Novel Topologically Complex Scaffold Derived from Alkaloid Haemanthamine

Abstract

The generation of natural product-like compound collections has become an important area of research due to low hit rates found with synthetic high-throughput libraries. One method of generating compounds occupying the areas of chemical space not accessible to synthetic planar heterocyclic structures is the utilization of natural products as starting materials. In the current work, using a ring-closing iodoalkoxylation reaction, alkaloid haemanthamine was transformed into a unique structural framework possessing an intricate ring system and a large number of stereocenters. The structure of the new compound was confirmed with an X-ray analysis. A small number of derivatives of this new compound were synthesized as a demonstration of the possibility of generating a large natural product-like compound collection based on the new structural framework.

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

“…Several strategies for the rapid and efficient synthesis of value-added complex compounds have been developed, including those that construct complex scaffolds from diverse collections of simple building blocks, 3,4 and those that begin with complexity and build in diversity. 5 For this later approach, natural products offer a rich and varied source of starting materials, and collections of compounds have been assembled using the Complexity-to-Diversity (CtD) strategy from the natural products adrenosterone, 6 gibberellic acid, 6 quinine, 6,7 abietic acid, 8 sinomenine, 9 lycorine, 10 yohimbine, 11 haemanthamine, 12 nitrogenous steroids of dutasteride and abiraterone acetate, 13 ilimaquinone, 14 and others. The resulting collections have been used to discover small molecules with anticancer and antimicrobial activities, 11,15 autophagy inhibitors, 16 and to identify predictive guidelines for broad-spectrum antibiotic discovery.…”

Preparation of Structurally Diverse Compounds from the Natural Product Lycorine

“…6 To take advantage of the distinctive features of natural products while leveraging the power of synthetic organic chemistry, we have reported a strategy termed complexity-to-diversity (CtD), 7 which uses ring system distortion and rearrangement reactions of natural products to rapidly generate collections of diverse compounds while maintaining desirable characteristics including a high fraction of sp 3 -hybridized carbons (Fsp3), ring fusion density, number of stereogenic centers, and rigidity of ring systems. Using this approach, compound collections have been reported from gibberellic acid, 7a adrenosterone, 7a quinine, 7a abietic acid, 8 sinomenine, 9 pleuromutilin, 10 yohimbine, 11 hemeanthamine, 12 ilimaquinone, 13 and others. 14 Structurally diverse, natural-product-like libraries have proven to be valuable tools in studying various biological processes.…”

Limonin as a Starting Point for the Construction of Compounds with High Scaffold Diversity

“…Coupling of the carboxylic acid of 4 with suitable amines provided amide derivatives (36)(37). Compound 37 was modified using the azide-alkyne cycloaddition to build as mall set of ring fusion analogs (38)(39)(40)(41).…”

“…TheC tD approach takes advantage of the structural complexity inherent within readily available natural products to generate unique complex compounds through ring distortion reactions (i.e., ring expansion, contraction, cleavage, fusion, and rearrangement). [32,33] This method has been applied to several natural products,i ncluding adrenosterone, [34] gibberellic acid, [34] quinine, [34] abietic acid, [35] sinomenine, [36] lycorine, [37] pleuromutilin, [38,39] yohimbine, [40] haemanthamine, [41] ilimaquinone [42] and steroids such as dutasteride and abiraterone acetate. [43] Theresulting collections of natural product-like compounds have been instrumental in developing predictive guidelines for small molecule accumulation in E. coli, [44] and led to Gp rotein-coupled receptor antagonists, [45] anew class of antiplasmodial agents, [46] and the discovery of an ovel and potent inducer of ferroptotic cell death.…”