Tandem Intramolecular Michael-Anion Exchange-Olefination Methodology: New Telescoped Approaches to alpha-Methylene Lactones

There is much current interest in the development of preparative procedures in which two or more transformations are carried out as a one-pot process. These processes offer a number of advantages to the organic chemist: in particular, they result in a reduced number of operations, giving significant time-cost benefits but also they can often allow difficult intermediate compounds to be prepared and elaborated in situ, thus preventing problems associated with their isolation and handling.The main aim of this proposal is to develop a generalised tandem intramolecular Michael-anion exchange-olefination (TIMO) sequence for the one-pot formation of alpha-methylene-lactones, thereby telescoping at 3/4 conventional processes into a one-pot procedure. The method is ideally suited to diversification/library synthesis and a solid-supported variant will be investigated leading to the possibility of an automated procedure. A range of variants will be explored tio evaluate the scope of the methodology.These TIMO methods will then be utilised to prepare a range of novel and natural alpha-methylene-lactones to validate the new chemistry. Alpha-methylene lactones are considerered to be privileged structures in terms of biological potential. Novel and natural compounds prepared in this study will therefore be made available to biological collaboratorsThe precise choice of targets will depend on the methodology studies but the starting point would be Ph. D.: paeonilactone then mayolide; PDRA: yomogin or 9-oxo-tournefolide then 5-oxo-jasoniolide then one of the more complex examples such as physalin A, ratiferolide, montahibisciolide etc.