A Ring Distortion Strategy to Construct Stereochemically Complex and Structurally Diverse Compounds from Natural Products

摘要

High-throughput screening is the dominant method to identify lead compounds in drug discovery. As such, the makeup of screening libraries will largely dictate the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for modulation of many drug targets. Here we describe a novel, general, and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show, through evaluation of chemical properties including fraction of sp³ carbons, ClogP, and the number of stereogenic centers, that these compounds are significantly more complex and diverse than those in standard screening collections, and guidelines are given for the application of this strategy to any suitable natural product.