Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• , Chiba 263-8522, Japan 10.3762/bjoc.21.43 Abstract β-Amino cyanoesters are important scaffolds because they can be transformed into useful chiral amines, amino acids, and amino alcohols. Halogen bonding, which can be formed between halogen atoms and electron-rich chemical species, is attractive because

• excellent enantioselectivities (Figure 1c). Despite these successful examples, the construction of only one stereocenter has been reported to date. The Mannich reaction has great importance because of its utility in the preparation of useful chiral molecules such as amines [36], amino acids [37], and amino

Binding of tryptophan and tryptophan-containing peptides in water by a glucose naphtho crown ether

• Gianpaolo Gallo and
• Bartosz Lewandowski

Beilstein J. Org. Chem. 2025, 21, 541–546, doi:10.3762/bjoc.21.42

• binding of tryptophan is therefore important for diagnostic and medicinal applications. Recently, we reported a glucose naphtho crown ether which is a chemoselective receptor for the esters of aromatic amino acids, in particular tryptophan, in water. Herein, we demonstrate that the same compound also

• binds free tryptophan selectively in aqueous media. Furthermore, it is capable of binding to tryptophan within model tripeptides. The naphthalene functionality in the glucose-derived receptor enables the study of guest binding using fluorescence spectroscopy. Keywords: amino acids; macrocyclic

• for the binding of free, unprotected tryptophan. To determine, if 1 binds tryptophan selectively over other amino acids we also studied phenylalanine, glutamic acid, lysine, and leucine as guests. We chose these amino acids to verify, how the character of their side chains (Phe – aromatic, Glu

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis

• Remi Peters,
• Levy A. Charleston,
• Karinan van Eck,
• Teun van Berlo and
• Daniela A. Wilson

Beilstein J. Org. Chem. 2025, 21, 47–54, doi:10.3762/bjoc.21.5

• functionalities of naturally occurring amino acids, synthetic polypeptides offer a robust platform for designing drug delivery systems that meet the criteria of biodegradability and biocompatibility [13]. The present study focuses on a polysarcosine and poly-ʟ-(benzyl glutamate) block copolymer (PSar-PBLG), as it

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• functionalization (LSF) of peptide scaffolds. α,β-Unsaturated amino acids like dehydroalanine (Dha) derivatives have emerged as particularly useful structures, as the electron-deficient olefin moiety can engage in late-stage functionalization reactions, like a Giese-type reaction. Cheap and widely available

• ]. Amid the growing popularity of biomolecular drug candidates, the late-stage modification of peptide scaffolds has gained significant importance [28]. A particularly interesting class of amino acids for late-stage diversification consists of dehydroamino acids (Dha). Dha derivatives have shown

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• synthesis of tripeptides incorporating new fluorinated heterocyclic hydrazino acids, based on the tetrahydropyridazine scaffold is described. Starting from simple fluorinated hydrazones, these non-proteinogenic cyclic β-amino acids were easily prepared by a zinc-catalyzed aza-Barbier reaction followed by an

• ; Introduction The synthesis of molecules capable of mimicking the various secondary structures and key functions of proteins is a major challenge in medicinal chemistry, especially in the fields of protein–protein interactions [1][2]. Accordingly, the incorporation of heterocyclic amino acids into peptides

• is known about its β-analog (Figure 3), although β-amino acids have been shown to strongly modulate the structural, metabolic, and biological characteristics of peptides [13]. Finally, it is well known that fluorine is a very useful tool in medicinal chemistry as the incorporation of fluorinated

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• substituted 1,4-benzodiazepin-3-ones using the UDC method. This process involves N-Fmoc-amino acids, isocyanides, amines, and derivatives of 2-fluorobenzaldehyde (Scheme 15). Ugi-4CR/reduction/cyclization (URC) strategy: The URC pathway enables the synthesis of benzodiazepines by using amine surrogates, such

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• recognizes and activates a specific substrate BB. Notably, the BBs are in most cases amino acids, wherein a much broader variety are used in NRP biosynthesis than the 20 canonical amino acids used in protein biosynthesis [52]. The modules are usually arranged co-linearly to the BGC sequence, which makes

• underexplored by two-fold a particular BB (or a group of BBs with similar chemical structures), respectively (Figure 3c). Phenylglycine and its derivatives (the sp2 group of BBs, Figure 3d) turned out to be the most oversampled group of BBs. This group of BBs included noncanonical amino acids characteristic of

• , respectively. Based on the position of the nucleophile, a NRP can be cyclized head-to-tail, via an amino acid side-chain, a nucleophilic heteroatom on the N-terminal fatty acyl chain, or as a multimer of repeating sub-structures (Figure 5b). The ring size, ratio of ʟ- and ᴅ-amino acids, etc. may also be the

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• acceptors [13][14][15][16][17]. The Michael addition with fluorinated acceptors finds application in the synthesis of, among others, fluorinated amino acids, which can be a structural motif in many biologically active compounds [18]. There are also known studies on the incorporation of highly reactive

