Amino acids

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.

Reaction of Cp2TiCl2 with the dianion of squaric acid yields a polymer in which the squarate ion is present as a simple bidentate ligand with two uncoordinated carbonyl groups. The polymeric structure was established using light scattering photometry and geometric arguments. The structure and bonding of the polymer was confirmed using infrared, Raman, and 1H-NMR spectroscopy, and mass spectrometry. The 1H-NMR spectrum of the polymer shows two complex multiplets for the cyclopentadienyl rings, and indicates inhibition of rotation of the Cp rings. Reaction of the tetrachloroplatinate ion with lysine, arginine, and histidine, using 1:1 ligand to metal ratios was investigated. The amino acids used were in the cationic, anionic and zwitterionic forms. The structures of the products obtained were investigated using infrared spectroscopy, light scattering photometry, 1H-NMR spectroscopy and mass spectrometry. Preliminary biological studies were conducted on the histidine products.