Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• –intramolecular cyclization cascade with excellent chemoselectivity in aqueous CH3CN [25]. Herein, as part of our continuing studies of heterocyclic scaffold synthesis mediated by hypervalent iodine reagents, we present the solvent-dependent chemoselective synthesis of a series of isoquinolinones mediated by PISA

• . Selected natural products, pharmaceuticals, and biologically active compounds having an isoquinolinone scaffold. Chemoselective and PISA-mediated, solvent-controlled synthesis of different isoquinolinone derivatives 2 and 3. Substrate scope for the synthesis of 4-substituted isoquinolinones 2. Reaction

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• (azetidin-2-one) scaffold to medicinal chemistry and drug design is self-evident. This four-membered heterocycle is a key fragment of many antibiotics [1], including penicillin and its analogues, as well as other pharmacologically important molecules [2]. Therefore, the search for new efficient and

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

• examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community. Keywords: bioisosteres; 2-heteroarylethylamines; medicinal chemistry; 2-phenethylamine; scaffold hopping; Introduction One of the major hit-2-lead exploration

• systems reveals a conserved pattern: most of the changes are related to bioisostere structure–activity exploration of the chemical space from original phenyl hits. The results with the imidazole analogues are different, since the ʟ-histidine unit marks a non-phenyl-based scaffold hopping. The main goal of

• these SAR expansions is creating new chemical matter with appealing potency and selectivity profiles. The impact of the scaffold hopping exercise in these target biomarkers depends on the nature of the targets themselves. It is noteworthy, that the use of molecular modelling tools, especially molecular

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• their reduced nucleophilicity. Also the synthesis of a bis-imidazo[1,2-a]pyridine scaffold was achieved in 43% yield from the pseudo-para-substituted bis-aldehyde, using the same conditions, but longer reactions times (6 days). Following the same approach, the authors also developed a one-pot protocol

• get 43 in an overall yield of 40–80% (Scheme 17). In this study, 14 distinct products were obtained, and the only limitation was observed using aliphatic aldehydes, due to the instability of the deprotected GBB adducts. Imidazopirimidines are a privileged scaffold incorporated in many bioactive

• -aminoimidazole scaffold prevented the GBB reaction to occur [52]. As it has already been described, DNA encoded GBB adducts can be effectively used in DEL screening techniques. Hwang et al. incorporated 2-amino-6-chloropyrimidine-4-carboxylic acid into a DNA sequence, reacted the resulting conjugate 51 through a

Synthesis and characterization of 1,2,3,4-naphthalene and anthracene diimides

• Adam D. Bass,
• Daniela Castellanos,
• Xavier A. Calicdan and
• Dennis D. Cao

Beilstein J. Org. Chem. 2024, 20, 1767–1772, doi:10.3762/bjoc.20.155

• related to non-radiative emission that is observed for N-phenyl-substituted imides [21]. It is possible this effect is more significant for 7-Ph than 8-Ph because the naphthalene core is less conformationally locked than the anthracene scaffold. As is expected for aromatic diimides, the title compounds

• undergo reversible chemical reduction processes, as determined by cyclic voltammetry in CH2Cl2 solvent (Figure 4). There are two factors at play. The imide substitution is impactful as the N-phenyl derivatives are roughly by 100 mV easier to reduce than the N-hexyl analogs. The anthracene scaffold also

• -delocalization. As part of our previous work constructing heteroacenes bearing cata-imide groups, we investigated the 9,10-diaza analog of compound 8-Hex (9, Figure 5). It is interesting to note that the all-carbon scaffold in 8-Hex results in a narrower bandgap than that of 9, with Δλmax = 85 nm. This

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

• prenyltransferase (PT) domain located at the C-terminus of BscA (Scheme 2A). Subsequently, the terpene cyclase (TC) domain at the N-terminal of BscA generates fusicocca-2,10(14)-diene (6), which bears the common 5/8/5 fused tricyclic scaffold common to this natural products family. Sequential oxidative conversions

• of scaffold 6 yield a series of intermediates and natural products, including cotylenol (1) and brassicicenes I and B (9 and 10), as well as brassicicene O (12), which possesses a distinct scaffold resulting from a skeletal rearrangement. To the core scaffold 6, the P450 enzymes, BscB and BscC

• tricyclic scaffold was produced through scalable chemical synthesis. Subsequently, in vitro enzymatic oxidative functionalizations were carried out during the oxidation stage. The exploration of Bsc9 homologs and directed evolution expanded the scope of substrates of the dioxygenase beyond the natural

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• synthesis of azetidinols. Mechanistically, the Norrish–Yang cyclization involves a 1,5-hydrogen abstraction (HAT) step followed by ring closure to forge the azetidine scaffold (Scheme 2a, 1 → 3, via 1,4-biradical 2) [26]. The respective α-aminoacetophenones 1 were synthesized using a modular approach

