Chemo- and site-selective derivatizations of natural products enabling biological studies

Abstract

Bioactive natural products and derivatives remain an enduring starting point for the discovery of new cellular targets for disease intervention and lead compounds for the development of new therapeutic agents. The former goal is accomplished through the synthesis of bioactive cellular probes from natural products enabling insights into the mechanism of action of these natural products by classical affinity chromatography or more recent proteome profiling methods. However, the direct and selective modification of native natural products for these purposes remains a challenge due to the structural complexity and the wide functional group diversity found in these natural substances. The lack of selective synthetic methods available to directly manipulate unprotected complex small molecules, in particular to perform structure-activity relationship studies and prepare appropriate cellular probes, has recently begun to be addressed benefitting from the broader emerging area of chemoselective synthetic methodology. Thus, new reagents, catalysts and reaction processes are enabling both chemo- and site-selective modifications of complex, native natural products. In this review, we describe selected recent examples of these functionalization strategies in this emerging area.

Chemoselective conversion of biologically sourced polyols into chiral synthons

“…Intermediate II′ differs from II in that its counterion is the non-coordinating B(C 6 F 5 ) 4 − instead of the reactive H−B(C 6 F 5 ) 3 − . 13 C{ 1 H} NMR spectroscopy revealed that the symmetric 3c converts to an asymmetric species with two methyl groups and four trisubstituted CH centres (Fig. 3a).…”

“…The number of products that could be accessed from ring-opened or ring-closed sugars by controlling the positional selectivity of a deoxygenation process is significant, and such products would have the properties of a fine or specialty chemical. The possibility of synthesizing multiple high-value materials by controlling the deoxygenation of a small number of base carbohydrate feedstocks is appealing but poorly supported by the literature, although the chemoselective functionalization of complex polyols is an emerging field of considerable importance [13][14][15][16][17][18] .…”

Reinvigorating natural product combinatorial biosynthesis with synthetic biology

“…Even today, the importance of natural products as drug leads cannot be overstated. They continue to account for the majority of antimicrobial and anticancer agents approved by the FDA 2 while similarly serving as indispensable molecular probes in illuminating fundamental cellular processes 3 . Nevertheless, the pharmaceutical industry has severely pulled back its support for natural products research in recent decades in favor of synthetic approaches in building chemical libraries that are more suitable for modern biological screening campaigns.…”

Structure Diversification of Vancomycin through Peptide-Catalyzed, Site-Selective Lipidation: A Catalysis-Based Approach To Combat Glycopeptide-Resistant Pathogens

“…In recent years, catalyst dependent diversification of complex drug molecules has gained considerable interest. 8-11 Many important approaches, including biocatalysis, may be brought to bear on the problem. 12 …”