Diastereoselective Synthesis of Highly Substituted, Amino- and Pyrrolidino-Tetrahydrofurans as Lead-Like Molecular Scaffolds.

A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead-like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF-containing compounds for inclusion in the Joint European Compound Library.

Densely functionalised spirocyclic oxetane-piperidine scaffolds for drug discovery.

A spirocyclic, sp3-atom rich oxetane-containing scaffold was synthesised in just two steps via a gold catalysed propargylic alcohol rearrangement. The key gold cyclisation can be undertaken on a 40 g scale allowing the preparation of 419 lead-like compounds based on the scaffold for the European Lead Factory.

Synthesis of 4-aminotetrahydropyran scaffolds for drug discovery.

Functionalised tetrahydropyran scaffolds were prepared using a tethered enol-ether Prins cyclisation and elaborated to show their potential use in library synthesis. The key 4-hydroxytetrahydropyran scaffold could be readily manipulated to the 4-azidotetrahydropyran that could be elaborated via copper catalysed azide-alkyne cycloaddition or by reduction to the amine, to provide sp3-rich scaffolds useful for drug discovery.

Expedient synthesis of an atypical oxazolidinone compound library.

In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library.

Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp(3)-rich library.

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp(3)-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp(3)-rich natural product-like library.

Synthesis of a hexahydropyrrolo indole (HPI) compound library.

Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library.

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective.

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

Solid-phase intermolecular radical reactions 2: synthesis of C-glycopeptide mimetics via a novel acrylate acceptor.

[reaction: see text] A novel tetrafluorophenol-linked acrylate is reported as an activated acceptor for intermolecular radical reactions. Addition of alkyl radicals led to pure products in good yields. We include here the first syntheses of C1- and C6-linked glycosides using a solid-phase radical methodology.