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

• amino acids is not tolerated by DivMT. It appears that the MT has a high specificity for the overall scaffold of divamide A [97]. Backbone-N-methyltransferases Borosins are a particular interesting RiPP family, and the first family containing maturases capable of backbone-N-methylation. Omphalotin A is

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• compared the GBB chemical space with common chemical databases (ChEMBL [42], PubChem [43], and ZINC15 [44]), as well as our stock screening compound collection [45]. Due to the enormous size of the databases, pairwise Tanimoto analysis was performed at the extended Bemis–Murcko scaffold level. First

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• applying the shear-flow method, negatively charged nanofibers of DA11 were assembled into a macroscopic soft scaffold when the solution was ejected into a shallow pool of calcium chloride solution (150 mM, Figure 4a). The high binding affinity between calcium ions and carboxylate groups enabled charge

• screening of DA11 and stabilization as macroscopic soft scaffold. Under an optical microscope, a deep-blue string with a diameter of ≈560 μm was observed in the macroscopic soft scaffold of DA11 (Figure S9, Supporting Information File 1), without any birefringence under crossed polarizers. A macroscopic

• soft scaffold of DA11 was imaged by scanning electron microscopy (SEM) to reveal bundled nanofibers partially aligned with the long axis of the macroscopic soft scaffold (Figure 4b). The degree of alignment (structural parameters and orientational order) of macroscopic soft scaffolds of DA11 were

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• ; organocatalysis; pyrazoles; Introduction N-Heterocycles are attractive molecules owing to their extensive applications in small-molecule drugs, natural products, and agrochemical products [1][2][3]. Among the N-heterocycles, pyrazole is an important structural scaffold, found in several marketed drugs and

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• rather similar Kd values. In order to rationalize this difference in binding mechanism, molecular models were obtained for selected low-energy conformations of E- and Z-isomers of a “model” scaffold of the para-azobenzene derivative in the binding site of LecA (Figure 5), by simple superpositioning of

• represents a ΔG value of −30 kJ/mol, corresponding to a Kd of approx 5 μM in the experimental conditions. (B) Manual docking of scaffold for compound 3 with selected low energy conformations of the E-isomer (yellow sticks) and Z-isomer (cyan sticks) superimposed on conserved position of galactose in all LecA

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• sources and thus as building blocks for synthesizing pyrazolyltriazoles by CuAAC reactions. To find a feasible approach to pyrazolyltriazoles of type 1 with a highly substituted scaffold, we decided to explore the benefits of a modification of the triazene-protected pyrazole core. In the next step, a

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• -epoxide 9, which readily crystallized (Figure 2A and Figures S5–S10, Table S1 in Supporting Information File 1). Similarly, the 6,7-epoxy derivatives of klysimplexin R (3) and microeunicellene (4) were recently synthesized and isolated [11][21]; 3 cyclized to the 6/6/6-scaffold after the addition of acid

• . Scaffold exploration of the eunicellane skeleton During protonation-induced cyclization of 1 and 2, the C6–C7 alkene showed higher nucleophilicity than either of the other two double bonds likely due to the unique conformation of the eunicellane skeleton. This selective reactivity was further supported

• of DFT calculations on the atropisomers 10a/10b and the free energy barriers for clockwise (blue) and counter-clockwise (red) rotations. Scaffold exploration of the 2E-trans-eunicellane skeleton. Supporting Information Supporting Information File 90: Experimental methods, NMR and MS spectra, and

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• catalytically active intermediate(s), possibly including chalcogen bonding activation ability of the substrates [38]. Conclusion In conclusion, we demonstrated the importance of the phenotellurazine scaffold, bearing both a Te(II) center as well as a N-bridge, for redox catalytic activity. However, although the

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines

• Stefan Jopp,
• Franziska Spruner von Mertz,
• Peter Ehlers,
• Alexander Villinger and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1246–1255, doi:10.3762/bjoc.20.107

• on the quinoline scaffold and on the arylalkyne moiety permits the fine tuning of the optical properties. Natural and synthetic compounds containing a quinoline or quinolone core-structure. ORTEP of 6b (CCDC 2322985). ORTEP of 9f (CCDC 2322983). ORTEP of 12d (CCDC 2322984). UV–vis and emission

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• , we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell

• aspects. Multicomponent reactions (MCRs) are remarkable tools which demonstrated great potential for more sustainable production of active pharmaceutical ingredients (API’s). These flexible and versatile one-pot transformations in which three or more reagents are combined to access a new complex scaffold

