Common Structural Motif Research Articles

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Pyridine and piperidine are common structural motifs in natural products and pharmaceutical compounds, underscoring the importance of their synthesis. Our group has developed chiral spiro‐bicyclic bisborane catalysts that enable the efficient and highly enantioselective reduction of pyridines to chiral piperidines. Subsequent transformations allow the conversion of the piperidine products into bioactive natural products. More details are discussed in the article by Wang et al. on pages 3088—3092. image

Ni-Catalyzed Asymmetric Reductive Arylation of α-Substituted Imides.

α-Aryl imides are common structural motifs in bioactive molecules and proteolysis-targeting chimeras designed for targeted protein degradation. An asymmetric Ni-catalyzed reductive cross-coupling of imide electrophiles and (hetero)aryl halides has been developed to synthesize enantioenriched α-arylglutarimides from simple starting materials. Judicious selection of electrophile pairs allows for coupling of both electron-rich and electron-deficient (hetero)aryl halides in good yields and enantioselectivities.

Peptide Catalyzed Conjugate Additions to β-Nitroacrylates - Steric Bulk Increases the Reaction Rate.

The organocatalytic conjugate addition of aldehydes to β-nitroacrylates provides direct access to β-ester-γ-nitroaldehydes and, thereby, common structural motifs of many bioactive compounds. However, the deactivation of amine-based catalysts by alkylation with the highly electrophilic nitroacrylates hampers this reaction. Here, we show that the peptide H-Mep-dPro-dGlu-NH2, which is reluctant to under alkylation,catalyzes this reaction at low catalyst loading (0.5-1 mol%) within short reaction times (15-60 min) to yield a broad range of β-ester-γ-nitroaldehydes with high stereoselectivity. Kinetic studies revealed that increased steric bulk on the β-nitroacrylate enhances the reaction rate by hindering catalyst alkylation.

Emerging Trends for the Direct Synthesis of Dithiocarbamates

Dithiocarbamates are common structural motifs in various bioactive compounds, attracting considerable attention due to their wide‐ranging applications in organic synthesis, material science, agrochemicals, and the pharmaceutical industry. Given the significant bioactivity and extensive applications of dithiocarbamates, the continuous pursuit of their efficient and diverse synthetic methods remains critical and urgent. Direct dithiocarbamation reactions can introduce ‐S‐C(S)NR2 group directly into parent molecules, providing shorter, greener, and more practical pathways for the synthesis of organodithiocarbamates. This article offers a comprehensive overview of the latest advancements in direct dithiocarbamation reactions, categorizing them based on the different sources of the ‐S‐C(S)NR2 group, with a particular emphasis on elucidating substrate scope and reaction mechanisms. Additionally, some synthetic limitations and applications of these methods are discussed. This review aims to provide the latest advancements in this field to both general readers and professional practitioners, inspiring innovative ideas for the synthesis of organosulfur compounds.

Bidirectional Electron Transfer Strategies for Anti-Markovnikov Olefin Aminofunctionalization via Arylamine Radicals.

Arylamines are common structural motifs in pharmaceuticals, natural products, and materials precursors. While olefin aminofunctionalization chemistry can provide entry to arylamines, classical polar reactions typically afford Markovnikov products. Nitrogen-centered radical intermediates provide the opportunity to access anti-Markovnikov selectivity; however, anti-Markovnikov arylamination is unknown in large part due to the lack of arylamine radical precursors. Here, we introduce bidirectional electron transfer processes to generate arylamine radical intermediates from N-pyridinium arylamines: Single-electron oxidation provides arylamine radicals that engage in anti-Markovnikov olefin aminopyridylation; single-electron reduction unveils arylamine radicals that engage in anti-Markovnikov olefin aminofunctionalization. The development of bidirectional redox processes complements classical design principles for radical precursors, which typically function via a single redox manifold. Demonstration of both oxidative and reductive mechanisms to generate arylamine radicals from a common N-aminopyridinium precursor provides complementary methods to rapidly construct and diversify arylamine scaffolds from readily available radical precursors.

