Abstract Late stage functionalization (LSF) is a synthetic strategy to derivatize medicinally interesting compounds to optimize key properties such as bioactivity, pharmacokinetics, etc. The challenge to the synthetic methodology for doing so is one of chemo- and site-selectivity as most such species are multi-functional, and even display multiple copies of a target functional group. We outline an approach that utilizes oxophilic silylium and borenium ions to target for subsequent derivatization, the C–O bonds common in bioactive natural products (NPs), all under catalyst or reagent control. The methods to be investigated first heterolytically cleave Si–X and B–X bonds (X= H, allyl, N3, etc), and then sequences their reactivity to achieve the C–O activation/functionalization goal. Fluoroaryl borane Lewis acids such as B(C6F5)3, BCF, are effective catalysts for generating the key reactive ion pairs and they will be optimized via high throughput screening techniques.