Chiral Proton Catalysis: New Applications in Enantioselective Hetero-Diels-Alder Reactions, Amino Acid Synthesis, and Tetrahydroisoquinoline Alkaloid Synthesis

Abstract

The proton is the smallest Lewis acid and has been utilized in nature by enzymes for catalysis and stereocontrol of a variety of reactions long before chemistry was pursued as the discipline it is today. This precedent notwithstanding, there are very few examples of asymmetric catalysis which utilize a polar ionic hydrogen bond (essentially, a chiral proton complex). We have developed bifunctional Bis(AMidine) (BAM) catalysts that are efficient chiral proton catalysts for several mechanistically distinct transformations. This dissertation explores a rationally designed extension of BAM catalysis to an aza-Henry reaction employing α-nitro esters as pronucleophiles. This allows for the enantio- and diastereoselective synthesis of α,β-diamino acid derivatives. A reagent-controlled diastereodivergence is observed from the selectivity typically observed in BAM catalysis and is further explored with preliminary computational analysis. This methodology was applied to the synthesis of a potent heterocyclic proteasome inhibitor. Additionally, a chiral proton chaperoned biomimetic hetero-Diels-Alder reaction was effected with moderate enantioselectivity, and preliminary results towards the synthesis of fluorinated tetrahydroisoquinoline alkaloids are reported.