Enantioselective synthesis of γ-chiral amides via copper-catalyzed reductive relay hydroaminocarbonylation

Chiral amides are common and effective structural motifs found in many pharmaceuticals and biologically active molecules. Despite their importance, existing synthetic methods are predominantly employed for the synthesis of α-amides and β-amides. The synthesis of remote chiral amides, characterized by distal stereocenters, typically requires intricate synthetic steps conducted under demanding conditions. Here, we present a general procedure for the copper-catalyzed enantioselective synthesis of γ-chiral amides, employing a reductive relay hydroaminocarbonylation strategy with trisubstituted allylic benzoates and hydroxylamine electrophiles. This approach demonstrates a wide substrate scope with excellent enantioselectivity and regioselectivity, thus providing access to challenging enantioenriched γ-chiral amides.

Structural diversity of crustacean exoskeletons and its implications for biomimetics.

The crustacean cuticle is a biological composite material consisting of chitin-protein fibres in a mineralized matrix. Recent research has revealed a surprising range of fibre architectures and mineral compositions of crustacean skeletal structures adapted to various mechanical demands. It is becoming increasingly clear that the organic fibres in the cuticle may be organized in patterns differing from the standard twisted plywood model. Observed fibre architectures in protruding skeletal structures include longitudinal and circular parallel fibre arrays. Skeletal minerals often include calcium phosphates in addition to calcium carbonates. Furthermore, skeletal properties are affected by protein cross-linking, which replaces mineralization as a stiffening mechanism in some structures. Several common structural motifs, such as the stiffening of the outer skeletal layers, the incorporation of non-mineralized cuticle in exposed structures, and interchanging layers of parallel fibres and the twisted plywood structure, can be identified in skeletal elements with similar functions. These evolutionary solutions have the potential for biomimetic applications, particularly as manufacturing technologies advance. To make use of this potential, we need to understand the processes behind the formation of the crustacean exoskeleton and determine which features are truly adaptive and worth mimicking.

Photoenzymatic Asymmetric Hydroamination for Chiral Alkyl Amine Synthesis.

Chiral alkyl amines are common structural motifs in pharmaceuticals, natural products, synthetic intermediates, and bioactive molecules. An attractive method to prepare these molecules is the asymmetric radical hydroamination; however, this approach has not been explored with dialkyl amine-derived nitrogen-centered radicals since designing a catalytic system to generate the aminium radical cation, to suppress deleterious side reactions such as α-deprotonation and H atom abstraction, and to facilitate enantioselective hydrogen atom transfer is a formidable task. Herein, we describe the application of photoenzymatic catalysis to generate and harness the aminium radical cation for asymmetric intermolecular hydroamination. In this reaction, the flavin-dependent ene-reductase photocatalytically generates the aminium radical cation from the corresponding hydroxylamine and catalyzes the asymmetric intermolecular hydroamination to furnish the enantioenriched tertiary amine, whereby enantioinduction occurs through enzyme-mediated hydrogen atom transfer. This work highlights the use of photoenzymatic catalysis to generate and control highly reactive radical intermediates for asymmetric synthesis, addressing a long-standing challenge in chemical synthesis.

Repurposing Drugs for Senotherapeutic Effect: Potential Senomorphic Effects of Female Synthetic Hormones.

Repurposing previously approved drugs may fast track the route to the clinic for potential senotherapeutics and improves the inefficiency of the clinical drug development pipeline. We performed a repurposing screen of 240 clinically approved molecules in human primary dermal fibroblasts for their effects on CDKN2A expression. Molecules demonstrating effects on CDKN2A expression underwent secondary screening for senescence-associated beta galactosidase (SAB) activity, based on effect size, direction, and/or molecule identity. Selected molecules then underwent a more detailed assessment of senescence phenotypes including proliferation, apoptosis, DNA damage, senescence-associated secretory phenotype (SASP) expression, and regulators of alternative splicing. A selection of the molecules demonstrating effects on senescence were then used in a new bioinformatic structure-function screen to identify common structural motifs. In total, 90 molecules displayed altered CDKN2A expression at one or other dose, of which 15 also displayed effects on SAB positivity in primary human dermal fibroblasts. Of these, 3 were associated with increased SAB activity, and 11 with reduced activity. The female synthetic sex hormones-diethylstilboestrol, ethynyl estradiol and levonorgestrel-were all associated with a reduction in aspects of the senescence phenotype in male cells, with no effects visible in female cells. Finally, we identified that the 30 compounds that decreased CDKN2A activity the most had a common substructure linked to this function. Our results suggest that several drugs licensed for other indications may warrant exploration as future senotherapies, but that different donors and potentially different sexes may respond differently to senotherapeutic compounds. This underlines the importance of considering donor-related characteristics when designing drug screening platforms.

