Semipinacol rearrangement of cis-fused β-lactam diols into bicyclic lactams

The 6-azabicyclo[3.2.1]octane ring system is found in a wide variety of biologically active natural and non-natural products. The aim of this project is to prepare the 7,8-diketo-6-azabicyclo[3.2.1]octane structure via a semipinacol rearrangement of ring-fused β -lactams. Chapter 1 introduces the pinacol and semipinacol rearrangement, including the use of cyclic sulfites and phosphoranes, and ring expansion of β -lactams. Previous work in the Grainger group for the synthesis of lactams via tandem radical cyclisation-dithiocarbamate group transfer is also discussed. Chapter 2 describes the methodology developed for the semipinacol rearrangement of β-lactams. Access to suitable precursors for the semipinacol rearrangement is achieved through a sequence of 4-exo trig radical cyclisation, base-mediated dithiocarbamate group elimination and dihydroxylation. Formation of the 7,8-diketo-6-azabicyclo[3.2.1]octane ring system occurs through semipinacol rearrangement of the corresponding cyclic sulfites and phosphoranes. In Chapter 3, the scope and limitations of the methodology are explored. Different substituents on the nitrogen of the β-lactam, groups on the cyclohexane moiety (methyl and oxygenation) and ring sizes are investigated. An original approach to the total synthesis of peduncularine is described in Chapter 4. Synthesis of a suitably functionalised β-lactam and attempts to further transform it into the desired 7,8-diketo-6- azabicyclo[3.2.1]oct-3-ene structure are reported. Work towards the total synthesis of calyciphylline D, calyciphylline F and caldaphnidine M is described in chapter 5. Reductive amination and stereoselective reduction of piperitone are investigated. Use of a model system for the addition of nucleophiles onto thiolactams is also described.