Oxidative processes - from amino acids to heterocycles, complexity from simplicity

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In our search for better medicines to improve healthcare in an ageing population, for safer agrochemicals to aid food production for a growing population, and for improved materials for reprographics and electronics to match our insatiable desire for new technology, chemical synthesis will play a dominant role. Without synthesis the new molecules required to address such issues will simply not be available.In searching for efficiency in synthesis, we can learn much from Nature, whose biochemical machinery can convert simple building blocks into complex molecules. Hence the overall aim of this Proposal is to emulate the ingenuity and efficiency of Nature in the arena of oxidation, a topic that is fundamental not only to chemical synthesis, but to life processes in general. We will develop new strategies using oxidative processes for the construction of complex biologically active molecules that comprise nitrogen-containing (heterocyclic) rings from simple amines or amino acids - complexity from simplicity.Oxidative processes in Nature depend upon oxygen, and therefore we propose to develop new oxidative protocols that use a catalytic amount of a non-metal oxidant, compounds known as quinones, in the presence of air/oxygen as oxidant. This protocol will then be employed in the oxidation of a simple tryptophan tetrapeptide to form more complex molecules that will then serve as precursor to the structurally unique anticancer compound diazonamide A. Two further oxidative processes are then planned to finalise the complete diazonamide framework, an overall increase in complexity from five rings to ten in just three oxidative steps.We will further demonstrate the power of oxidative processes in the synthesis of the unusual heterocycle violatinctamine, a fascinating molecule very closely related to the natural pigments of human red hair. Again, we approach the problem using oxidative transformations of simple building blocks - amines and aminoacids such as dopamine, cysteine and phenethylamines - to form a more complex, and biologically relevant molecule.Natural compounds from the oceans often possess potent medicinal activity, and there are already three marine derived drugs in clinical use. However, full biological evaluation of such natural substances is usually hampered by lack of material, and chemical synthesis is the only recourse to obtain enough material for study. The pterocellins are a case in point. They possess anticancer, antibacterial and antifungal activity, and although they have been obtained by chemical synthesis, a more efficient route is required. We speculate that well known naturally occurring substances known as beta-carbolines serve as precursors to the pterocellins via a series of oxidative processes, and propose to demonstrate this in the laboratory. Thus simple beta-carbolines, readily available from tryptamines, can undergo oxidative transformation into the complex oxygenated structures exemplified by the medicinally active heterocyclic compound pterocellin A.The Proposed Research derives inspiration from natural routes to complex molecules that possess biological activity. Oxidative processes are at the heart of all the proposed work, and feature throughout as pivotal steps, often initiating a cascade of reactions that result in extremely efficient syntheses, embodying the principle of complexity from simplicity. The methodology is illustrated in routes to a range of heterocyclic molecules, a class of compounds of enormous commercial importance. The strategies and chemistry embodied in the Proposal will enable the facile preparation of a wide range of heterocyclic ring systems, and will impact on the UK fine chemicals industry. All concerned with the development of new medicines, agrochemicals, reprographic materials etc, where heterocyclic compounds completely dominate the field, will benefit immediately from the proposed research programme.