Double your pleasure: A new double‐tagging approach is validated by making eight individual stereoisomers of passifloricin through the intermediacy of a pair of four‐compound quasi‐isomeric mixtures.
Alkaloid and terpenoid natural products display an extensive array of chemical frameworks and biological activities. However such scaffolds remain underrepresented in current screening collections and are, thus, attractive targets for the synthesis of natural product-based libraries that access underexploited regions of chemical space. Recently, we reported a systematic approach to the stereoselective synthesis of multiple alkaloid/terpenoid-like scaffolds using transition metal-mediated cycloaddition and cyclization reactions of enyne and diyne substrates assembled on a tert-butylsulfinamide lynchpin. We report herein the synthesis of a 190-membered library of alkaloid/terpenoid-like molecules using this synthetic approach. Translation to solid-phase synthesis was facilitated by the use of a tert-butyldiarylsilyl (TBDAS) linker that closely mimics the tert-butyldiphenysilyl protecting group used in the original solution-phase route development work. Unexpected differences in stereoselectivity and regioselectivity were observed in some reactions when carried out on solid support. Further, the sulfinamide moiety could be hydrolyzed or oxidized efficiently without compromising the TBDAS linker to provide additional amine and sulfonamide functionalities. Principal component analysis of the structural and physicochemical properties of these molecules confirmed that they access regions of chemical space that overlap with bona fide natural products and are distinct from areas addressed by conventional synthetic drugs and drug-like molecules. The influences of scaffolds and substituents were also evaluated, with both found to have significant impacts on location in chemical space and three-dimensional shape. Broad biological evaluation of this library will provide valuable insights into the abilities of natural product-based libraries to access similarly underexploited regions of biological space. diversity-oriented synthesis | multiscaffold library | asymmetric synthesis | cheminformatics A major goal in the field of diversity-oriented synthesis is the efficient production of small-molecule libraries that address underexploited regions of biologically relevant chemical space to enable the discovery of new biological probes and potential therapeutic lead compounds (1). A key approach to addressing this challenge is to emulate natural products and other biogenetic molecules, which have coevolved with macromolecular biological targets (2). Toward this end, a variety of natural product-based libraries have been synthesized, with promising early results (3). These libraries can be validated initially by evaluation of their structural and physicochemical properties using principal component analysis (PCA) to determine the regions of chemical space that are accessed. Subsequently, screening across a wide range of biological assays provides direct biological validation of the functional capabilities of these libraries.Alkaloids and terpenoids have long served as important small-molecule drugs and leads for drug discovery (4, ...
Anredera diffusa is used as a wound-healing agent in traditional Peruvian medicine. Acid hydrolysis of the bioactive ethanolic extract, followed by in vivo activity-guided fractionation, yielded oleanolic acid, with a wound-healing activity equivalent to 42.9% (p < 0.01) above the control. The highest cicatrizant activity in mice was obtained by applying 40 microg of oleanolic acid per gram of body weight.
A new fluorous SCS pincer palladium complex is synthesized and shown to efficiently promote typical Heck reactions under microwave or thermal heating. The complex is air stable and can be recovered after reactions for reuse by fluorous solid phase extraction. By analogy to related complexes, it may function as a precursor of soluble ligandless palladium metal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.