Brønsted Acid Catalyzed [3 + 2]-Cycloaddition of Cyclic Enamides with in Situ Generated 2-Methide-2H-indoles: Enantioselective Synthesis of Indolo[1,2-a]indoles

Abstract

An efficient formal [3 + 2]-cycloaddition toward the highly diastereo- and enantioselective synthesis of indolo[1,2-a]indoles is disclosed. A chiral BINOL-derived phosphoric acid catalyzed the highly enantioselective conjugate addition of cyclic enamides to in situ generated 2-methide-2H-indoles and subsequent aminalization to give rise to acetamide-substituted indolo[1,2-a]indoles carrying three contiguous stereogenic centers. Importantly, these products were formed as single diastereomers and with excellent yields and enantioselectivities. Mild reaction conditions at ambient temperatures, the facile removal of the acetamido group, and the possibility of a scale-up highlight the practicality of this methodology.

Organocatalytic enantioselective dearomatization of thiophenes by 1,10-conjugate addition of indole imine methides

“…Indole-based imine methides have been demonstrated to be versatile intermediates in a range of organocatalytic asymmemtric transformations, particularly in 1,4- or 1,6-conjugate addition 22 – 29 and cycloaddition 30 – 34 , leading to diverse enantioenriched indole derivatives 35 – 38 . Among them, we have reported an asymmetric 1,6-conjugate addition of such intermediates for the synthesis of chiral tetraarylmethanes containing an indole unit 29 .…”

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

“…The utilization of cyclic enamides derived from tetrahydronaphthalenones 30 is also effective in the reaction with 2‐indolylmethanols 29 in the presence of chiral phosphoric acid 31 (Scheme ) . The activation mode of the reactants by the catalyst is supposed to be identical to that observed with linear enamides but the intermediate N ‐acylimine formed upon addition reacts with the indole nitrogen atom leading to pentacyclic derivatives 32 as single diastereoisomers in high enantioselectivity.…”

Enamides and dienamides in phosphoric acid-catalysed enantioselective cycloadditions for the synthesis of chiral amines

“…Afterwards, Schneider et al 58 developed a similar strategy to access chiral cyclopenta[a]indoles 60, 59 using cyclic enamides…”