A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels-Alder Products Having the Norcarane Scaffold.

Abstract

An enantioselective methodology to construct trans-Diels-Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels-Alder reaction allowing for the subsequent formation of trans-Diels-Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels-Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN 2-like reaction at a tertiary center to obtain the trans-Diels-Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.