| Central to this work is the development of the first catalyzed reaction of ketenes with imines to form β-lactams in extremely high enantio- and diastereoselectivity using the cinchona alkaloid based catalyst benzoylquinine (BQ). The class of β-lactams synthesized are known to be potent inhibitors of serine proteases, which have been implicated in many diseases. The ketene-BQ catalyst system is then studied through molecular mechanics calculations to better understand the reasons for the high stereoselectivity. This knowledge was then utilized to screen and design new Lewis basic catalyst systems.; The β-lactam forming reaction was then adapted to a continuous flow system allowing us to synthesize β-lactams using polymer-supported reagents and catalysts, which obviated the need for work-up or column chromatography. This system which we termed Column Asymmetric Catalysis (CAC), was studied and expanded to perform three separate reactions and one purification step in one synthesis machine.; Finally, the BQ-ketene catalyst system was used as the keystone for the first catalytic asymmetric α-chlorination and α-bromination reactions resulting in enantiopure α-haloesters. These products are not only pharmaceutically active, but are also densely functionalized synthetic intermediates for many much larger molecules. No only does the halogenated center serve as a functionality to perform a myriad of substitution reactions, but the resulting activated ester provides an additional handle for further elaboration. By using commercially available perhalogenated quinones, acid chlorides and alkaloid based catalysts, our protocol is both simple and inexpensive to employ.; Two themes tie these discoveries together: (1) the use of cinchona alkaloid based neucleophilic catalysts and (2) the use of highly reactive mono-substituted ketenes. While mono-substituted ketenes are known to be excellent synthetic intermediates, there use is hampered by their instability. In this dissertation four new protocols for the generation of monokenetes in situ are outlined. These protocols produce pure solutions of ketenes without deleterious byproducts which can severely hamper asymmetric reactions (vide infra). |
