Chemoselective enrichment for natural products discovery

Abstract

Natural products account for a significant proportion of modern day therapeutic agents. However, the discovery of novel compounds is hindered by the isolation process, which often relies upon extraction and chromatographic separation techniques. These methods, which are dependent upon the physicochemical properties of the compounds, have a limited ability to both purify and concentrate the minor components of a biological extract. We have devised an isolation strategy based upon an orthogonal chemical feature, namely, functional group composition. Development of a functional group-targeted method is expected to achieve exceptional resolution given the large number of distinct moieties present in natural product extracts. Here, we describe the generation of controllably reversible covalent enrichment tags for the chemoselective isolation of alcohol-containing natural products from complex mixtures.

Fig. 1

Depiction of the chemoselective enrichment strategy. Compounds from a crude natural product extract are immobilized onto reversible tagging agents. After enrichment, compounds are released from the solid support to enable direct structural and functional characterization.

Fig. 2

Extracted ion chromatograms of alcohols captured from Streptomyces griseolus broth. Endogenously-produced anisomycin (8) was captured (30.5 nmol, 82% recovery). Two additional alcohols were spiked into the extract (223 nmol each) and enriched, cortisone (6, 113 nmol, 51% recovery) and trans-androsterone (7, 119 nmol, 53% recovery).

Scheme 1

General strategy for enrichment of alcohol-containing natural products.

Scheme 2

Synthesis and regeneration of benzyl alcohol-derived resins. Hydroxylmethyl polystyrene resin can be functionalized with a variety of dichlorodialkyl silanes yielding the capture reagents. Following alcohol enrichment and cleavage, the starting resin is regenerated as indicated by the green arrow.