Developing Click Chemistry for Chemical Arrays In Situ Formation and Diverse Transformations of Organic Azides

Click chemistry is a philosophy introduced in the face of the bleak reality that an estimation of the number of 'reasonable' drug candidates, those with less than 30 non-hydrogen atoms; have mass lower than 500 Daltons consisting of only H, C, N, O, P, S, F, Cl and Br; likely to be stable at ambient temperature in the presence of water and oxygen, is in the order of 1x 1062 molecules. Faced with this fact, it might seem obvious that synthetic propositions aimed at drug discovery should be aimed at molecules which are easy to make. The rules defining a click chemistry approach are as follows: a reaction must be modular, wide in scope, give very high yields, generate only inoffensive by-products which are easily separated, and be stereospecific. The process must include simple reaction conditions, readily available starting materials and reagents, the use of no solvent, or a solvent that is benign or easily removed, and simple product isolation. The azide functional group is perhaps one of the most versatile of all, yet, it is has been neglected by the modern organic chemist. This is mainly due to the explosive potential of organic azides. However, advances in azide synthesis allow for this group to be used without ever being isolated. This essentially eliminates the risk.In this proposal, we aim to exploit the reactivity of organic azides for the synthesis of a range of nitrogen containing heterocylcles. Heterocyclic compounds, cyclic molecules in which one or more carbon atoms are replaced by a heteroatom, account for well over half of all known organic compounds. Many classes of natural products, as well as a large majority of commercially important drugs contain heterocyclic rings. Hence the synthesis and study of heterocyclic compounds, in particular nitrogen containing rings, is a subject of immense importance for both academia and industry. The commercial relevance of heterocyclic compounds is demonstrated by the list of best selling pharmaceuticals. This proposal, which has the full support of GSK, seeks support to develop new methods for the safe and efficient use of organic azides, and rapid laboratory preparation of arrays of heterocyclic compounds as potential medicines. Arrays are sets of molecules, prepared simultaneously by automated methods, where structural components of the molecule are varied systematically. Although array synthesis is a fundamental tool in modern medicinal chemistry, the reactions that can be used remain limited, and therefore new methods and protocols are urgently required.