Synthesis of sp3-rich scaffolds for molecular libraries through complexity-generating cascade reactions

An efficient strategy for the synthesis of complex small molecules from simple building blocks is presented.</p

Exploitation of the Ugi-Joullie Reaction in the Synthesis of Libraries of Drug-Like Bicyclic Hydantoins

A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi–Joullié reaction/cyclisation sequence was exploited as the key complexity-generating process in which trifluoroacetic acid was employed as synthetic equivalent for chloroformic acid. Exemplar diversification of the bicyclic scaffolds was performed to enable subsequent translation to the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory

Translation of Innovative Chemistry into Screening Libraries: An Exemplar Partnership from the European Lead Factory

The identification of high-quality starting points for drug discovery is an enduring challenge in medicinal chemistry. Yet, the chemical space explored in discovery programmes tends be limited by the narrow toolkit of robust methods that are exploited in discovery workflows. The European Lead Factory (ELF) was established in 2013 to boost early-stage drug discovery within Europe. In this Feature, we describe an exemplar partnership that has led to the addition of 21 119 distinctive screening compounds to the ELF Joint European Compound Library. The partnership could serve as a blueprint for the translation of innovative academic chemistry into discovery programmes

Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory

Realisation of small molecule libraries based on frameworks distantly related to natural products

The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory