Dual‐Mode Thio‐MacMillan Organocatalysts: Stereoselective Diels–Alder Reactions or Sacrificial Self‐Cyclization to <i>N</i> ‐Bridged Bicyclic Lactams

Chiral secondary amines in lactams are commonly used as chiral organocatalysts (MacMillan catalysts) in a broad range of transformations. The related thiolactam derivatives are less explored although possessing some significantly differing properties originating from the stereoelectronic characteristics of sulfur. In the present study, we present a streamlined synthesis and application of imidazolidine-4-thiones from naturally abundant L-phenylalanine. Suitable substituents enable asymmetric Diels-Alder reactions with high enantioselectivity and yield. Here, we discovered the formation of a novel bicyclic thiolactam aldehyde motif in absence of the diene. The obtained hetero-bicycle, with four consecutive stereocenters, is formed in high yield and stereoselectivity from imidazolidine-4-thione and two cinnamaldehyde units, whereas the first gen. MacMillan catalyst shows no reactivity. We propose a mechanism of formation which is supported by DFT calculations, revealing a combination of thermodynamic and kinetic factors for the observed selectivity. Our results demonstrate the surprising versatility of imidazolidine-4-thiones, as this compound class can not only engage as a catalyst but can simultaneously participate as a reagent to form complex structures. The hetero-bicyclic skeleton is accessible in a single step and allows for facile structural modifications.