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

## TL;DR

Researchers developed a new type of organocatalyst that can both catalyze reactions and form complex structures, offering a versatile tool for stereoselective synthesis.

## Contribution

A novel dual-mode thio-MacMillan catalyst is introduced, capable of both catalyzing Diels–Alder reactions and forming N-bridged bicyclic lactams.

## Key findings

- A streamlined synthesis of imidazolidine-4-thiones from L-phenylalanine was developed.
- The catalyst forms a new bicyclic thiolactam aldehyde motif with high stereoselectivity.
- DFT calculations support a mechanism involving both thermodynamic and kinetic factors.

## Abstract

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.

The study of the Diels–Alder reaction of cinnamaldehyde and cyclopentadiene, catalyzed by chiral imidazolidine‐4‐thiones, led to the discovery of a highly regio‐ and stereoselective Michael‐addition and consecutive ring closure. Here, the imidazolidine‐4‐thione not only catalytically activates cinnamaldehyde but also participates as the nucleophile to form a complex N‐bridged bicyclic system, as elucidated by DFT calculations.