Rational Design of Minimal Artificial Diels–Alderases Based on the Copper(II) Cation–Aromatic π Attractive Interaction

Abstract

We have designed a minimal artificial metalloenzyme that is prepared in situ from Cu(OTf)₂ or Cu(NTf₂)₂ (1.0 equiv) and l-DOPA-derived monopeptide (1.1 equiv) based on the cation–π attractive interaction between copper(II) and the aromatic arm of the ligand, which is postulated on the basis of X-ray diffraction analysis and theoretical calculations. This catalyst (2–10 mol %) is highly effective for not only the enantioselective Diels–Alder reaction with α,β-unsaturated 1-acyl-3,5-dimethylpyrazoles but also the enantioselective Mukaiyama–Michael reaction with these compounds. Products bearing a 3,5-dimethylpyrazolyl auxiliary may be transformed into a range of carboxylic acid derivatives, such as the corresponding carboxylic acids, esters, amides, alcohols, aldehydes, ketones, and β-ketoesters, by known methods. The present results demonstrate that monopeptides are chirally economical and readily tunable ligands compared to bis(oxazoline)s, which have been reported to be notably useful ligands in various enantioselective reactions with bidentate electrophiles.