(aka Brominating the secondary metabolome)
Reactivity-guided isolation is an innovative method for the discovery of specific natural products (NPs) in complex extracts. It identifies metabolites based on their reactivity and has the potential to transform the way in which natural products chemists uncover certain classes of NPs. Specifically, the approach entails the covalent labeling of targeted NPs using chemoselective reagents or “probes” with prominent UV/vis properties and a distinct bromine isotopic signature (79Br:81Br 1:1) and is tied to the well-established practice of using reactive bromoarenes such as 4-bromobenzoyl chloride to yield crystalline material amenable to X-ray crystal structure analysis. Despite the fact that it does not directly furnish unaltered NPs, the method provides profound insight into the chemical space of an extract. It is a precise examination into the presence and abundance of a specific functionality or structural moiety that can be directly coupled to genome-mining studies. The method promises to de-orphan a large number of biosynthetic gene clusters and lead to the discovery of new NPs in a chemocentric manner.
To date, we have designed and applied probes that target NPs with electrophilic moieties (α,β-unsaturated carbonyl groups, epoxides, β-lactones, β-lactams), conjugated alkenes, enediynes, isocyanides, terminal alkynes, phosphonates, and amino groups.