Highly efficient synthesis of heterocycles via 5-endo radical cyclisation

Abstract

The principal aim of this project was to synthesise a range of functionalised heterocycles using novel transition metal promoted radical cyclisation reactions as an alternative to the well-established tin hydride method. On achieving this we hoped to successfully apply these methods towards the synthesis of natural product templates. In chapter two, a series of copper(l)-amine catalysts were employed to mediate the 5- endo-trig radical cyclisation of trichloroacetamides, which led to the formation of a variety of highly functionalised bicyclic y-Iactams in good to excellent yield. A variety of cyclisation precursors were examined. This work was also extended towards the synthesis of analogues of the heterocyclic ring fragment of non-peptide bradykinin inhibitor, L-755,807. In chapter 3, the reaction of a series of tertiary bromoacetamides with catalytic copper(I) bromide/N,N,N',N',N",N" -hexamethyltriethylenetetramine (Me6-tren) at room 'temperature is described. This reaction furnished regioisomeric mixtures of unsaturated pyrrolidinones via a highly efficient 5-endo-trig radical cyclisation reaction. We also illustrated that a variety of less activated secondary bromoacetamides undergo efficient 5-endo-trig radical cyclisation reactions to give a,l3-unsaturated monoene lactams under atom transfer conditions mediated by copper(l) bromide and tripyridylamine (TP A) in refluxing toluene. Changing the solvent for this reaction to 1,2-dichloroethane caused a,l3-unsaturated diene lactams to be produced instead. This approach was used towards the synthesis of analogues of the sesquiterpenic alkaloid, eremophilene y-Iactam. Chapter 4 describes an alternative route to constrained bicyclic ring systems mediated by ceric ammonium nitrate (CAN). In addition, the first reported 5-endo-trig radical cyclisation of l3-amido esters to afford functionalised y-Iactams was developed. This methodology was exploited in the production of analogues of the heterocyclic ring fragments of a' number of biologically active natural products