Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

• Published in: Chemical reviews 2017-09, Vol.117 (18), p.11894-11951
• Main Authors: Shugrue, Christopher R, Miller, Scott J
• Format: Article
• Language: English
• Subjects: Alkaloids; Biological activity; Biological Products - chemical synthesis; Biological Products - chemistry; Carbohydrates; Catalysis; Catalysts; Chemical synthesis; Enzymes; Functional groups; Glycopeptides; Hydrogen bonds; Hydroxyl groups; Microenvironments; Mode of action; Molecular Conformation; Molecules; Natural products; Oxidation; Reagents; Scaffolds; Selectivity; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Stereoselectivity; Terpenes
• ISSN: 0009-2665; 1520-6890
• DOI: 10.1021/acs.chemrev.7b00022

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential “late-stage functionalization” exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C–H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C–C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.