Efficient, multi-hundred-gram scale access to E3 ubiquitin ligase ligands for degrader development.

Small molecule heterobifunctional degraders (commonly also known as PROTACs) offer tremendous potential to deliver new therapeutics in areas of unmet medical need. To deliver on this promise, a new discipline directed at degrader design and optimization has emerged within medicinal chemistry to address a central challenge, namely how to optimize relatively large, heterobifunctional molecules for activity, whilst maintaining drug-like properties. This process involves simultaneous optimization of the three principle degrader components: E3 ubiquitin ligase ligand, linker, and protein of interest (POI) ligand. A substantial degree of commonality exists with the E3 ligase ligands typically used at the early stages of degrader development, resulting in demand for these compounds as chemical building blocks in degrader research programs. We describe herein a collation of large scale, high-yielding syntheses to access the most utilized E3 ligase ligands to support early-stage degrader development.

Developing asymmetric iron and ruthenium-based cyclone complexes; complex factors influence the asymmetric induction in the transfer hydrogenation of ketones.

The preparation of a range of asymmetric iron and ruthenium-cyclone complexes, and their application to the asymmetric reduction of a ketone, are described. The enantioselectivity of ketone reduction is influenced by a single chiral centre in the catalyst, as well as by the planar chirality in the catalyst. This represents the first example of asymmetric ketone reduction using an iron cyclone catalyst.