| Natural product isolation is a laborious task, yet it has yielded myriad drug candidates and inspired synthetic chemists for over a century. Considerable advances have been made in separation technology; however, additional methods are needed to streamline discovery efforts. Purification of the active components of a crude extract, which often represent significantly less than 1% by weight, is a major bottleneck in natural product discovery. Current isolation techniques are dependent upon the physicochemical properties of the molecules such as polarity or charge. Often, many components of a crude sample are physicochemically similar, making their separation using these methods exceptionally difficult. To address this challenge, we have developed a complementary strategy to isolate subsets of natural products based upon an orthogonal property, their functional group composition. This technique utilizes tagging reagents, which react chemoselectively with the desired moiety, facilitating enrichment from complex mixtures. We have developed functional group-specific methods for enrichment of molecules containing hydroxyl, carboxylic acid, and alkyne moieties. Further separation of aryl and aliphatic hydroxyl-containing molecules can be accomplished using selective release conditions. These tags either utilize an activated alkylsilane as the capture group or employ this moiety as a readily cleavable linker and their development required extensive exploration of the reactivity and selectivity of alkylsilane- functionalized resins. The devised enrichment reagents generate unique pools of molecules that can subsequently be more readily resolved by traditional chromatography methods. In addition, we have demonstrated that chemoselective enrichment facilitates detection of low abundance species, a characteristic that is crucial for new molecule discovery. As the drug pipeline continues to shrink, a resurgence of natural product discovery is essential to fill that void. New methods, such as reversible enrichment tagging, will enable the discovery of previously undetected molecules and expedite time- consuming dereplication and isolation processes. |
