| Ketenes are an important reactive class of compounds that have received much attention in the literature over the past 20 years. The electrophilic nature of the alpha carbon makes ketenes highly susceptible to nucleophilic attack. Tertiary amine nucleophiles thus react with ketenes to generate putative zwitterionic enolates, where the charges are stabilized due to their close proximity. These enolates are capable of attacking electrophiles to afford a wide variety of useful compounds.;This work revolves around the use of ketenes and their catalyst-derived enolates in the synthesis of a variety of synthetically useful and/or biologically active compounds. These transient intermediates are formed via a facile, catalyst-driven, shuttle deprotonation system using acetyl acid chlorides as starting materials and cinchona alkaloids derivatives as the tertiary amine catalysts.;The ketene enolate generated are first used in a catalytic, asymmetric alpha-halogenation reaction to produce synthetically versatile alpha-halo-esters. The success of the alpha-chlorination led us to develop an analogous bromination reaction which, unlike its predecessor, failed upon scale up. A detailed analysis of the reaction through a series of mechanistic studies and the de novo design of a more selective catalyst results in an optimized reaction that is scalable and produces a wider range of products.;Also discussed in this work is a remarkably enantioselective inverse electron demand hetero Diels-Alder reaction between the in situ generated ketene enolate and o-benzoquinone imides. The resulting benzooxazinones are readily converted to alpha-amino acid derivatives through a simple, two-step ring opening and deprotection.;Finally, the [4+2] cycloaddition is shown to be enhanced by the addition of a catalytic amount of Sc(OTf)3. Addition of this Lewis acid creates a bifunctional system with the chiral Lewis base which enhances the rate of the Diels-Alder. |
PDF Full Text Request