Catalytic Atroposelective Synthesis for Revealing Elusive Bioactive Conformations and Shapes

Atropisomeric molecules (atropisomers) are separable conformational isomers arising from restricted rotation around a single bond. Atropisomers have revolutionized the treatment of several deadly diseases.

The principal goal of AtropShape is to create pharmaceutical leads with unusual conformations and shapes by developing catalytic stereoselective (atroposelective) synthesis methods toward difficult-to-access drug-like atropisomers. Because atropisomers are chiral, they give rise to two or more isomers that have different pharmacological properties.

These attributes relate to a crucial, yet minimally investigated and poorly understood fundamental question of how conformational changes, from achiral and relatively planar to chiral and more tridimensional atropisomeric forms, impact a molecule’s ability to interact with biological receptors. But to study such range of atropisomers and related concepts, one must first of all create them.

Therefore, I will introduce three new catalytic atroposelective methods. (1) We will develop unprecedented atroposelective amide-bond formations and apply them to synthesis of the first examples of peptidomimetics with an atropisomeric amide moiety. (2) We will efficiently generate, by alkyne cyclization strategies, sphere-shaped atropisomers.

This rarely investigated area of molecular shape is much sought-after in drug discovery. (3) We will introduce the first instances of atroposelective decarboxylation of esters.

The proposed methods will offer direct access to an assortment of bioactive atropisomers, which will be easily modifiable to generate, by diversity-oriented synthesis approaches, libraries of drug-like molecules which will be tested broadly in medicinal chemistry.

Collectively, the resulting knowledge will shed light on key differences between pharmacological properties of achiral compounds and chiral atropisomeric molecules, constituting an invaluable insight for drug discovery and development.