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.

Challenging Atroposelective C–H Arylation

“…Targeting elaboration of unprecedented chiral scaffolds, Colobert and Wencel-Delord in 2018 were interested in the conception of optically pure molecules containing two contiguous atropisomeric axes. 15 They envisaged that such molecules might be obtained by combining diastereoselective C-H functionalization 16 of biaryls and stereoselective C-H arylation. Such triaryl scaffolds should exhibit a unique tridimensional structure, thus becoming an appealing platform to construct unprecedented chiral ligands.…”

“…Recently, compounds with contiguous chiral elements have been recognized as important scaffolds with various topologies and application as chiral ligand, catalysts and optical resolution agents. 15 Following this goal, a double intermolecular C-H arylation of 1,5-dibromo-2,6-dimethoxynaphthalene with 1-methyl-4-phenyl-1H-1,2,3-triazole was achieved, affording the triaryl product bearing two stereogenic axes (Scheme 8). Interestingly no meso-isomer was observed.…”

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

“…Axial chirality is one of the most important properties of nature, resulting from the nonplanar arrangement of four groups in pairs about a chirality axis. These include atropisomerism [ 1 ], chiral allenes, spiranes, spiroindanes, and so on [ 2 – 3 ]. Recently, there emerged an enormous demand for enantiopure compounds, not only for pharmaceutical and fine chemical industries, but also for fragrance, flavor, agrochemical, and food industries [ 4 ].…”

Organocatalytic Enantioselective Construction of Chiral Azepine Skeleton Bearing Multiple‐Stereogenic Elements

“…Thedefined structure of chiral molecules bearing multiple stereogenic elements holds aspecial place in the development of bioactive compounds,advanced materials and asymmetric catalytic systems,w hose absolute and relative configurations are both critically important for their inherent properties. [1] To date,an umber of asymmetric catalytic strategies have been developed for the construction of multi-stereogenic chiral centers, [2] and af ew atroposelective protocols of multiaxis, [3,4] multihelical [5] and multiplanar [6] systems have been recently explored (Figure 1a). However,t ot he best of our knowledge,c atalytic enantioselective approaches installing more than three types of stereochemical elements into different sites of as ubstrate within as ingle step are intrinsically challenging and have not been reported.…”