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

点击化学是一种面对惨淡现实的哲学，即对“合理”候选药物数量的估计，那些具有少于30个非氢原子的药物;具有低于500道尔顿的质量，仅由H，C，N，O，P，S，F，Cl和Br组成;在水和氧存在下在环境温度下可能是稳定的，大约为1 × 1062个分子。面对这一事实，似乎显而易见的是，旨在发现药物的合成主张应该针对容易制造的分子。定义点击化学方法的规则如下：反应必须是模块化的，范围宽，产率非常高，只产生容易分离的无害副产物，并且是立体特异性的。该方法必须包括简单的反应条件、容易获得的起始材料和试剂、不使用溶剂或使用良性或容易除去的溶剂以及简单的产物分离。叠氮官能团可能是最通用的官能团之一，然而，它一直被现代有机化学家所忽视。这主要是由于有机叠氮化物的爆炸潜力。然而，叠氮化物合成的进展允许使用该基团而无需分离。这基本上消除了风险。在这个提议中，我们的目标是利用有机叠氮化物的反应性来合成一系列含氮杂环。杂环化合物，其中一个或多个碳原子被杂原子取代的环状分子，占所有已知有机化合物的一半以上。许多种类的天然产物以及大多数商业上重要的药物含有杂环。因此，杂环化合物，特别是含氮环的合成和研究对于学术界和工业界都是非常重要的课题。杂环化合物的商业相关性通过最畅销的药物列表来证明。该提案得到了GSK的全力支持，旨在寻求支持，以开发安全有效使用有机叠氮化物的新方法，并快速实验室制备作为潜在药物的杂环化合物阵列。阵列是通过自动化方法同时制备的分子组，其中分子的结构组分系统地变化。虽然阵列合成是现代药物化学中的基本工具，但可以使用的反应仍然有限，因此迫切需要新的方法和方案。

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.