Synthesis of a library of 3-oxopiperazinium and perhydro-3-oxo-1,4-diazepinium derivatives and identification of bioactive compounds

The design and synthesis of a library of novel families of 3-oxopiperazinium and perhydro-3-oxo-1,4-diazepinium derivatives is reported. The library was composed of 44 3-oxopiperazinium derivatives (11 of these compounds had a spiranic skeleton) and 22 perhydro-3-oxo-1,4-diazepinium compounds. The synthetic procedure involved a 6-step sequence carried out in solution, along with the use of solid-phase linked scavengers and microwave activation for the rapid removal of the excess of amine reagents. A final cyclization step performed under mild conditions led to the charged heterocyclic moiety. Screening of this library in two biological assays identified active compounds that inhibit the activity of the vanilloid receptor TRPV1 and modulators of the multidrug resistance phenomenon. Thus, this synthetic sequence represents a facile and convenient entry to unprecedented libraries of this sort of tetraalkylammonium derivatives that may be of use for identification of novel scaffolds of diverse biological activity.     

Applications of Multicomponent Reactions to the Synthesis of Diverse Heterocyclic Scaffolds

The sequencing of multicomponent reactions (MCRs) and subsequent cyclization reactions is a powerful stratagem for the rapid synthesis of diverse heterocyclic scaffolds. The optimal MCR is sufficiently flexible that it can be employed to generate adducts bearing a variety of functional groups that may then be selectively paired to enable different cyclization manifolds, thereby leading to a diverse collection of products. The growing interest in diversity‐oriented synthesis has led to increased attention to this paradigm for library synthesis, which has inspired many advances in the design and implementation of MCRs for the construction of diverse heterocyclic scaffolds.     

Development of a Terpenoid Alkaloid‐like Compound Library Based on the Humulene Skeleton

Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp³‐rich terpenoid scaffolds and nitrogen‐containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid‐like compounds based on Lewis‐acid‐catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid‐like compound library has a high level of three‐dimensional‐shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid‐like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid‐like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries.     

Organocatalytic Asymmetric Cascade Reactions Based on Gamma‐Nitro Carbonyl Compound

The significant advancements in asymmetric organocascade reactions have been accomplished during the past decades, paving the way to the efficient and stereoselective construction of structurally complex scaffolds from simple and readily available starting materials. Nitro‐containing cyclic compounds have become a privileged molecular library given their broad and promising activities in various therapeutic areas. In various approaches to build these valuable scaffolds, the utility of γ‐nitrocarbonyl intermediates is one of the most efficient approaches due to its high efficiency, reliability and versatility. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of nitro‐containing cyclic molecules via organocascade strategies based on γ‐nitrocarbonyl intermediates. Various organocatalysts with distinct activation modes have found application in providing these sophisticated compounds. This review is organized according to the types of organocatalyst. These methods are of importance for the construction of complex chiral cyclic frameworks and the design of new pharmaceutical compounds. We believe that compounds based on nitro‐containing cyclic skeletons have the potential to provide novel therapeutic agents and useful biological tools.     

Synthesis of N-alkyl-octahydroisoquinolin-1-one-8-carboxamide libraries using a tandem Diels-Alder/acylation sequence

A synthetic sequence was developed in which a diene containing an attached secondary amine was reacted with maleic anhydride to afford the title structures in one step. The reaction involves a Diels-Alder reaction combined with a transacylation reaction of the imide group. A series of six scaffolds was constructed using this methodology. Each scaffold was subsequently reacted with 12 amines to afford a library containing 72 compounds.     

Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks

In the search for new bioactive compounds, there is a trend toward increasingly complex compound libraries aiming to target the demanding targets of the future. In contrast, medicinal chemistry and traditional library design rely mainly on a small set of highly established and robust reactions. Here, we probe a set of 58 such reactions for their ability to sample the chemical space of known bioactive molecules, and the potential to create new scaffolds. Combined with ~26,000 common available building blocks, the reactions retrieve around 9% of a scaffold-diverse set of compounds active on human target proteins covering all major pharmaceutical target classes. Almost 80% of generated scaffolds from virtual one-step synthesis products are not present in a large set of known bioactive molecules for human targets, indicating potential for new discoveries. The results suggest that established synthesis resources are well suited to cover the known bioactivity-relevant chemical space and that there are plenty of unexplored regions accessible by these reactions, possibly providing valuable "low-hanging fruit" for hit discovery.     

Synthesis of Privileged Scaffolds by Using Diversity‐Oriented Synthesis

An elegant reagent‐controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug‐like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14 .     

