Direct and Highly Enantioselective Iso-Pictet–Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures

Abstract

Direct, one-pot, operationally simple, and highly enantioselective iso-Pictet–Spengler reactions are reported. The reactions involve the condensation of either (1<i>H</i>-indol-4-yl)methanamine or 2-(1<i>H</i>-Indol-1-yl)ethanamine with a variety of α-ketoamides, followed by the addition of a simple and commercially available chiral silicon Lewis acid. These reactions are the first asymmetric examples of these cyclization modes and provide access to 3,3-disubstituted-1,3,4,5-tetrahydropyrrolo[4,3,2-<i>de</i>]isoquinolines and 1,1-disubstituted-1,2,3,4-tetrahydropyrazino[1,2-<i>a</i>]indoles, respectively, two relatively underexplored indole-based core structure motifs in medicinal chemistry