An organocatalytic approach to the stereoselective synthesis of N-N atropisomeric hydrazides via relay catalysis

The dynamic nature of single bonds in organic molecules is often overlooked despite the great potential offered by altering such rotation, as observed in atropisomers. Completely different biological, physical or chemical properties can be obtained when two different axial configurations of the same molecule are considered, with their asymmetric synthesis being of enormous importance. In the well explored scenario of C-C and C-X atropisomeric biaryls and non biaryls, atropisomerism deriving from an X-X axis is totally underdeveloped, with only few examples of asymmetric synthesis. In this context, N-N atropisomers represent interesting scaffolds for their widespread occurrence among natural products and their possible application in catalysis as chiral ligands or catalysts, or in material science. Being aware of the properties of hydrazides as bioactive compounds, my PhD project focused on the asymmetric synthesis of tetrasubstituted hydrazides featuring a N-N restricted bond. Initial investigation through computational analysis aimed to the design of a suitable hydrazide possessing sufficient restriction to rotation. Asymmetric synthesis of such compound was then achieved for the first time through a two-step organocatalytic protocol, starting from commercially available starting materials and providing high level of enantio- and diastereoselectivity on two distinct stereogenic elements. The synthesis features a sequential catalysis realized in a one-pot fashion, which makes the approach even more challenging and appealing. In depth analysis on the mechanism elucidated the factors controlling the enantioselectivity for both steps of the reaction. Finally, an even more straightforward synthesis of such hydrazides was planned through an auto-relay catalytic process. As side project, visible-light promoted deaminative functionalization of primary amines was explored during the period abroad spent in the research group of prof. Tortosa at the Universidad Autonoma de Madrid. Deaminative fluorination and arylation were developed to provide valuable final products from abundant starting materials.