Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

Abstract

Atropisomers possessing multiple stereogenic axes are intriguing molecules with huge potential. However, only few approaches for their enantioselective synthesis are available due to the difficulties in assembling various stereogenic axes with high enantiocontrol. Only recently, innovative methods have emerged, opening new possibilities for the synthesis of this original class of atropisomeric compounds. This Minireview describes the development of this field based on a classification of the multi‐axis systems according to the distance between the stereogenic axes and the strategy used to build them.

A nonneglectable stereochemical factor in drug development: Atropisomerism

“…Studies on atropisomers in drug discovery date back to 1983 41 . With the increasing attention on atropisomerism, research on various aspects of the asymmetric synthesis, resolution, and biological evaluation of atropisomers is substantially increasing 4,30,42–50 . Herein, we focus on the biological activities and pharmacokinetic and toxicity properties of various atropisomers and highlight the role of atropisomerism in drug design.…”

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…Dihydroxy arene 292 has been coupled with β ‐chloro, β ‐nitro substituted styrene 293 in presence of squaramide H′ as the catalyst under basic condition to form bis ‐dihydrobenzofuran derivatives 294 [119] . 2,6‐dihydroxy naphthalene and 2,6‐dihydroxy anthracene reacted with a series of electronically diverse aryl substituted 293 to afford enantioenriched products 294 with good chemical yields and high diastereoselectivities.…”

Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N -Aryl Indoles via Vinylidene Ortho -Quinone Methides

“…[50][51][52][53][54] Stereoselective methods toward the preparation of individual compound with multiple stereogenic axes are highly desirable. [55][56][57][58][59][60][61][62][63] As a result, with 5a as the substrate and NIS as the iodation agent, the reaction proceeded smoothly to give the corresponding product 6a bearing both C-C and C-N axes in good yield by using cinchona-squaramide catalysts. After screening reaction conditions, catalyst C was identified as the optimal catalyst and high enantioselectivity was achieved with toluene as the solvent at 25 o C (Table 4a, entry 10), albeit the diastereoselectivity of the transformation was not satisfactory (dr = 7:1) under current reaction conditions.…”