A modular approach for the stereoselective synthesis of bioinspired C-N atropisomeric molecules

Molecular chirality is a fundamental topic in synthetic chemistry and also impacts upon many different areas of modern society such as agrochemistry, pharmaceuticals and materials science. The most widely investigated type of chirality is

"point chirality", which typically involves a sp3 carbon atom bearing four different substituents. Such motifs are widespread in pharmaceuticals, and there are a huge variety of synthetic methods available to access them in a stereo controlled manner. In contrast, atropisomerism is an unusual class of chirality which results from the inability of a molecule to rotate about a single bond, and is an emerging and underexplored class of three dimensionality.

Most examples studied to date involve chirality about C-C bonds but more recent studies have shown that atropisomerism is also possible about C-N single bonds, making it increasingly useful in pharmaceutical design.1 There are several exciting new pharmaceutical agents that feature C-N atropisomerism in their structure. For example, Sotorasib2 is a KRASG12C inhibitor used in the treatment of non-small cell lung cancer and is the first of its kind to target this specific type of cancer and Telenzipine3

is an M1 antimuscarinic used in the treatment of gastric ulcers. The importance of atropisomerism in pharmaceuticals is underlined by a recent study which calculated that 26% of all small-molecule drugs approved by the FDA in 2019-2022 contained an atropisomeric axis, of which almost half (47%) involve restricted rotation about a C-N bond.1 The challenge is, that unlike point chiral molecules, methods for the stereocontrolled synthesis of atropisomeric molecules are highly underdeveloped.

This project aims to develope new stereoselective methods for the synthesis of bioinspired C-N atropisomeric molecules. A particular focus of the project will be upon the synthesis of C-N atropisomeric peptide analogues. Peptides are arguably the most important nitrogen containing functionality in the natural world, and the prospect of forming new three-dimensionalized C-N atropisomeric analogues is very exciting. The project will begin by expanding upon

preliminary work by the Armstrong group in this area to develop new multicomponent chemistry targeting related bioinspired C-N atropoisomeric scaffolds, including the introduction of alternative heteroatoms and access to annulated scaffolds.4 The products of these reactions contain an additional element of point stereogenicity, leading to the possibility for formation of diastereomers and our goal is to develop reactions conditions which are capable of selectively targeting either stereoisomer. Beyond these aims, a further key ambition of the project is to introduce a chiral catalyst which can control absolute stereochemistry.

In particular, the focus here will be upon dynamic kinetic resolution processes, in which a rapidly racemizing precursor or intermediate is converted to a configurationally stable, enantiopure product. 5 The resulting DKR chemistry will initially be explored in the context of C-N atropoisomeric peptide analogues, but may also have broader applications for the asymmetric synthesis of other atropisomeric scaffolds. Overall, the aim of the project is to develop new methods that enable access to bioinspired C-N atropoisomeric molecules and allow their stereochemistry to be precisely controlled.

1. M. Basilaia, M. H. Chen, J. Secka and J. L. Gustafson, Acc. Chem. Res., 2022, 55, 2904-2919. 2. L. Zhang, D. J. Griffin, et al., OPR&D, 2022, 26, 3115-3125. 3. B. Testa, G. Vistoli and A. Pedretti, Eur. J. Pharm. Sci., 2016, 88, 101-123. 4. N. J. Roper, A. D. G. Campbell, P. G. Waddell, A. K. Brown, K. Ermanis and R. J. Armstrong, Chem. Sci., 2024, 15,

16743-16751 5. JP. Heeb, J. Clayden, M. D. Smith, R. J. Armstrong, Nat. Protoc., 2023, 18, 2745-2771.