Total Synthesis of Laurane and Guaiane Sesquiterpenoids via Oxidative Nazarov Reaction

Comprehensive SummaryAs one of the most common structural motifs in natural products, cyclopentenones usually can be fabricated by Nazarov cyclization using divinyl ketones or functionalized tertiary divinyl carbinols (TDCs) as substrates. However, straightforward method for transforming unfunctionalized TDCs to their corresponding cyclopentenones is currently lacking. Herein, we wish to report the total syntheses of four structurally distinct terpenoids, namely laurane‐type marine sesquiterpenoids isolaurene, debromoaplysin and aplysin, and guaiane sesquiterpenoid guaiadienone A, all using a novel synthetic method, named oxidative Nazarov cyclization, as the key step. This work demonstrated our robust method is suitable for synthesizing various highly substituted cyclopentenones.

The Impact of Second-Shell Nucleotides on Ligand Specificity in Cyclic Dinucleotide Riboswitches.

Ligand specificity is an essential requirement for all riboswitches. Some variant riboswitches utilize a common structural motif, yet through subtle sequence differences, they are able to selectively respond to different small molecule ligands and regulate downstream gene expression. These variants discriminate between structurally and chemically similar ligands. Crystal structures provide insight into how specificity is achieved. However, ligand specificity cannot always be explained solely by nucleotides in direct contact with the ligand. The cyclic dinucleotide variant family contains two classes, cyclic-di-GMP and cyclic-AMP-GMP riboswitches, that were distinguished based on the identity of a single nucleotide in contact with the ligand. Here we report a variant riboswitch with a mutation at a second ligand-contacting position that is promiscuous for both cyclic-di-GMP and cyclic-AMP-GMP despite a predicted preference for cyclic-AMP-GMP. A high-throughput mutational analysis, SMARTT, was used to quantitatively assess thousands of sites in the first- and second-shells of ligand contact for impacts on ligand specificity and promiscuity. In addition to nucleotides in direct ligand contact, nucleotides more distal from the binding site, within the J1/2 linker and the terminator helix, were identified that impact ligand specificity. These findings provide an example of how nucleotides outside the ligand binding pocket influence the riboswitch specificity. Moreover, these distal nucleotides could be used to predict promiscuous sequences.

Catalytic Enantioselective Protonation of Gold Enolates Enabled by Cooperative Gold(I) Catalysis.

Enantioselective protonation is a versatile approach to the construction of tertiary α-stereocenters, which are common structural motifs in various natural products and biologically relevant compounds. Herein we report a mild access to these chiral centers using cooperative gold(I) catalysis. From cyclic ketone enol carbonates, this asymmetric catalysis provides highly enantioselective access to cyclic ketones featuring an α tertiary chiral center, including challenging 2-methylsuberone. In combination with the gold-catalyzed formation of cyclopentadienyl carbonates in a one-pot, two-step process, this chemistry enables expedient access to synthetically versatile α'-chiral cyclopentenones with excellent enantiomeric excesses from easily accessible enynyl carbonate substrates.

N-substituted pyrrole carboxylic acid derivatives from 3,4-dihydroxyketons.

