Central‐to‐Axial Chirality Conversion Approach Designed on Organocatalytic Enantioselective Povarov Cycloadditions: First Access to Configurationally Stable Indole–Quinoline Atropisomers

Abstract

The first stereoselective synthesis of enantioenriched axially chiral indole-quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloadditiono f3 -alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unre-porteda xially chiral indole-quinoline biaryls. The methodology is also implementedf or the design and the preparation of challengingc ompounds exhibitingt wo stereogenic axes. DFT calculations shed light on the stereoselectivityo ft he central-to-axial chirality conversion,s howing unconventional behavior.Scheme1.Combining organocatalytice nantioselective Povarovc ycloadditions with the oxidative central-to-axial chirality conversion concept.

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

“…Very recently, Bertuzzi and co‐workers developed a closely related central‐to‐axial chirality conversion approach to construct enantiomerically enriched indole‐quinoline atropisomers . As an extension of this methdology, two examples of 1,3‐diaxially chiral atropisomers were constructed (Scheme ).…”

Construction of Axially Chiral Compounds via Central‐to‐Axial Chirality Conversion

“…The same year, Corti, Bertuzzi and co‐workers performed the catalytic asymmetric construction of axially chiral 3‐quinolinylindole frameworks via an asymmetric Povarov reaction and the oxidative central‐to‐axial chirality conversion approach (Scheme ) . A CPA‐catalyzed Povarov cycloaddition of 3‐vinylindoles 67 with N ‐arylimines 66 to prepare tetrahydroquinolines 68 bearing central chirality, followed by an oxidative central‐to‐axial chirality conversion process were developed, affording the axially chiral 3‐quinolinylindoles 69 in generally good yields with high enantioselectivities.…”

Organocatalytic Asymmetric Methodologies towards the Synthesis of Atropisomeric N-Heterocycles

“…ent-L for structure see Scheme 8) Povarov cycloadditions 54 of N-arylimines 92 and 3-alkenylindoles 93, 55 to establish the chiral information of highly enantioenriched products 94, in combination with the oxidative (DDQ-mediated) central-to-axial chirality conversion approach. 56 This enables the efficient formation of atropisomeric products 95 with translation and excellent retention of the initial enantiomeric excess (Scheme 22, top). The methodology displayed broad tolerance towards different substrate modifications and resulted in precise substrate design to construct axially chiral architectures characterized by the presence of two stereogenic axes (96 and 97).…”