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

受阻酰胺的天体选择性合成-合成肽催化剂的探索-

• 批准号: 504378162
• 负责人: Dr. Tobias Morack
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/504378162?language=en
• 关键词: Atroposelective; Synthesis; Hindered; Amides; Exploration

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).

轴向手性酰胺被认为是“药物发现中的潜在威胁”。如果酰胺基团中阻转异构的存在仍未被发现，则其可显著增加药物研究和药物开发的成本和努力。虽然轴向手性一般是一个未充分研究的现象，它基本上是未探索的酰胺基团，并已在几个研究活动的障碍，已经。因此，控制稳定阻转异构体出现的参数以及以（对映体）纯的方式产生它们的合成方法是未知的。此外，显而易见的是，即使发现了具有轴向手性酰胺的有希望的候选药物，也优先开发非手性衍生物以绕过阻转异构的问题。然而，突出的例子如Telenzepine，其显示出轴向手性酰胺基团，证明了开发对映选择性制备手性酰胺的合成方法和研究控制相应阻转异构体稳定性的参数的必要性。本奋进旨在开发一种手性酰胺的抑制选择性制备方案，并确定和量化决定出现的参数，酰胺中手性轴的稳定性。在该项目的第一部分中，小合成肽将作为人工“迷你酶”，提供一个手性环境，使制备具有高阻旋选择性的轴向手性酰胺成为可能。经典的肽合成方法作为设计新的催化活性官能团的平台，这些官能团将被并入合成肽中。因此，从简单的羧酸和容易获得的胺开始，形成所需的酰胺将是可能的。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DFT为基础的量子力学方法反转障碍的不同设置的阻转异构体酰胺将被确定，以探讨空间和电子因素，环的大小和饱和度的手性轴的稳定性的影响。Hammett和塔夫脱相关性预计有助于量化任何观察到的关系。由此获得的数据将作为基础，促进识别，预测和设计的阻转异构体的amides.In本项目的最后一部分，这些研究结果将被应用于开发，合成和生物学评价新的，稳定的轴向手性类似物的vaptan型药物家族（治疗低钠血症）。