Since the chemical industry is largely dependent on petrol-based feedstocks, new sources are required for a sustainable industry. Conversion of biomass to high-value compounds provides an environmentally friendly and sustainable approach, which might be a potential solution to reduce petrol-based starting materials. This also applies for N-heterocycles, which are a common structural motif in natural products, pharmaceuticals and functional polymers. The synthesis of pyrroles is a well-studied and established process. Nevertheless, most routes described are not in line with the principles of green and sustainable chemistry and employ harsh reaction conditions and harmful solvents. In this study, 3,4-dihydroxyketons are used as excellent platform chemicals for the production of N-substituted pyrrole-2-carboxylic- and pyrrole-2,5-dicarboxylic acids, as they can be prepared from glucose through the intermediate d-glucarate and converted into pyrrolic acid derivatives under mild conditions in water. The scope of this so far unknown reaction was examined using a variety of primary amines and aqueous ammonium chloride leading to pyrrolic acid derivatives with N-substituents like alkane-, alkene-, phenyl- and alcohol-groups with yields up to 20 %. The combination of both, enzymatic conversion and chemical reaction opens up new possibilities for further process development. Therefore, a continuous chemo-enzymatic system was set up by first employing an immobilized enzyme to catalyze the conversion of d-glucarate to the 3,4-dihydroxyketone, which is further converted to the pyrrolic acid derivatives by a chemical step in continuous flow.

Design of Organic Radical Cations as Potent Hydrogen‐Atom Transfer Catalysts for C−H Functionalization

AbstractHydrogen‐atom transfer (HAT) catalysis offers an atom‐ and step‐economical approach to the direct functionalization of aliphatic C−H bonds. While the structure of HAT catalysts largely affects the reactivity and selectivity in the step where the C−H bond is cleaved, the choice of viable catalysts for HAT from strong C−H bonds is limited. The recent development of organic HAT catalysts based on the flexibly modifiable molecular platform has enabled fine‐tuning of the steric and electronic properties of these catalysts, thus greatly expanding their structural diversity. This review focuses on the design of HAT catalysts with cationic moieties as common structural motifs and their application to the selective manipulation of the C−H bonds of challenging substrates, including unactivated hydrocarbons.

Recent asymmetric synthesis of natural products bearing an α-tertiary amine moiety via temporary chirality induction strategies.

Covering: 2013 to 2023The α-tertiary amine moiety is a common structural motif in natural alkaloids and is frequently associated with intriguing biological activities and inherent synthetic challenges. A major hurdle in the total synthesis of these alkaloids is the asymmetric construction of the α-tertiary amine moiety. Temporary chirality inductions have been effective strategies employed to address this issue, particularly in natural product synthesis. The temporary chirality induction strategies in α-tertiary amine synthesis can be broadly classified into three categories based on the types of temporary chirality involved: Seebach's self-regeneration of stereocenters (SRS), C-to-N-to-C chirality transfer, and memory of chirality (MOC). This review highlights the recent advancements in temporary chirality induction strategies for the total synthesis of α-tertiary amine-containing natural products between 2013 and 2023.

Direct Electrochemical Reductive Synthesis - a Tool for Novel Classes of N-Oxy Heterocycles

Nitrogen containing heterocycles represent an important and common structural motif in natural products and blockbuster pharmaceuticals. Thus, their synthesis plays a crucial role in the chemical industry. The N-oxy motif is commonly found as major metabolites for such nitrogen containing heterocycles. As an innovative tool, electrochemistry enables direct access to N-oxy heterocycles via direct reduction of easily accessible nitro arenes. By using electrical current from renewable resources as an inherently safe and inexpensive reagent, electrochemistry contributes to an increased sustainability of chemical processes.[1,2] A simple galvanostatic set-up in an undivided beaker-type cell with inexpensive electrolytes was used to access a broad variety of quinoline N-oxides and 1-oxy quinazolin-4-ones in up to a multi-gram scale. This toolset offers an innovative synthetic protocol for synthesizing this novel class of compounds by only using sustainable chemicals and electricity as an inherently safe reagent.[3,4]

Chemo-Enzymatic Synthesis of Isomeric I-branched Polylactosamines Using Traceless Blocking Groups.

