Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

Abstract

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, ...

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