Scaffold Remodelling of Diazaspirotricycles Enables Synthesis of Diverse sp3 -Rich Compounds With Distinct Phenotypic Effects.

A 'top down' scaffold remodelling approach to library synthesis was applied to spirotricyclic ureas prepared by a complexity-generating oxidative dearomatisation. Eighteen structurally-distinct, sp3 -rich scaffolds were accessed from the parent tricycle through ring addition, cleavage and expansion strategies. Biological screening of a small compound library based on these scaffolds using the cell-painting assay demonstrated distinctive phenotypic responses engendered by different library members, illustrating the functional as well as structural diversity of the compounds.

Three-Component Synthesis of Pyridylacetic Acid Derivatives by Arylation/Decarboxylative Substitution of Meldrum's Acids.

A convenient and simple three-component synthesis of substituted pyridylacetic acid derivatives is reported. The approach centers on the dual reactivity of Meldrum's acid derivatives, initially as nucleophiles to perform substitution on activated pyridine-N-oxides, then as electrophiles with a range of nucleophiles to trigger ring-opening and decarboxylation.

A unified "top-down" approach for the synthesis of diverse lead-like molecular scaffolds.

A "top-down" synthetic approach enabled the step-efficient synthesis of 21 diverse novel molecular scaffolds. The scaffolds were derived from four complex intermediates that had been prepared using cycloaddition chemistry. Scaffold-hopping of these intermediates was achieved through attachment of an additional ring, ring cleavage, ring expansion and/or ring fusion. It was shown that the resulting scaffolds could be decorated to yield diverse lead-like screening compounds.

Synthesis of ß-Diamine Building Blocks by Photocatalytic Hydroamination of Enecarbamates with Amines, Ammonia and N-H Heterocycles.

3-Amino-substituted saturated nitrogen heterocycles are an important subclass of ß-diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox-mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N-H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks.

Synthesis and evaluation of the performance of a small molecule library based on diverse tropane-related scaffolds.

A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.

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.

Design and synthesis of a fragment set based on twisted bicyclic lactams.

Current fragment sets tend to be dominated by flatter molecules, and their shape diversity does not reflect that of the fragments that are theoretically possible. The design and synthesis of a set of bridged fragments containing a bridgehead nitrogen is described. Many of these fragments contain twisted lactams whose modulated electronic properties may present unusual opportunities for interaction with target proteins. The demonstrated novelty, three-dimensionality and molecular properties of the set of 22 fragments may provide valuable, and highly distinctive, starting points for fragment-based drug discovery.

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3 -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.

Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods.

A convergent, umpoled synthesis of 2-(1-amidoalkyl)pyridines.

A convenient, one-pot, two-component synthesis of 2-(1-amidoalkyl)pyridines is reported, based upon the substitution of suitably-activated pyridine N-oxides by azlactone nucleophiles, followed by decarboxylative azlactone ring-opening. The synthesis obviates the need for precious metal catalysts to achieve a formal enolate arylation reaction, and constitutes a formally 'umpoled' approach to this valuable class of bioactive structures.

A unified lead-oriented synthesis of over fifty molecular scaffolds.

Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.

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.

Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries.

The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production.

Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development.

Cu-catalysed arylation reactions devoted to the formation of C-C and C-heteroatom bonds (Ullmann-type couplings) have acquired great importance in the last decade. This review discusses the history and development of coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years. Selected mechanistic investigations are treated more in depth than others. For example, evidence in favour or against radical mechanisms is discussed. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalcohol arylation are discussed. A separate section has been dedicated to the synthesis of heterocyclic rings through intramolecular couplings. Finally, recent developments in green chemistry for these reactions, such as reactions in aqueous media and heterogeneous catalysis, have also been reviewed.

Picolinamides as effective ligands for copper-catalysed aryl ether formation: structure-activity relationships, substrate scope and mechanistic investigations.

The use of picolinic acid amide derivatives as an effective family of bidentate ligands for copper-catalysed aryl ether synthesis is reported. A fluorine-substituted ligand gave good results in the synthesis of a wide range of aryl ethers. Even bulky phenols, known to be very challenging substrates, were shown to react with aryl iodides with excellent yields using these ligands. At the end of the reaction, the first examples of end-of-life Cu species were isolated and identified as Cu(II) complexes with several of the anionic ligands tested. A preliminary mechanistic investigation is reported that suggests that the substituents on the ligands might have a crucial role in determining the redox properties of the metal centre and, consequently, its efficacy in the coupling process. An understanding of these effects is important for the development of new efficient and tunable ligands for copper-based chemistry.

Synthesis of spirocyclic 1,2-diamines by dearomatising intramolecular diamination of phenols.

The stereocontrolled synthesis of complex spirotricyclic systems containing an embedded syn-1,2-diaminocyclohexane unit is reported, based upon a dearomatising oxidation of phenols bearing pendant ureas capable of acting as double nucleophiles. This complexity-generating transformation yields products with rich functionality suitable for application in the synthesis of potentially bioactive compounds.

Modular synthesis of bicyclic twisted amides and anilines.

Bridged amides and anilines display interesting properties owing to perturbation of conjugation of the nitrogen lone-pair with the adjacent π-system. A convergent approach to diazabicyclic scaffolds which contain either twisted amides or anilines is described, based on the photocatalysed hydroamination of cyclic enecarbamates and subsequent cyclisation. The modular nature of the synthesis allows for variation of the degree of 'twist' and hence the properties of the amides and anilines.

Recent advances and applications of iridium-catalysed asymmetric allylic substitution.

Since their discovery in 1997, iridium-catalysed asymmetric allylic substitutions have been developed into a broadly applicable tool for the synthesis of chiral building blocks via C-C and C-heteroatom bond formation. The remarkable generality of these reactions and the high levels of regio- and enantioselectivity that are usually obtained in favour of the branched products have been made possible by a thorough investigation of the catalyst system and its mode of action. Therefore, today the Ir-catalysed asymmetric allylic substitution is a powerful reaction in the organic chemist's repertoire and has been used extensively for several applications. This article aims to provide an overview of the development of iridium catalysts derived from an Ir salt and a chiral phosphoramidite and their application to the enantioselective synthesis of natural products and biologically relevant compounds.

Multicomponent synthesis of substituted pyridines via a catalytic intermolecular aza-Wittig/Diels-Alder sequence.

A three-component synthesis of polysubstituted pyridines has been developed, based upon the synthesis of 2-azadienes by a redox-neutral catalytic intermolecular aza-Wittig reaction and their subsequent Diels-Alder reactions. The two-pot process has been demonstrated using a range of aryl and heteroaromatic aldehydes, substituted α,ß-unsaturated acids and push-pull enamines, to give rapid access to diverse tri- and tetrasubstituted pyridines.

Catalyst control in sequential asymmetric allylic substitution: stereodivergent access to N,N-diprotected unnatural amino acids.

The sequential use of Cu-catalyzed asymmetric allylic alkylation, olefin cross-metathesis, and Ir-catalyzed asymmetric allylic amination allows the concise, stereodivergent synthesis of complex chiral amines with complete regiocontrol and good diastereoselectivity, exemplified by the synthesis of a pair of diastereoisomeric unnatural branched amino acid derivatives.