Poly-N-acetyl lactosamines (polyLacNAc) are common structural motifs of N- and O-linked glycan, glycosphingolipids and human milk oligosaccharides. They can be branched by the addition of β1,6-linked N-acetyl-glucosamine (GlcNAc) moieties to internal galactoside (Gal) residues by the I-branching enzyme beta-1,6-N-acetylglucosaminyltransferase 2 (GCNT2). I-branching has been implicated in many biological processes and is also associated with various diseases such as cancer progression. Currently, there is a lack of methods that can install, in a regioselective manner, I-branches and allows the preparation of isomeric poly-LacNAc derivatives. Here, we described a chemo-enzymatic strategy that addresses this deficiency and is based on the enzymatic assembly of an oligo-LacNAc chain that at specific positions is modified by a GlcNTFA moiety. Replacement of the trifluoroacetyl (TFA) moiety by tert-butyloxycarbonyl (Boc) gives compounds in which the galactoside at the proximal site is blocked from modification by GCNT2. After elaboration of the antennae, the Boc group can be removed, and the resulting amine acetylated to give natural I-branched structures. It is also shown that fucosides can function as a traceless blocking group that can provide complementary I-branched structures from a single precursor. The methodology made it possible to synthesize a library of polyLacNAc chains having various topologies.

Fungal Laccases: Fundamentals, Engineering and Classification Update.

Multicopper oxidases (MCOs) share a common catalytic mechanism of activation by oxygen and cupredoxin-like folding, along with some common structural determinants. Laccases constitute the largest group of MCOs, with fungal laccases having the greatest biotechnological applicability due to their superior ability to oxidize a wide range of aromatic compounds and lignin, which is enhanced in the presence of redox mediators. The adaptation of these versatile enzymes to specific application processes can be achieved through the directed evolution of the recombinant enzymes. On the other hand, their substrate versatility and the low sequence homology among laccases make their exact classification difficult. Many of the ever-increasing amounts of MCO entries from fungal genomes are automatically (and often wrongly) annotated as laccases. In a recent comparative genomic study of 52 basidiomycete fungi, MCO classification was revised based on their phylogeny. The enzymes clustered according to common structural motifs and theoretical activities, revealing three novel groups of laccase-like enzymes. This review provides an overview of the structure, catalytic activity, and oxidative mechanism of fungal laccases and how their biotechnological potential as biocatalysts in industry can be greatly enhanced by protein engineering. Finally, recent information on newly identified MCOs with laccase-like activity is included.

Putative staphylococcal enterotoxin possesses two common structural motifs for MHC-II binding

Staphylococcus aureus has become a significant cause of health risks in humankind. Staphylococcal superantigens (SAgs) or enterotoxins are the key virulent factors that can exhibit acute diseases to severe life-threatening conditions. Recent literature reports S. aureus has steadily gained new enterotoxin genes over the past few decades. In spite of current knowledge of the established SAgs, several questions on putative enterotoxins are still remaining unanswered. Keeping that in mind, this study sheds light on a putative enterotoxin SEl26 to characterize its structural and functional properties. In-silico analyses indicate its close relation with the conventional SAgs, especially the zinc-binding SAgs. Additionally, important residues that are vital for the T-cell receptor (TcR) and major histocompatibility complex class II (MHC-II) interaction were predicted and compared with established SAgs. Besides, our biochemical analyses exhibited the binding of this putative enterotoxin with MHC-II, followed by regulating pro-inflammatory and anti-inflammatory cytokines.

Spatially embedded recurrent neural networks reveal widespread links between structural and functional neuroscience findings

Brain networks exist within the confines of resource limitations. As a result, a brain network must overcome the metabolic costs of growing and sustaining the network within its physical space, while simultaneously implementing its required information processing. Here, to observe the effect of these processes, we introduce the spatially embedded recurrent neural network (seRNN). seRNNs learn basic task-related inferences while existing within a three-dimensional Euclidean space, where the communication of constituent neurons is constrained by a sparse connectome. We find that seRNNs converge on structural and functional features that are also commonly found in primate cerebral cortices. Specifically, they converge on solving inferences using modular small-world networks, in which functionally similar units spatially configure themselves to utilize an energetically efficient mixed-selective code. Because these features emerge in unison, seRNNs reveal how many common structural and functional brain motifs are strongly intertwined and can be attributed to basic biological optimization processes. seRNNs incorporate biophysical constraints within a fully artificial system and can serve as a bridge between structural and functional research communities to move neuroscientific understanding forwards.