Rearrangement of cis-fused beta-lactams into the 6-azabicyclo[3.2.1]octane ring system

Two thirds of clinically used drugs contain nitrogen heterocyclic ring systems. Inspiration for the design of these drugs has often been found in Nature, where alkaloids such as cocaine, morphine, quinine, nicotine and caffeine all contain one or more nitrogen atoms contained within a ring system. This proposal concerns the synthesis of a particular type of nitrogen heterocyclic ring system, found both in naturally occurring alkaloids and also in compounds synthesized by medicinal chemists searching for molecules which can act, like cocaine, as dopamine uptake inhibitors. These compounds contain a bridging carbon atom that is frequently also bound to atoms other than hydrogen, and can thus be described as functionalized at this position of the ring system. New and improved means of accessing this molecular arrangement is important for chemists working in the pharmaceutical, agrochemical and fine-chemical industries, and in academic laboratories.We propose that beta-lactams fused to a second ring can be isomerised (rearranged) into bridged bicyclic amines that importantly contain a functional group (a ketone) at the bridging carbon that can be easily modified in further chemical transformations. Beta-lactams are four-membered nitrogen-containing ring systems, which are somewhat strained (are less energetically favourable) compared with larger ring systems, but which are simple to prepare using chemical reactions we have previously developed. The proposed rearrangement relieves the strain energy through increasing the size of the ring. An additional driving force for the rearrangement is provided by the formation of a ketone, such that the overall transformations can be related to a well-known chemical reaction called the pinacol rearrangement. Having established the correct conditions to achieve the proposed rearrangement and used them in a number of relevant examples, application in the synthesis of two naturally occurring compounds will be investigated. Peduncularine is an alkaloid isolated from a Tasmanium shrub and is reported to show cytotoxicity activity towards breast cancer cell lines. The structure of peduncularine contains two nitrogen heterocycles, an indole and a 6-azabicyclo[3.2.1]octene, the latter of which is directly accessible using the proposed rearrangement chemistry. Calyciphylline D contains a particularly complex pentacyclic skeleton which has never been synthesized, but has embedded within it a 6-azabicyclo[3.2.1]octane system. Addition of an additional three rings to this system, again prepared through rearrangement of a beta-lactam, will be investigated through the use of a tandem free radical reaction, where two carbon-carbon bonds and a carbon-sulfur will be formed in one synthetic operation.The results of this project, in addition to applications in the synthesis of biologically important compounds, will greatly add to our understanding of structure and reactivity of small ring systems in organic chemistry.