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

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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).