Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

Abstract

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 analogs 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 non-enzymatic 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.

Site- and Stereoselective Chemical Editing of Thiostrepton by Rh-Catalyzed Conjugate Arylation: New Analogues and Collateral Enantioselective Synthesis of Amino Acids

“…1 Although efficient in principle, this approach necessarily confronts a series of challenges, including (a) the compatibility of the reagents and reaction conditions with a highly functionalized substrate and (b) the site- and stereoselectivity with which reactions occur. 1 Nonetheless, a growing number of reports have demonstrated the potential to achieve catalyst-controlled, site- and, when applicable, stereoselective functionalizations of several functional groups present in biologically relevant compounds. 2 …”

An Efficient Chemo‐Selective N‐Alkylation Methodology for the Structure Diversification of Indolylbenzimidazoles

“…Structure diversification of polyfunctional scaffolds in a chemo‐ or site‐selective fashion has emerged as a highly efficient chemical approach for drug discovery efforts . Such strategies allow organic/medicinal chemists to generate a library of novel structural analogs very rapidly, and without the need for extensive protective group manipulation .…”

“…Structure diversification of polyfunctional scaffolds in a chemoor site-selective fashion has emerged as a highly efficient chemical approach for drug discovery efforts. [1][2][3] Such strategies allow organic/medicinal chemists to generate a library of novel structural analogs very rapidly, and without the need for extensive protective group manipulation. [4][5][6] Nitrogen containing heterocyclic compounds, including indole, benzimidazole and indolylbenzimidazoles are an important class of bioactive scaffolds due to their broad spectrum of bioactivity.…”

Cobalt(III)‐Catalyzed C−H Amidation of Dehydroalanine for the Site‐Selective Structural Diversification of Thiostrepton

“…[1a] Although site-specific modification of 1 is ap ossible approach for improving its aqueous solubility,a rchitectural complexity and ah igh density of delicate functionalities provide af ormidable barrier to successful, site-selective chemical modification. [3,4] Thedehydroalanine (Dha) residues characteristic of 1 and other thiopeptides are reactive sites,most notably as Michael acceptors for av ariety of nucleophilic species. [5] Previously, several studies have been carried out on additions to the Dha residues in 1 (Figure 1, middle).…”