A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

Abstract

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.

Figure 1

Ring distortion reactions can be used to readily convert natural products to complex and diverse scaffolds.

Figure 2

Application of ring distortion reactions in the synthesis of complex and diverse small molecules from gibberellic acid (G).

Figure 3

Application of ring distortion reactions in the synthesis of complex and diverse small molecules from adrenosterone (A).

Figure 4

Application of ring distortion reactions in the synthesis of complex and diverse small molecules from quinine (Q).

Figure 5

Compounds created through the complexity-to-diversity (CtD) method have markedly different properties from those in commercial screening collections, and are structurally diverse from each other and from the partent natural products. For this analysis, a 150,000 compound collection from ChemBridge Corporation was utilized and compared to the 49 CtD compounds (synthesized in Figures 2–4) for a) fraction of sp³-hybridized carbons (Fsp3), b) calculated logP (ClogP), and c) number of stereogenic centers per compound. d) Tanimoto similarity coefficients for CtD compounds relative to the three natural products and to each other, where 1.0 represents perfect similarity. For full Tanimoto matrix analysis on the 49 compound set, please see Supplementary Figure 3.