Skeletal and appendage diversity as design elements in the synthesis of a discovery library of nonaromatic polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas

Amino-acid derived cross-conjugated trienes were used as a starting point for the synthesis of a discovery library of over 200 polycyclic 5-iminooxazolidin-2-ones, hydantoins, and acylureas. The main feature of this library synthesis is a triple branching strategy, which provides efficient access to five skeletally diverse scaffolds. In addition, four sets of building blocks were applied in both a front end and a back end diversification strategy. Multiple fused rings were obtained by cyclization of diamides with phosgene and stereoselective Diels-Alder reactions with maleimides. The 5-iminooxazolidin-2-one scaffold was rearranged into the isomeric hydantoin scaffold through a sequence of ring-opening and ring-closing reactions.     

Synthesis of a novel fused pyrrolodiazepine-based library with anti-cancer activity

Development of drugs for new and persistent diseases will increasingly rely on the expansion of accessible chemical space to allow exploration of novel molecular targets. Here we report the synthesis of a library of novel fused heterobicyclic small molecules based on the 1,4-diazepine and 2,4-pyrrolidinedione scaffolds. Key chemical transformations included a Mannich-type condensation and chemoselective N-acylation reactions. Screening shows anti-cancer activity of several library compounds which suggests translational potential of this novel chemical scaffold.     

Synthesis and Evaluation of a 2,11‐Cembranoid‐Inspired Library

The 2,11‐cembranoid family of natural products has been used as inspiration for the synthesis of a structurally simplified, functionally diverse library of octahydroisobenzofuran‐based compounds designed to augment a typical medicinal chemistry library screen. Ring‐closing metathesis, lactonisation and SmI₂‐mediated methods were exemplified and applied to the installation of a third ring to mimic the nine‐membered ring of the 2,11‐cembranoids. The library was assessed for aqueous solubility and permeability, with a chemical‐space analysis performed for comparison to the family of cembranoid natural products and a sample set of a screening library. Preliminary investigations in cancer cells showed that the simpler scaffolds could recapitulate the reported anti‐migratory activity of the natural products.     

Organocatalytic Dynamic Kinetic Resolution Enabled Asymmetric Synthesis of Phosphorus-Containing Chiral Helicenes

The catalytic asymmetric synthesis of phosphorus-containing helicenes remains a formidable challenge, presumably due to the lack of rational design of substrates, right choice of reactions together with highly effective catalysis systems. Herein, we disclosed an efficient and practical DKR-involving (dynamic kinetic resolution) cascade strategy toward synthesizing a novel family of phosphorus-installing helicenes by peptide-mimic phosphonium salt (PPS) catalysis. The sequential process of PPS-catalyzed phospha-Michael attack and copper salt-facilitated aromatization led to the formation of unprecedented phosphorus-containing oxa[5]helicene scaffolds. A wide variety of substrates bearing an assortment of functional groups were compatible with this protocol, furnishing the expected helical compounds in high yields and excellent stereoselectivities. Additionally, the helical products could be conveniently elaborated to promising phosphine ligands with perfectly retained helical chirality, which turned out to be highly efficient chiral ligands in transition metal-catalyzed reactions. These findings not only expand the current library of phosphorus-containing helicenes but also offer insights to explore other challenging scaffolds with molecular chirality.     

Development of a method to consistently quantify the structural distance between scaffolds and to assess scaffold hopping potential

We introduce a method to determine a structural distance between any pair of molecular scaffolds. The development of this approach was motivated by the need to accurately evaluate scaffold hopping studies in virtual screening and medicinal chemistry and assess the degree of difficulty involved in facilitating a transition from one structure to another. In order to consistently derive structural distances, scaffolds of different composition and topology are subjected to molecular editing procedures that abstract from original scaffolds in a defined manner until compositional and topological equivalence can be established. Pairs of corresponding scaffold representations are transformed into one-dimensional atom sequences that are aligned using approaches adapted from biological sequence comparison. From best scoring atom sequence alignments, interscaffold distances are derived. The algorithm is evaluated at different levels including the analysis of a series of model scaffolds with defined chemical changes, a scaffold library, and scaffolds from reference compounds and hits of successful virtual screening applications. It is demonstrated that chemically intuitive scaffold distances are obtained for pairs of scaffolds with varying composition and topology. Distance threshold values for close and remote structural relationships between scaffolds are also determined. The methodology is made publicly available in order to provide a basis for a consistent assessment of scaffold hopping ability and to aid in the evaluation and comparison of virtual screening methods.     

Unified synthesis of diverse building blocks for application in the discovery of bioactive small molecules

The synthesis of large numbers of diverse molecular scaffolds with controlled molecular properties is a significant challenge in synthetic organic chemistry. A modular unified synthesis was developed, and was exploited in the synthesis of sixteen diverse three-dimensional scaffolds. The approach exploited two cyclisation precursors to be converted, using a toolkit of cyclisation reactions, into spirocyclic and fused-ring scaffolds. Remarkably, Pd-catalysed aminoarylation of substituted N-Boc-hex-5-enylamine cyclisation precursors to yield N-Boc piperidine-containing scaffolds was successful which was ascribed to a significant Thorpe−Ingold effect. Computational property analysis showed that the decorated scaffolds are shape-diverse, and enable diverse lead-like chemical space to be targeted.     

