Understanding the Stereoselection Induced by Chiral Anthracene Templates in Diels−Alder Cycloaddition: A DFT Study

Abstract

Recyclable chiral anthracene templates have emerged as an effective and well-designed approach in preparing complex biologically active molecules such as butenolides, alpha,beta-unsaturated lactams, and related compounds in their enantiomerically pure forms. Highly diastereoselective initial cycloaddition serves as the key element of the total process, as it determines the final stereochemistry of the product. The diastereoselectivity of chiral anthracene templates is explored by using density functional theory (DFT) methods, and the reliability and applicability of the previously proposed models, mostly based on steric arguments, are tested by mechanistic means. The diastereomers A and B are identified according to the stereochemistry around the formed stereocenter on the dienophile attached to C9, as being R or S, respectively. The reactions of (R)-9-(1-methoxyethyl)anthracene and (S)-9-(1-methoxy-2,2,2-trifluoroethyl)anthracene with maleic anhydride both give exclusively diastereomer A via a similar transition state in which the CH(3)/CF(3) group is antiperiplanar to the approaching dienophile. The major product of the reaction between (R)-9-(1-phenylethyl)aminoanthracene and maleic anhydride is diastereomer B. The geometry around nitrogen is close to planar in the transition state (10-25 degrees out of plane), and the nitrogen lone pair is antiperiplanar to the incoming dienophile. Both of the lowest energy diastereomeric transition states giving A and B benefit from the favorable interaction between the carbonyl oxygen and the amine hydrogen; this interaction does not play a substantial role in the selectivity of the reaction as previously proposed. The diastereomeric transition states leading to A and B for the reaction between (R)-9-acyloxyanthracene and maleic anhydride have very similar interactions around the reaction center, leading to a very small energy difference between the diastereomeric transition states. The product distribution ratios for all templates calculated from Boltzmann distributions agree very well with the experimental results.