Synthesis of enantioenriched atropisometric indolylquinolines following a central-to-axial chirality conversion approach

In this work, the enantioselective synthesis of atropisomeric indolylquinoline systems using a central-to-axial chirality conversion approach is presented. This methodology consists, first of all, in the synthesis of enantioenriched tetrahydroquinolines displaying central chirality. Then, conversion of central chirality to axial chirality by means of an oxidation reaction in order to obtain the corresponding atropisomeric quinolines has been carried out. Axial chirality is a type of unconventional chirality in which the molecules do not possess a stereogenic center but a chiral axis. Thanks to the spatial arrangement of the substituents around the axis, these molecules can exist in two non-superimposable mirror images, that is in two enantiomeric forms. The tetrahydroquinoline scaffolds are synthetized exploiting an acid catalyzed inverse-electron-demand [4 + 2] cycloaddition: the Povarov reaction. This cycloaddition consists in the reaction between an electron poor diene, an N-arylimine, and an electron rich dienophile, a 3-alkenylindole bearing a bulky substituent at the 4-position of the indole. The Povarov cycloaddition is promoted by the presence of (R)-TRIP, a bifunctional chiral phosphoric acid, that is able to deliver enantioenriched tetrahydroquinolines in excellent yields, stereo- and enantioselectivities. The tetrahydroquinoline scaffolds obtained in this way are subsequently oxidized to atropisomeric indolylquinolines with retention of the chiral information imparted in the Povarov reaction. Different oxidation reaction conditions were tested in order to achieve configurationally stable atropisomeric indolylquinolines with good yields and retention of enantiomeric excess. With the best reaction conditions in hand, the reaction scope has been thoroughly evaluated by modifying both the N-arylimine and 3-alkenylindole reaction partners.