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.

Organocatalytic Atroposelective Reactions of Alkynes

“…Scheme 2 Representative chiral organocatalysts in the atroposelective reactions of alkynes Therefore, the atroposelective reactions of typical electronrich and electron-deficient alkynes were established. 3 For example, phenol, aniline and indole substituted electron-rich alkynes could undergo electrophilic activation/nucleophilic addition to afford axially chiral products via vinylidene orthoquinone methides (VQMs) and allene-iminium intermediates (Scheme 3a and 3b). On the other hand, carbonyl group substituted electron-deficient alkynes could undergo amine or NHC activation/nucleophilic addition to give axially chiral products via Michael acceptor intermediates (Scheme 3c and 3d).…”

“…Typically, axially chiral molecules could be synthesized through the catalytic enantioselective crosscoupling of aryl halides, dehydrogenative cross-coupling of arenes, organocatalytic C−H arylation of aromatic nucleophiles with electrophiles, de novo arene formation reactions and others. 3…”

Catalytic Synthesis of Atropoisomers via Non‐Canonical Friedel‐Crafts Reactions

“…N‐N bonds containing motifs are important and ubiquitous in natural products and bioactive compounds. [33–37] …”

Recent Advances in Catalytic Nitrogen–Nitrogen Bond Formation Reactions

“…Until now, incorporation of a hydrazine synthon remains the most frequently used method in the synthesis of N–N bond-containing molecules. , Despite efforts on the late-stage modification of nitrogen–nitrogen bond-containing structures, direct nitrogen–nitrogen bond construction remains a highly efficient and useful way for the preparation of a substituted N–N or NN skeleton. Unlike their C–C and C–N analogues, new methods toward selective formation of bonds between nitrogen and nitrogen centers have been one of the main challenges in synthetic chemistry as both nitrogen atoms to be linked are inherently nucleophilic.…”