Catalytic Generation of Remote C–N Axial Chirality through Atroposelectivede novoArene Construction

Abstract

The first atroposelective desymmetrization of prochiral N-aryl maleimides through its conversion to axially chiral phthalimides is developed by applying a de novo arene construction strategy. Catalyzed by bis(3,5-dimethylphenyl)prolinol TMSether, this reaction proceeds through oxidative [4 + 2]-cycloaddition with α,β-unsaturated aldehydes to generate only a chiral C−N axis remote from the reaction sites with excellent enantioselectivity (up to 97.5:2.5 er).

Centrally Chiral Arenes: From Concept to Catalytic Enantioselective Synthesis

“…19 Although the objective of this article was to discuss centrally chiral arenes and their enantioselective synthesis, we cannot resist the temptation of mentioning a few words about the successful extension of this de novo arene construction strategy to axially chiral arenes. 22 We were particularly interested in the desymmetrization of maleimide derivatives bearing a bulky ortho-substituted aryl group on the nitrogen center. 23 This class of compounds contains a plane of symmetry (σ), and their desymmetrization is typically carried out either through cycloaddition 24 or conjugate addition.…”

“…Using a combination of (S)-bis(3,5-dimethylphenyl)prolinol TMS-ether (II) and 2-fluorobenzoic acid as the catalyst, the resulting N-aryl phthalimide derivatives, bearing only a chiral C−N axis, were obtained with excellent enantioselectivities in most cases (Scheme 14). 22 However, due to the lower ring diversification simply through the choice of α,β-unsaturated aldehydes. This is the first example of enantioselective de novo construction of centrally chiral unfunctionalized arenes.…”

N‐Heterocyclic Carbene Control over Multiple Stereogenicities: Atroposelective Synthesis of Axially Chiral Phthalimides

“…The products are obtained as only one diastereomer, out of the 64 possible stereoisomers, and with excellent enantioselectivity. Upon treatment under basic conditions, these bis ‐adducts eliminate one equivalent of N ‐aryl maleimide to allow for the first time [19] a two‐step direct access to hitherto unknown enantiomerically enriched N ‐aryl phthalimides. Interestingly, promising investigations regarding a one‐pot version of this two‐step sequence open the way to an expedient atroposelective route to this family of phthalimides.…”

Atropselective Organocatalytic Synthesis of Chiral Compounds Containing Nitrogen along the Axis of Chirality

“…When instead of α,β-unsaturated ketones, the corresponding enals 42 are used to react with maleimides 35 in the presence of a secondary amine, C17, N-substituted phthalimides 43 are produced in an atropselective desymmetrization reaction (Figure 15). This de novo arene construction, proceeding through an oxidative [4 + 2] cycloaddition, was described by Mondal and Mukherjee in 2022 [49]. The dienamine catalysis obtained allows the formation of products in very high ees, using remote stereocontrol via the endo TS.…”