Novel binaphthyl and biphenyl α- and ß-amino acids and esters: organocatalysis of asymmetric Diels-Alder reactions. A combined synthetic and computational study.

Asymmetric catalysis of the Diels-Alder reaction between cyclopentadiene and cinnamaldehydes has been studied using as catalysts a range of novel α- and ß-aminoacids and aminoesters with binaphthyl and biphenyl backbones, providing enantioselectivities of up to 62% ee. B3LYP/6-31G* calculations, including free energy corrections, have been carried out on a binaphthyl catalyst example to identify transition state structures and to aid in the identification of major enantiomers. The calculated product ratios agree well with the experimental data; the transition states identified involve preferential approach of cyclopentene along a trajectory adjacent to the acid/ester group. The four lowest energy transition states display a stabilizing dipolar interaction between the carbonyl group oxygen atom and a terminal proton of the diene unit.

Diastereoselective Synthesis of Highly Substituted, Amino- and Pyrrolidino-Tetrahydrofurans as Lead-Like Molecular Scaffolds.

A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead-like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF-containing compounds for inclusion in the Joint European Compound Library.