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• patterns of these compounds differ by approximately four amino acids. The Tanimoto coefficient for compound 5e is significantly lower (≈0.42), indicating that the interaction pattern of compound 5e is significantly different from that of voriconazole, which may explain its low predicted affinity. The

The scent gland composition of the Mangshan pit viper, Protobothrops mangshanensis

• Jonas Holste,
• Paul Weldon,
• Donald Boyer and
• Stefan Schulz

Beilstein J. Org. Chem. 2024, 20, 2644–2654, doi:10.3762/bjoc.20.222

• , proline-containing diketopiperazines were identified for the first time in snake scent glands, although an artificial formation from amino acids likely present in the secretion cannot be excluded. Keywords: carboxylic acids; identification; mass spectrometry; pheromones; snakes; Introduction Located in

• -diastereomers [34]. Unfortunately, the absolute configuration of these compounds could not be determined due to the small amounts available. Diketopiperazines can be formed either enzymatically or non-enzymatically, e.g., by heat dimerization of amino acids [35]. Both antibacterial and antifungal activities

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• oxidation strategy to obtain α-chlorosulfoxides from sulfides using hydrochloric acid as a bifunctional reagent [22]. This strategy accommodates a broad range of substrates and offers high diastereoselectivity and regioselectivity. Several LSF modifications of amino acids and pharmaceutical derivatives

• and cross-coupling of different kinds of amines for approaching symmetric and unsymmetric imines [76]. This method achieved the bioconjugation of several amino acids with benzylamine, the use of phenylalanine (Phe), serine (Ser), and isoleucine (Ile) as substrates led to 85%, 59%, and 29% yield

• , respectively. However, other amino acids such as glycine (Gly), histidine (His), and tyrosine (Try) resulted in much lower yields (Scheme 52). 2 LSF via cathodic

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• , reaction conditions were developed, and the scope of this cyclization studied. Keywords: cyclization; DFT; hypervalent iodine; mechanism; proline; Introduction Proline is one of the 20 DNA-encoded proteinogenic amino acids that are essential to life [1][2]. In addition, the pyrrolidine core is present in

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• -ion catalysis to operate. Moreover, three amino acids (20 mol %) were utilized to generate iminium ions and subsequently to stabilize them by the presence of a carboxyl group. However, no conversion was observed after 7 days despite the additional structural elements as a carboxylic group in AA-2 or

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• Strecker reaction [44][45] where a cyanide, aldehyde, and amine react to afford α-aminonitriles. Compound 5c was converted to the deuterated amino acid 5d under acidic conditions. This finding opens up the possibility of scale-production of deuterium-labeled α-amino acids. Deuterated Strecker products are

• . No deuterium scrambling observed. Ugi-azide reaction products, no deuterium scrambling observed. Passerini products, no deuterium scrambling observed. aWater was used as solvent. Strecker reaction products (precursors to [D1]-α-amino acids), no deuterium scrambling was observed. aThe cyano-group was

Cell-free protein synthesis with technical additives – expanding the parameter space of in vitro gene expression

• Tabea Bartsch,
• Stephan Lütz and
• Katrin Rosenthal

Beilstein J. Org. Chem. 2024, 20, 2242–2253, doi:10.3762/bjoc.20.192

• nucleotides and amino acids, as well as energy molecules, salts, buffer, etc., are added. After successful protein synthesis, further substrates can be added for an enzyme activity assay. Although mimicking of cell-like conditions is an approach for optimization, the physical and chemical properties of CFPS

• encoding for the target protein, amino acids and nucleoside triphosphates as substrates, an energy regeneration system and other additives such as polyethylene glycol (PEG) [9]. Although CFPS has been used and improved since the 1960s, there are challenges in its application such as low production volumes

• deviations in the measurements or by the undefined addition of amino acids via the cell-free extract. Irrespective of this, the high concentration of sfGFP obtained shows the high level of optimization of the synthesis. Therefore, it is not expected that the addition of technical additives will further

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• are able to recognise carboxylic acid and sulphate groups along glycosaminoglycan chains using clusters of positively charged amino acids [33], also mediate a wide variety of cell–cell and cell–pathogen communication, controlling immune cell functions, and overseeing cellular trafficking [34]. Another

• input files for molecular dynamics by adding missing atoms, removing H atoms, and analysing the proton state of amino acids. The registration of the user to the web-site is required to access these tools (https://playmolecule.com/proteinPrepare/). Several MD simulation packages, including CHARMM-GUI [52

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• Matteo Gasparetto Balazs Fodi Gellert Sipos X-Chem Zrt., Záhony u. 7, DA Building, Graphisoft Park, Budapest, 1031, Hungary 10.3762/bjoc.20.168 Abstract Amino acids are vital motifs in the domain of biochemistry, serving as the foundational unit for peptides and proteins, while also holding a

• crucial function in many biological processes. Due to their bifunctional character, they have been also used for combinatorial chemistry purposes, such as the preparation of DNA-encoded chemical libraries. We developed a practical synthesis for α-heteroaryl-α-amino acids starting from an array of small

• heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation–hydrolysis–reverse amidation protocol. Keywords: amino acids; DEL

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• tumor bed of a vast diversity of human tumor types. As phenylalanine is the preferred substrate of IL4I1 catalytic activity, Presset et al. [6] reported novel phenylalanine derivatives as a strategy to inhibit IL4I1 activity, as this enzyme has a preference for hydrophobic amino acids. Among them

• requirements for access to γ-aminobutyric receptor type B (GABAB) [18]. Amino acids 10–12 were demonstrated [19][20][21] to act as substrates of GABAB (Scheme 3), key metabotropic receptors from the G-protein-coupled receptor superfamily responsible for CNS inhibitory synapses [22]. The authors concluded that

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• lichenicidin A1 [48], FlvA.1 [42], FlvA.2 [42], BhtA α [49], SmB β [50], Smb α [50], and thusin β [47] (Figure 3B). We find that, especially in the first 20 amino acids of the alignment or the first half of the mature peptide, there are significant sequence differences. Of particular interest, cellulosin forms

• two larger heterocycles (of seven and nine amino acids) in this sequence region, whilst most lanthipeptides only form small ones (up to five) or none at all. As for the second part of the alignment, where most lanthipeptides form various heterocycles, cellulosin shares a very similar profile to

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• ]oxazinan)-6'-one derivatives with two types of molecular diversity as part of their efforts to produce inhibitors of 17β-HSDs [61]. The first type of diversity was achieved by introducing different amino acids through the opening of the oxirane ring on compound 127. After lactonization of compounds 128

• as a 17β-HSD3 inhibitor [42]. The same research group reported a new family of 3-spiromorpholinones derived from ADT bearing hydrophobic substituents [43][62]. The synthetic key step involved a regioselective aminolysis of the oxirane 131 with different ʟ- or ᴅ-amino acids (53–99% yields) to obtain

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• hydrolysis of the ester and oxidation of the phenol rings allowed concise access to jorunnamycin A (103) in just 4 pots from 86 and 101 [102][106]. In subsequent work, Tanifuji and Oguri designed and applied eight variants of the peptidyl aldehyde (e.g., 104, 105) bearing various ʟ- and ᴅ-amino acids in

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• contrast to ribosomal peptide biosynthesis, many non-proteinogenic amino acids can be incorporated as building blocks. However, RiPP pathways are more flexible and they represent interesting biotechnological production routes. In this review, we will focus on post-translational methylation reactions. A

• functionalities. Review Methylation strategies The main section of this paper discusses different RiPP MTs involved in the biosynthesis of methylated peptide natural products. This section serves as an introduction and outlines additional synthetic strategies for methylated amino acids and peptides. There are

• . Additionally, stereoselectivity can be achieved by using potassium bis(trimethylsilyl)amide for deprotonation and methylation with MeI [33][39]. Any of these routes would yield methylated amino acids that can then be incorporated into an oligopeptide in solid-phase peptide synthesis (SPPS). Additionally, N

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• , substituted 3-fluoropyrrolidines, particularly in the form of 2-carboxy derivatives (fluoroprolines), have been extensively explored. These compounds represent valuable nonnatural amino acids, and depending on the regio- and stereochemistry of fluorine substitution, fluoroproline substututions can enhance the

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• in 1998 [18]. This domain is typically around 300 amino acids in length and has a conserved CHX10CHX25-27CHX25-26CH motif which comprises the active site of the burpitide cyclase. The resulting number of stand-alone transcripts from this filtering step were mapped onto a cladogram of the 647 species

• transcriptome analysis supports the prevalence of cyclopeptide alkaloids in Rhamnaceae with multiple species transcribing 20+ potential split precursor peptides. Alignment of the predicted recognition and core sequences shows the core peptides are 4–5 amino acids in length and appear to exclusively encode for

• . arabica, and Coffea eugenioides (Eugenioides coffee plant) all contained >30 unique transcripts for potential precursor peptides. The core sequences themselves were typically 4 or 5 amino acids in length and most often contained a tyrosine for cyclization. However, a few sequences appeared to have a

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• different functional groups at the 5-position. The Shi group reported the use of Pd(II) and Selectfluor to enable the enantioselective β-fluorination of α-amino acids (Figure 6) [40]. The presence of 2-(pyridin-2-yl)isopropylamine (PIP) as directing group was essential for the formation of a four-coordinate

• ; however, the methodology was only shown on secondary benzylic positions. The stereoselective benzylic monofluorination of α-amino acids was also reported by Yu and co-workers, employing a similar directing group strategy (Figure 7) [41]. The use of the monodentate directing group 2,3,5,6-tetrafluoro-4

• -(trifluoromethyl)aniline in conjunction with external ligand 5 facilitated the formation of a series of fluorinated α-amino acids. Xu and co-workers also disclosed a palladium-catalysed protocol for the fluorination of simple benzylic substrates bearing a bidentate directing group (Figure 8) [42]. Yields varied