J.W.T. Spinks Lecture Series - Prof. M. Christina White

Lecture 2: Molecular Surgery

The atomistic change of transforming inert C—H bonds to oxygen, nitrogen, and carbon can have a profound impact on the properties of small molecules (taste, smell, pharmacological profile). Traditional synthetic approaches rely on the use of pre-installed functional groups to direct installation of new functionality. In contrast, nature uses allylic and aliphatic C(sp3)—H hydroxylations mediated by powerful iron enzymes. During this lecture, we will discuss the discovery and development of iron (PDP) catalysts for aliphatic C—H hydroxylations, and iron and manganese phthalocynine catalysts for intramolecular C(sp3)-H aminations and alkylations. These catalysts proceed with unprecedented levels of reactivity and tunable selectivities in complex molecule settings, without the need for directing groups. We have delineated siteselectivity
rules based on the physical organic properties of C-H bonds (electronic, steric, and stereoelectronic) that have proven general across a variety of aliphatic C-H functionalization reactions. Using these novel transition metal catalysts we have validated late stage C-H oxidation, i.e. direct introduction of oxidized functionality into C(sp3)-H bonds of molecule scaffolds, as a powerful approach for streamlining synthetic sequences and directly diversifying natural products, including complex peptides.