Density Functional Theory Guided Design of Exo-Selective Dehydroalanine Dienophiles for Application Toward the Synthesis of Palau'amine

Diels−Alder cycloadditions of dehydroalanine derivatives with cyclopentadiene, applicable to the synthesis
of palau'amine, were investigated experimentally and using DFT computations at the B3LYP/6-31G*
level of theory. Oxazolone and thiohydantoin dienophiles were found to be significantly more reactive
than hydantoins or dehydroalanine methyl esters. The increased reactivity of the thiohydantoins relative
to hydantoins is attributed to increased conjugation of nitrogen lone pairs into the thiocarbonyl group.
β-Substitution greatly decelerates the cycloadditions due to steric interactions in the transition states
outweighing any electronic activation by chlorine. Hydantoins and thiohydantoins were found to be exo-selective, while the corresponding oxazolones and dehydroalanines were unselective.