The Importance of Iminium Geometry Control in Enamine Catalysis: Identification of a New Catalyst Architecture for Aldehyde–Aldehyde Couplings

Abstract

Central to the design of a new organocatalyst system for aldehyde–aldehyde aldol reactions is the necessity of iminium geometry control during the enamine addition step (see scheme). Significant structural variation in both the aldol donor and aldol acceptor are possible while maintaining high reaction efficiency and enantioselectivity. TFA=trifluoroacetic acid.

Origins of Stereoselectivity in Diels−Alder Cycloadditions Catalyzed by Chiral Imidazolidinones

“…38 A stepwise pathway was found, and the activation barrier for the cycloaddition to the C=C bond was 4.2 kcal/mol lower than that to the C=N bond. (10). The relative energy differences between the 10 s-trans iminium intermediate and the three located 10 s-cis1-3 conformers are lower than in the case of N-2-butenylidene-N-methylmethanaminium cations (9) (3.5, 2.9, and 3.8 kcal/mol respectively).…”

“…10 The computations were performed for the reaction involving protonated 4-hexen-3-one, and the results for the lowest energy path are shown in Figure 7. The isomeric reactants complexes, and transition states are given in the supporting information.…”

“…In water the calculated endo:exo ratio was 7.5:1 the same value found in the experiment for the reaction catalyzed by imidazolidinone 1. 10 …”

“…9 More recently, the same research group used imidazolidinone 2 for aldehyde-aldehyde aldol reactions obtaining as major compound the enantiomer of the most favored product in the proline catalyzed process. 10 List and coworkers have also obtained good yields and enantioselectivities in asymmetric hydrogenations of α,β-unsaturated aldehydes using amine 2 as organocatalyst. 11 One important factor that determines efficiency of imidazolidinone catalysts in their asymmetric enantioselective reactions is the reversible formation of iminium ions from chiral imidazolidinones and α,β-unsaturated carbonyl compounds.…”

Organocatalytic Asymmetric Synthesis Using Proline and Related Molecules. Part 2.

“…prolinol, 157 imidazolidinone 28, 158 pyrrolidine-2,5-dicarboxylic acid 29, 159 indoline-2-carboxylic acid 30, 160,161 spiroborate ester, 162 pyrrolidinylphosphonic acid 31, 163 and 4-pyrrolidinylproline 32. 164,165 Chart 4.…”