Development of a Natural-Product-Derived Chemical Toolbox for Modulation of Protein Function

Examples of some of the most used techniques for producing libraries of natural products (NPs) or NP-inspired compounds are reviewed. Natural-product-derived libraries are generated around a scaffold that is identical to that of the leading NP and which is obtained by means of chemical modification or degradation. The library members are then synthesized from the scaffold using a step-by-step derivatization. The scaffolds of compound collections inspired by NPs usually are closely related to the guiding NP. Multistep sequences are used to build up the scaffold from preassembled functionalized building blocks. This strategy allows variation of substitution pattern and stereochemistry, which can be different from the inspiring NP. Solid-support-based synthesis techniques allow one to easily remove surplus reagents typically used to ensure high conversion. Transition-metal-catalyzed transformations on solid support have offered novel opportunities for NP-inspired library synthesis.