• and Figure 2). Like the oxindole scaffold, 1,2,3-triazole is also considered a privileged unit in drug discovery since compounds having this structure have a broad spectrum of biological activities, and have been widely used to create anticancer drug candidates [24][25]. The copper-catalyzed azide

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• scaffold, compounds Va–c (Figure 1B), in which the N3 atom present in the nucleobase of IV is replaced by CH2. We assumed that this change should not significantly affect the inhibitory potential but rather increase the stability of the target nucleosides in water and allow chemical incorporation into

• combination of both. Difficulties in the Hilbert–Johnson reaction and the low yield observed for nucleoside 14 prompted us to use an alternative option for the synthesis of the target nucleosides based on the assembly of a nucleobase on the 2-deoxyribofuranos-1-yl scaffold. Hydrogenation of azide 15 [69

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

• Luca Julianna Tóth,
• Kateřina Krejčová,
• Milan Dejmek,
• Eva Žilecká,
• Blanka Klepetářová,
• Lenka Poštová Slavětínská,
• Evžen Bouřa and
• Radim Nencka

Beilstein J. Org. Chem. 2024, 20, 1029–1036, doi:10.3762/bjoc.20.91

• modifications of HeE1-2Tyr: conversion of the core from a benzothiazole to a benzoxazole moiety and two different scaffold simplifications, respectively. We provide a novel synthetic approach and, in addition, evaluate the final molecules in an in vitro polymerase assay for biological activity. Keywords

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• ready-to-screen drug-like molecules remains a key challenge in the medicinal chemistry field [5][6]. Tetrazole is considered as a privileged scaffold in pharmaceutical and medicinal chemistry, used as a carboxylic acid bioisostere and a cis-amide mimic contributing to improvements in lipophilicity

• moiety is introduced in a late-stage-modification approach, mostly from nitriles or isocyanides (Figure 1b) [13]. On the other hand, accessing diverse tetrazole scaffolds from MCRs, typically involves first de novo construction of the tetrazole scaffold and subsequent post-modifications (Figure 1c) [14

• of the de novo approach and furthermore provides an extra efficiency, complexity and diversity in the same number of steps (Figure S1, Supporting Information File 1). Also, it offers a flexibility of placement of the tetrazole moiety in the scaffold and enables additional facile post-modifications

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• -lactam ring is a privileged scaffold widely present in drugs and natural products [12][13][14], as shown in Scheme 1. Herein, we report the effective desymmetrization strategy of N-protected 2,5-dihydro-1H-pyrroles using aryldiazonium salts and the chiral N,N-ligand (S)-PyraBox (Scheme 2). The obtained

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• development of these important bioisosteres. We will highlight both the synthetic routes used to access the proposed bioisosteric scaffolds, as well as any subsequent derivatization thereof which help expand their utility. Our aim is to provide an overview of the types of scaffold that can be prepared with

• isosteres and bioisosteres. Scaffolds suggested for the replacement of ortho- or meta-benzenes shall be defined as a geometrical isostere if they exhibit similar geometric properties to the parent compound. A scaffold shall be defined as a bioisostere only if both its geometrical properties and its

• 1,2-BCH (+)-23 and ortho-benzene telmisartan has been reported by Walker and co-workers (Figure 4) [34]. They found that both the substituent distance d and scaffold carbon distance r of 1,2-BCH (+)-23 closely resemble the ones found in telmisartan. While this agreement extends to the substituent

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• , share the drimanyl scaffold, their biosynthetic pathways, particularly the terpene cyclases synthesizing the drimanyl structures, show substantial divergence from DMT pathways [21][30][31][32]. This fundamental difference in biosynthetic mechanisms serves to categorize DMSs and drimentines into distinct

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

• Fumito Sato,
• Terutaka Sonohara,
• Shunta Fujiki,
• Akihiro Sugawara,
• Yohei Morishita,
• Taro Ozaki and
• Teigo Asai

Beilstein J. Org. Chem. 2024, 20, 714–720, doi:10.3762/bjoc.20.65

• TCs subsequently catalyze the second cyclization to construct the polycyclic scaffold of natural products [5]. In plants, two independent αβγ tri-domain TCs, ent-CPP synthase (CPS) and ent-kaurene synthase (KS), are often used for this conversion [6], and a single bifunctional enzyme that successively

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• the development of the azidobenziodazolone scaffold [17]. This class of derivative showed an improved safety profile while retaining the redox properties of the original reagent. A single example of azido-alkynylation has been reported by Ramasastry and co-workers during a mechanistic study for an

• homopropargylic azide was formed using pyrrole 1e it could not be isolated due to its instability. No conversion was observed when the transformation was attempted directly on the indole scaffold 1f. Only a small amount of product was formed using styrene 1g bearing an extra α-phenyl substituent. A slightly