Domino reaction to functionalized 2-hydroxybenzophenones from electron-deficient chromones and 1,3-dicarbonyl compounds

A base-promoted one-pot tandem reaction sequence has been developed to transform electron-deficient chromone-fused dienes 1 and 1,3-dicarbonyl compounds 2 to functionalized 2-hydroxybenzophenones 3 under mild conditions. This domino process, which involves multiple reactions, including Michael addition/cyclization/elimination, serves as an efficient, economic, and eco-friendly method for the construction of diversified 2-hydroxybenzophenone scaffolds without a transition-metal catalyst and inert atmosphere.     

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high yields (up to 99 %) and good to excellent enantiomeric excesses (up to 99% ee). The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are important skeletons in biological and pharmaceutical compounds.     

Solution-phase parallel synthesis of hexahydro-1H-isoindolone libraries via tactical combination of Cu-catalyzed three-component coupling and Diels-Alder reactions

Parallel solution-phase synthesis of combinatorial libraries of hexahydro-1 H-isoindolones exploiting a novel "tactical combination" of Cu-catalyzed three-component coupling and Diels-Alder reactions was accomplished. Three distinct libraries consisting of 24 members (library I), 60 members (library II), and 32 members (library III) were constructed. Variation of three substituents on the isoindolone scaffold in library I was exclusively achieved by the choice of the building blocks. In the syntheses of libraries II and III, sublibraries of isoindolone scaffolds were prepared initially in a one-pot/two-step process and were further diversified via Pd-catalyzed Suzuki cross-coupling reaction with boronic acids at two different diversification points. The Lipinski profiles and calculated ADME properties of the compounds are also reported.     

Recent trends in synthetic strategies using magnetic nanostructures as green catalysts in synthesis of pyran analogues

In recent years, magnetic nanoparticles and nanocomposites play an important role as a nanocatalyst in the creation of a wide range of bioactive heterocycles with extraordinarily high activity and selectivity, low energy consumption, and extended life. Among all heterocycles, many natural products, pharmaceuticals, and bioactive compounds contain pyran scaffolds which have a wide range of uses in biomedical research, industry, and medicine. Additionally, these are also widely used in the synthesis of novel heterocyclic systems as precursors. This study focused on recent advances in the last 5 years in using various magnetic recoverable and recycled nanoparticles and nanocomposites to synthesize pyran derivatives and their pharmacological activity. This article has been classified into three subsections: (i) MNPs-metal nanocomposite catalyzed reactions, (ii) MNPs-organic based nanocomposite catalyzed reactions, and (iii) MNPs-ionic liquid nanocomposite catalyzed reactions and (iv) MNPs-acid based nanocomposite to describe catalytic efficiency of magnetic nanocomposites for the synthesis of pyran derivatives. A comparative study of nanocomposites and different approaches for green synthesis of pyrans by highlighting the advantages and disadvantages along with catalyst recovery and recyclability has been mentioned, which will help scientists to probe and stimulate the study of these scaffolds.     

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds in high yields (up to 99 %) and good to excellent enantiomeric excesses (up to 99% ee). The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions. Moreover, this strategy also provides valuable and easy access to chiral chromene, naphthoquinone and acetylacetone derivatives, which are important skeletons in biological and pharmaceutical compounds.     

Parallel solution-phase synthesis of acrylonitrile scaffolds carrying L-alpha-amino acidic or D-glycosyl residues

A practical and straightforward protocol for the preparation of a solution-phase library of acrylonitrile scaffolds is reported. Target compounds were obtained in high yield, stereoselectivity, and purity by two simple and practical steps from cyanoacetic acid. Moreover, our study proposes a synthetic approach starting from the constructed library to obtain three-membered heterocycles.     

Organocatalytic Strategies for the Development of the Enantioselective Inverse-electron-demand Hetero-Diels-Alder Reaction

Cycloaddition reactions, in particular Diels-Alder reactions, have attracted a lot of attention from organic chemists since they represent one of the most powerful methodologies for the construction of carbon-carbon bonds. In particular, inverse-electron-demand hetero-Diels-Alder reactions have been an important breakthrough for the synthesis of heterocyclic compounds. Among all their variants, the organocatalytic enantioselective version has been widely explored since the asymmetric construction of diversely functionalized scaffolds under reaction conditions encompassed within the green chemistry field is of great interest. In this review, a profound revision on the latest advances on the organocatalytic asymmetric inverse-electron demand hetero-Diels-Alder reaction is shown.