Multiple Enone-Directed Reactivity Modes Lead to the Selective Photochemical Fluorination of Polycyclic Terpenoid Derivatives

In the realm of aliphatic fluorination,
the problem of reactivity
has been very successfully addressed in recent years. In contrast,
the associated problem of selectivity, that is, directing fluorination
to specific sites in complex molecules, remains a great, fundamental
challenge. In this report, we show that the enone functional group,
upon photoexcitation, provides a solution. Based solely on orientation
of the oxygen atom, site-selective photochemical fluorination is achieved
on steroids and bioactive polycycles with up to 65 different sp3 CH bonds. We have also found that γ-, β-,
homoallylic, and allylic fluorination are all possible and predictable
through the theoretical modes reported herein. Lastly, we present
a preliminary mechanistic hypothesis characterized by intramolecular
hydrogen atom transfer, radical fluorination, and ultimate restoration
of the enone. In all, these results provide a leap forward in the
design of selective fluorination of complex substrates that should
be relevant to drug discovery, where fluorine plays a prominent role.