The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry

Abstract

This review summarizes and highlights recent advances in medicinal chemistry of natural products enabled by total synthesis that provide “supernatural products” with improved properties superseding the natural products themselves.

Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS‐STING Pathway

“…Due to the insufficient availability of the compound from natural sources and limitations of current late‐stage peripheral modification methods, a broad structure–activity study of vermiculine can only be facilitated by total synthesis. In recent years, even very complex scaffolds has been brought within the realm of traditional medicinal chemistry through diverted total synthesis [23–27] . By design of typically highly modular [28, 29] synthetic routes, a whole family of natural products and analogues bearing multiple modifications can be achieved within a minimized number of steps to facilitate biological studies [30, 31] .…”

Facile and Divergent Optimization of Chromazonarol Enabled the Identification of Simplified Drimane Meroterpenoids as Novel Pharmaceutical Leads

“…The accumulated evolutionary wisdom endows natural products with novel and diverse scaffolds and activities, which demonstrated an unparalleled valuable significance for the discovery of pharmaceutically important molecules, including both drugs and agrochemicals [1][2][3][4][5]. Either the natural scarcity or the structural complexity often hampers further optimization and investigation of potential natural products in the discovery pipeline of pharmaceutical candidates.…”

Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS‐STING Pathway

“…Due to the insufficient availability of the compound from natural sources and limitations of current late-stage peripheral modification methods,abroad structure-activity study of vermiculine can only be facilitated by total synthesis.Inrecent years,e ven very complex scaffolds has been brought within the realm of traditional medicinal chemistry through diverted total synthesis. [23][24][25][26][27] By design of typically highly modular [28,29] synthetic routes,awhole family of natural products and analogues bearing multiple modifications can be achieved within aminimized number of steps to facilitate biological studies. [30,31] In addition, alternative synthesis paradigms that for example,s eek to fuse natural product building blocks through unnatural connections [32,33] or construct new complex scaffolds from abundant natural products [34,35] has also been developed to access natural-product-like chemical space.Being am odest-sized member of the C 2 -symmetric macrodiolide family [36,37] vermiculine has attracted the attention of synthetic chemists,w ith the first (racemic) synthesis reported by Corey.…”