Pyrrole Macrocyclic Ligands for Cu-Catalyzed Asymmetric Henry Reactions

Abstract

New chiral perazamacrocycles containing four pyrrole rings have been synthesized by the [2+2] condensation of (R,R)-diaminocyclohexane and 5,5'-(alkane-2,2-diyl)bis(1H-pyrrole-2-carbaldehydes). These macrocycles, differing for the alkyl/aryl meso-substituents, were used as ligands in the copper-catalyzed Henry reactions of aromatic and aliphatic aldehydes with nitroalkanes. In the optimized experimental conditions, the condensations of nitromethane and aromatic and aliphatic aldehydes in the presence of catalytic amounts of copper diacetate and methyl-substituted macrocyclic ligand (2:1 ratio) in ethanol at room temperature provided products often with high enantiomeric excesses (up to 95% ee). The positive influence of the macrocyclic structure on the efficiency/enantioselectivity of the catalytic system was demonstrated by comparison with the outcomes of Henry reactions performed using analogous macrocyclic ligands (trianglamines) and open-chain ligands derived from (R,R)-diaminocyclohexane.