| Since their official discovery in 1905 by Hermann Staudinger, ketenes have played an important role in organic chemistry. Very recently, they have been rediscovered as valuable precursors in asymmetric Lewis acid and Lewis base catalysis. Although many protocols have been developed for the preparation of disubstituted ketenes, monosubstituted ketenes are the synthetically more useful class of substrates. Unfortunately, the latter are highly reactive and tend to dimerize therefore requiring specialized reaction conditions. In many applications, they are accessed through in situ dehydrohalogenation from acid halides and must be reacted quickly thereafter. This dissertation describes the use of mostly monosubstituted ketenes and their application in asymmetric catalysis. Through the use of chiral nucleophilic catalysts we have successfully developed the first catalytic, asymmetric β-lactam synthesis as well as the first catalytic, asymmetric α-halogenation protocol.; Following a detailed introduction on the history and preparation of ketenes and their application in organic synthesis, a description of several novel procedures developed in our labs for the in situ generation of mono- and disubstituted ketenes is detailed. Of central importance to the following work is the formation of a zwitterionic enolate when a chiral nucleophilic catalyst, such as benzoylquinine (BQ), reacts with these ketenes. This chiral enolate provides the source of induction to our β-lactam and α-halogenation reactions.; Adaptation of the β-lactam forming reaction using polymer-supported reagents and catalysts in a continuous flow system obviated the need for work-up or column chromatography. This system that we termed Column Asymmetric Catalysis (CAC), was studied and expanded to perform three separate reactions and one purification step in a single continuous flow assembly.; Our synthesis of β-amino acids is unique in that the chiral nucleophile BQ catalyzes five distinct sequential steps in one reaction flask. In this reaction scenario, BQ acts as a dehydrohalogenating agent for the synthesis of ketenes and N-acylimines from the acid chlorides and N-acyl-α-chloroamines, respectively, an asymmetric catalyst for the [2+2] cycloaddition between the ketene and imine, a nucleophilic catalyst for ring-opening, and a transesterification catalyst for ester exchange.; Finally, the BQ-ketene catalyst system was used as the cornerstone 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. |
