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High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates 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 the 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 the evaluation of chemical properties (which include fraction of sp 3 carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.

The preparation of 1β-hydroxygibberellin A5 from gibberellin A3 is described.Unlike its naturally occurring allylic isomer gibberellin A3, 1β-hydroxygibberellin A5 is stable to aqueous alkali and acid-catalysed aromatisation of ring A does not occur.Reasons for these differences, and for the hitherto unreported 3-epimerisation of gibberellin A3 by base, are discussed in terms of O-alkyl fission of the lactone bridge.