Improbable folded macrocycle shapes through interactional frustration

控制分子的形状对于分子功能的设计是必不可少的。因此，对新分子形状的探索为新性质铺平了道路。折叠和大环化都是稳定分子形状的既定方法，但它们通常会产生可能的形状，即在未折叠或无环前体的范围内的形状，在这个意义上，它们不是热力学或熵不利的。在最近发表了关键的初步结果之后，该项目旨在开发两种新的策略，即结合联合收割机折叠和大环化以产生不可能的分子形状。在第一种策略中，具有强折叠倾向的分子骨架将通过大环化被阻止以其偏好的方式折叠，即受阻。为此，将引入折叠破坏剂以允许发生大环化并随后移除。在第二种策略中，动态共价大环，即其单元可以可逆重组的大环，将配备有可以促进非共价相互作用的官能团，其方式使得这些不能在小环中实现，使得大环（多达23个单元！），产生熵不利的大环，其具有良好限定的折叠形状。因此，这两种策略都利用了非共价相互作用的某种形式的挫折的编排。它们还基于涉及芳香族和肽单元的相关结构单元。将研究所获得的不可能的分子形状，沿着它们的分子识别特性和它们将构象应变传递到插入主链中的分子功能的能力。

Controlling molecular shape is essential to the design of molecular function. Accessing to new molecular shapes thus paves the way to new properties. Both folding and macrocyclization are established approaches to the stabilization of molecular shape, but they generally produce probable shapes, that is, shapes that are within the reach of the unfolded or acyclic precursors in the sense that they are not enthalpically or entropically disfavored. Following the recent publication of key preliminary results, this project aims at developing two new strategies that combine folding and macrocyclization to generate improbable molecular shapes. In the first strategy, a molecular backbone with a strong folding propensity will be prevented from folding the way it prefers, i.e. frustrated, through macrocyclization. For that purpose, folding disruptors will be introduced to allow for macrocyclization to take place and removed afterwards. In the second strategy, dynamic covalent macrocycles, i.e. macrocycles whose units can reversibly recombine, will be equipped with functionalities that can promote non covalent interactions in such a way that these cannot be fulfilled in the small rings so that large (up to 23 units!), entropically disfavored, macrocyles are generated that possess well defined folded shapes. Both strategies thus exploit the orchestration of some form of frustration of non-covalent interactions. They are also based on related building blocks involving aromatic and peptidic units. The obtained improbable molecular shapes will be investigated, along with their molecular recognition properties and their ability to transmit conformational strain to molecular functions inserted in the backbones.