Atroposelective Synthesis of Hindered Amides - Exploration of Synthetic Peptide Catalysts -

轴向手性酰胺被认为是“药物发现的潜在威胁”。如果酰胺基团中的阿托异构体的存在仍未被发现，这将大大增加药物研究和药物开发的成本和工作量。虽然轴向手性通常是一个研究较少的现象，但对于酰胺基团来说，它基本上是未被探索的，并且已经成为几个研究活动的障碍。因此，控制稳定的阿托品异构体出现的参数以及以(对映体)纯方式产生它们的合成方法是未知的。此外，值得注意的是，即使发现了具有轴向手性酰胺的有希望的候选药物，也优先开发了非手性衍生物来绕过阿托品异构化的问题。然而，突出的例子，如Telenzepine，表现出轴向手性酰胺基团，表明有必要开发合成方法来对映选择性地制备手性酰胺，并研究控制相应阿托品异构体稳定性的参数。因此，本研究旨在开发一种手性酰胺的手性制备方案，并识别和量化决定手性轴在酰胺中的出现和稳定性的参数。在本项目的第一部分，小的合成肽将作为人工的“迷你酶”来提供一个能够以高阿托选择性制备手性酰胺的手性环境。经典的多肽合成方法是设计新的具有催化活性的官能团的平台，这些官能团将被合并到合成肽中。因此，从简单的羧酸和容易获得的胺开始形成所需的酰胺是可能的。该项目的第二部分旨在提高对酰胺中轴向手性的理解和可预测性。利用基于密度泛函理论的量子力学方法，测定了不同系列阿托品的反转势垒，探讨了立体和电子因素、环的大小和饱和度对手性轴稳定性的影响。Hammett和Taft的相关性预计将有助于任何观察到的关系的量化。在本项目的最后部分，这些发现将被应用于开发、合成和生物学评价新的、稳定的轴向手性类似物(治疗低钠血症)。

Axially chiral amides are considered a "lurking menace in drug discovery". If the existence of atropisomerism in an amide group remains undiscovered, it can substantially increase the cost and effort of pharmaceutical research and drug development. Whilst axial chirality in general is an understudied phenomenon, it is basically unexplored for the amide group and has been an obstacle in several research campaigns, already. Parameters that govern the emergence of stable atropisomers, as well as synthetic methods to generate them in an (enantio-)pure fashion, are hence unknown. Furthermore, it is conspicuous that even if promising drug candidates that possess an axially chiral amide are discovered, preferentially achiral derivatives are developed to circumnavigate the issue of atropisomerism. Yet, prominent examples such as Telenzepine, which exhibit an axially chiral amide group, demonstrate the necessity to develop synthetic methods to enantioselectively prepare chiral amides and to study parameters that govern the stability of the corresponding atropisomers.For this reason, this research endeavor aims to develop a protocol for the atroposelective preparation of chiral amides and to identify and quantify the parameters that dictate emergence and stability of chiral axes in amides.In the first part of this project small synthetic peptides will serve as artificial "mini-enzymes" to provide a chiral environment that enables the preparation of axially chiral amides in high atroposelectivity. Classic methods of peptide synthesis serve as platform for the design of new, catalytically active functional groups, which will be incorporated into the synthetic peptide. Thereby formation of the desired amides will be possible starting from simple carboxylic acids and easily accessible amines.The second part of the project aims to improve understanding und predictability of axial chirality in amides. Utilizing DFT-based quantum mechanical methods inversion barriers of different sets of atropisomeric amides will be determined to explore the influence of steric and electronic factors, ring size and degree of saturation on the stability of the chiral axis. Hammett and Taft correlations are anticipated to aid quantification of any observed relationship. The thus obtained data will serve as basis for facilitated identification, prediction and design of atropisomerism of amides.In the last part of this project these findings will be applied to develop, synthesize and biologically evaluate new, stable axially chiral analogs of the vaptan-type drug family (treatment of hyponatremia).