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而引入的哲学，即对“合理”候选药物的数量进行估计，即少于30个非氢原子的候选药物；质量小于500道尔顿的，仅由H、C、N、O、P、S、F、Cl和Br组成；在有水和氧存在的环境温度下可能是稳定的，大约是1 × 1062个分子。面对这一事实，似乎很明显，以药物发现为目标的合成命题应该以容易制造的分子为目标。定义点击化学方法的规则如下：反应必须是模块化的，范围广，产率高，只产生易于分离的无害副产物，并且具有立体特异性。该工艺必须包括简单的反应条件，易于获得的起始材料和试剂，不使用溶剂，或使用良性或易于去除的溶剂，以及简单的产物分离。叠氮化物官能团可能是所有官能团中用途最广的一个，然而，它却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，叠氮化物合成的进步使得这一基团无需被分离就可以使用。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，即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，以及绝大多数商业上重要的药物都含有杂环。因此，杂环化合物的合成和研究，特别是含氮环的合成和研究，对学术界和工业界来说都是一个非常重要的课题。杂环化合物的商业意义可以通过畅销药物的列表来证明。该提案得到了GSK的全力支持，旨在寻求支持开发安全有效地使用有机叠氮化物的新方法，以及作为潜在药物的杂环化合物阵列的快速实验室制备。阵列是一组分子，通过自动化方法同时制备，其中分子的结构成分系统地变化。虽然阵列合成是现代药物化学的基本工具，但可用的反应仍然有限，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.