Improbable folded macrocycle shapes through interactional frustration

分子形状的控制是分子功能设计的关键。因此，获得新的分子形状为获得新的性质铺平了道路。折叠和大环化都是稳定分子形状的既定方法，但它们通常产生可能的形状，也就是说，在没有折叠或非环前体的意义上，它们不会在热效应或熵上不利的形状。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，将折叠和大环化相结合来生成不太可能的分子形状。在第一种策略中，具有很强折叠倾向的分子主链将通过大环化被阻止以其喜欢的方式折叠，即受挫。为此，将引入折叠干扰物，以允许发生大环化并在之后移除。在第二种策略中，动态共价大环，即其单元可以可逆地重组的大环，将配备能够促进非共价相互作用的功能，使得这些作用不能在小环中实现，从而产生具有明确折叠形状的大(最多23个单元！)、熵不利的大环。因此，这两种策略都利用了某种形式的非共价相互作用受挫的协调。它们还基于涉及芳香族和多肽单元的相关构建块。将研究获得的不可能的分子形状，以及它们的分子识别特性和它们将构象应变传递给插入骨架的分子功能的能力。

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.