Exploration of haloalkylated β-ketoesters in C–C bond fragmentation and radical cascade reactions

Abstract

The development of novel transformations is a key paradigm of synthetic organic chemistry. In order to be of practical significance, ready access to a range of starting materials with broad structural variety is an important consideration when developing new methodologies. The research detailed in this PhD thesis takes advantage of the ubiquity of cyclic β-ketoesters and their ready conversion to the corresponding haloalkylated derivatives, and applies the resultant β-haloalkylated β-ketoesters in C–C bond fragmentation and radical cascade reactions. In the introductory chapter, a short overview of synthetic approaches to cyclic β-ketoesters is given. Their ability to undergo C-alkylation with electrophilic dihaloalkanes is then discussed, followed by an overview of previous synthetic efforts to apply the resultant β-haloalkylated β-ketoesters in organic transformations. It is concluded that, while some attention has been focused on their use in subsequent reactions, a number of avenues for reaction discovery exist that are largely unexplored. In the second chapter of this thesis, Grob-Eschenmoser-type C–C bond fragmentation reactions are introduced. Traditionally, the fragmentation is restricted to small sized ring systems, working efficiently only on cyclopentanones. By inclusion of an electron-withdrawing group in β position to the carbonyl, it is shown that facile C–C bond fragmentation can be achieved with a wide range of nucleophiles, and on cycloalkanones of varying ring size and substitution. Mechanistic studies are conducted, which provide greater support for a concerted Grob fragmentation over a two step retro-Dieckmann/elimination sequence. Application of the fragmentation products to the synthesis of 1,2-dicarbonyls, substituted g-lactones and the side chain of the natural product eriolangin are also discussed. The studies detailed in the third chapter describe the application of the C–C bond fragmentation reaction to the divergent synthesis of dendritic molecules. By iterative C–C bond fragmentation/thio-Michael addition a fourth generation dendrimer is assembled, which is thoroughly characterised. In addition, a number of structurally diverse first and second generation dendrimers are synthesised. Combination of the C–C bond fragmentation with a deprotection step allows for the assembly of internally functionalised AB2C dendrimers. Water solubility is targeted, and found to be best achieved by inclusion of oligoether moieties into the dendritic structure. Efforts to immobilise catalytically active chiral secondary amines onto the dendritic support are then discussed. While a range of first generation organocatalytic dendrimers are synthesised, their performance in the a-amination of aldehydes proceeds with only moderate enantioinduction. In the fourth chapter, the Beckwith-Dowd ring expansion is introduced, a reaction that furnishes ring expanded cycloalkanones from haloalkylated cyclic β-ketoesters. It is demonstrated that radical cascades can be triggered by inclusion of an allylic or propargylic ester substituent, leading to spirocyclic g-lactones. Following reaction development and optimisation, the scope of the cascade with regards to the ester substituent, the cycloalkanone ring size and the length of the haloalkylated side chain are investigated. The chapter concludes with short studies on the application of the cascade reaction to the synthesis of spirocyclic g-lactams or all-carbon spirocycles. The fifth chapter provides a summary of the chemistry detailed in the preceding chapters and outlines future directions for this research project. Finally, the sixth chapter contains experimental procedures utilised within this project and all the spectroscopic data derived from the compounds introduced in the preceding chapters.