation of 5- and 6-membered heteroarenes and can employ chiral axes beyond restricted C­(sp 2 )–C­(sp 2 ) bonds, including C–N, N–N, and C–B axes among others. Additionally, the breadth of atropisomers has been expanded beyond restricted rotation of two aromatic rings, and nonbiaryl atropisomers anilides and amides, diaryl amines, diaryl ethers, styrene, and even atropisomeric alkyl C­(sp 3 )–C­(sp 3 ) systems have been reported.…”

On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides

“…In recent years, novel types of atropisomers with stereogenic axes different from the C-C single bond have received massive attention from the scientific community. N-N atropisomers signify the latest frontier in atroposelective synthesis; they are valuable for their useful biological activity and their significance as noteworthy "smart" materials [1]. In the past, this class of compounds has been rarely studied by a few research groups that have analyzed the conformational properties of different types of substituted hydrazines, quinazoline-diones, and aminocamphorimides featuring a hindered N-N single bond [2][3][4][5][6][7].…”

Catalytic Asymmetric Synthesis of Aza-Quaternary Carbon Cyclohexadieneones Enabled by Aminative Dearomatization of Phenols

“…For instance, treatment of product 3a with methyl magnesium bromide afforded the 1,2-addition product 4 . N-Alkylation with ethyl bromoacetate led to product 5 as two diastereoisomers due to the newly formed N–N axial chirality . The subsequent intramolecular cyclization delivered bicyclic compound 6 .…”