Convergent Acyliminium Methodology: Diversity in Heterocyclic Scaffolds

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Heterocyclic compounds are the cornerstone of the pharmaceutical and agrochemical industries. As part of our on-going research programme geared towards the synthesis of heterocyclic systems of biological interest, we have placed a great deal of emphasis on designing streamlined and environmentally friendly cascade and telescoped processes leading to valuable heterocycles. We now propose to develop Convergent Acyliminium Methodology (CAM) to establish an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of highly functionalised heterocyclic systems. We believe that such a simple and reliable procedure leading to novel heterocyclic scaffolds will be a valuable addition to existing "diversity-oriented" synthetic protocols and will be of great utility to synthetic chemists in both academia and industry. Preliminary studies have been carried out which establish the viability of this novel approach; the main aims of the proposal are therefore: (i) to optimise the novel Convergent Acyliminium Methodology (CAM) to develop an efficient "one-pot" route to convert readily available imines and carboxylic acids into a diverse range of heterocyclic systems, (ii) to expand the range of acylating agents to include benzannelated examples and functionalized sulfonic acids, phosphonic acids, chloroformates and isocyanates,(iii) to explore asymmetric catalysis to prepare heterocycles in enantio-enriched forms,(iv) to extend the range of imine substrates to encompass acyclic imines, imidates, oxazolines, imidazolines and thiazolines,(v) to exploit the CAM sequence in an iterative sense utilising repeated ring-expansions to produce medium-sized and macrocyclic lactams and cyclic peptides,(vi) to extend the methodology to prepare the complex natural product, 'upenamide, in order to showcase this new synthetic approach,(vii) to apply, and therefore validate, the new CAM sequence in simple target synthesis with jamtinine and loracarbef as possible targets (although targets from collaborators will also be considered).It is our aim to develop this new procedure into a powerful synthetic procedure with far-reaching applications in academic research, industrial medicinal chemistry and scale-up processes (letters of support from AstraZeneca and Novartis (pharma) and Bayer (Agro) are attached and plans for collaborations with these companies are well advanced). This ambitious programme will be carried out by a PDRA over a 3 year period.