Drug discovery programs often rely on screening of compound libraries to find protein ligands. It is crucial that these libraries consist of structurally diverse drug-like compounds within acceptable physical property ranges (molecular weight, lipophilicity, H-bond donors/acceptors, etc.) to maximise screening success rates. To obtain these large numbers of compounds, library synthesis often employs early-stage synthesis of a common functionalised building block, followed by parallel addition of large numbers of monomers using a common reaction. This restricts the diversity of the resulting compounds. The development of a late-stage diversity-oriented library synthetic protocol that allows a series of compounds to be transformed into a range of drug-like scaffolds would provide an efficient route to the production of libraries of greater structural diversity. To illustrate this concept, we selected the 4-oxo-2-butenamide scaffold as a suitable precursor scaffold that can undergo a series of different transformations towards diverse drug-like cores. We have developed a range of transformations that can be applied to compounds containing the 4-oxo-2-butenamide moiety. So far, eighteen different reactions including 3,4-cyclisations, 1,4-cyclisations, 1,4-additions and reductions have been developed (See Figure). These reactions yield the desired product in one step with good yields, providing a small library of drug-like compounds in an efficient manner. These late-stage transformations can be applied to library design or structure-activity relationships for drug discovery. Indeed, the different products have various lipophilicity, size, and H-bond donor and acceptor geometries. Further reaction development, and scope exploration should provide a diverse library of compounds ready for screening.

Diversity-oriented library synthesis: Late-stage transformations of the 4-oxo-2-butenamide scaffold

ACS Fall 2020 Virtual Meeting

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