Esters

The present dissertation will be largely focused on the synthesis of various [3.2.1] bridged bicycles using allenyl esters. Chapter one will present the importance of various [3.n.1] bridged bicycles in medicinal chemistry. A three-step synthetic route will then be described on how to produce a small library of [3.n.1] bridged bicycles using allenyl esters in an annulation reaction. The [3.n.1] bicyclic diketones can then undergo Grob fragmentation to deliver highly functionalized medium sized rings. Studies towards the total synthesis of vitisinol D, a highly functionalized [3.2.1] bridged bicycle will be discussed. In chapter two, synthesis knowledge gleamed from chapter one will be used to create a model route to form simplified versions of vitisinol D, called resveramorphs. These resveramorphs are structurally similar to resveratrol but possess rigid three-dimensional configuration desired in drug design. The synthetic route to create a variety of resveramorphs will be reported. The sub-nanomolar results of various resveramorph compounds in a Drosophila melanogaster neural tissue model under oxidative stress will be reported. Chapter three will focus on the use of allenyl esters as prenucleophiles to produce triply diastereoselective β-hydroxy esters containing all carbon α-quaternary centers. The challenges in the opitmization of this novel reaction will be described. The relative stereochemistry of the β-hydroxy ester products will be presented using various techniques including X-ray crystallography, 1D NMR, 2D NMR, and force field calculations (MM2). A closed transition state mechanism will be proposed to describe the diastereoselectivity that is observed in the reaction. Additionally, a short indanone synthesis will be shown as a potential application for this novel reaction.

In this dissertation, we discuss the development of a synthetic method to functionalize various α-haloglycine esters, as key precursors to a large variety of non-proteinogenic α-amino acids (Xaas). At first, we discovered a very practical and high yielding acetyl chloride-mediated cascade reaction to synthesize α-arylated amino esters in one-pot. In this multicomponent reaction (MCR), a primary carbamate was condensed with a glyoxylate, followed by an in situ halogenation which proved essential to trigger the final Friedel−Crafts functionalization. After careful reaction optimization, a plethora of arene nucleophiles were reacted with high regioselectively in CHCl3 at low temperatures (Method A) while less activated arenes reacted more cleanly in CH3CN and at higher temperatures (Method B). To broaden the scope of this reaction to acid sensitive nucleophiles, a one-pot reaction was designed via evaporation of all acid by-products at the α-haloglycine stage. The anion-binding Schreiner’s thiourea catalyst proved to be extremely efficient to promote this complementary approach (Method C) which relies on the chloride leaving group activation by the catalyst to assist the functionalization stage and deliver the α-amino ester product.
In the second chapter, some highly practical and efficient preparations of α-haloglycine esters in one-pot have been developed to generate useful precursors of non-proteinogenic α-amino esters. Also, a mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation/deoxy halogenation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. Friedel–Crafts reaction between α-chloroglycine and N-methylindole have been studied in details to understand the mechanistic intricacy of this reaction. Our findings through the initial kinetic profiling support that the arylation likely proceeds via a SN1-like (or SN2C+) mechanism.
In third chapter, we discuss the development of the most challenging α,α-disubstituted amino esters in a multicomponent fashion. Our results highlight that the MCR proceeds via the formation of an enamide intermediate, which is further tautomerized to corresponding iminium to produce the desired product. In collaboration with Eli Lilly at the Automated Synthesis Laboratory (ASL), we have developed silver (I) salts mediated Friedel–Crafts reaction for synthesis of α-trifluoromethylated α-amino esters on a fully automatized robot.