Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• ; 3,4,5-trisubstituted isoxazoles; Introduction Isoxazoles are a privileged class of five-membered heterocycles, which are found in numerous bioactive natural products [1][2] and synthetic small molecule drugs [3][4], and are used as important precursors for the synthesis of β-hydroxycarbonyl compounds

Mechanistic studies of the solvolysis of alkanesulfonyl and arenesulfonyl halides

• Malcolm J. D’Souza and
• Dennis N. Kevill

Beilstein J. Org. Chem. 2022, 18, 120–132, doi:10.3762/bjoc.18.13

• methanol lead to the simple two molecule formulation of the SN2 process for the hydrolysis being an oversimplification. The observation that the small molecule H2O is in bulk a liquid at room temperature requires a dynamic situation where water molecules are to a large extent associated by hydrogen-bonding

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• peptide-like structure. Heterocyclic amino acids and related compounds have been used to prepare synthetic DNA-encoded compound libraries for the discovery of small molecule protein ligands [23][24][25]. Recently, a highly specific and potent p38α kinase inhibitor containing a 3-amino-1-phenyl-1H-pyrazole

• -4-carboxylic acid residue was identified directly from the 12.6-million-member DNA-encoded small molecule library using yoctoReactor technology [26]. We have developed efficient protocols that provide easy access to highly functional heterocyclic compounds as novel amino acid-like building blocks by

A photochemical C=C cleavage process: toward access to backbone N-formyl peptides

• Haopei Wang and
• Zachary T. Ball

Beilstein J. Org. Chem. 2021, 17, 2932–2938, doi:10.3762/bjoc.17.202

• , byproducts or transiently stable intermediates were sometimes indicated by HPLC and/or NMR of these photocleavage reactions [16][17]. These observations prompted a more detailed study of the components present during photocleavage reactions of small-molecule models, leading to the identification of the N

Effect of a twin-emitter design strategy on a previously reported thermally activated delayed fluorescence organic light-emitting diode

• Ettore Crovini,
• Zhen Zhang,
• Yu Kusakabe,
• Yongxia Ren,
• Yoshimasa Wada,
• Bilal A. Naqvi,
• Prakhar Sahay,
• Tomas Matulaitis,
• Stefan Diesing,
• Ifor D. W. Samuel,
• Wolfgang Brütting,
• Katsuaki Suzuki,
• Hironori Kaji,
• Stefan Bräse and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2021, 17, 2894–2905, doi:10.3762/bjoc.17.197

• lifetimes are of a similar magnitude to that of ICzTRZ (τp = 11.5 ns) [14] while the average delayed fluorescence decays much faster for DICzTRZ (τd = 252.8 µs for ICzTRZ) [14]. We next focused on the photophysical study in a suitably high triplet energy small molecule host material, CzSi (9-(4-tert

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• chemically or physically crosslinked cryogels [11][12][13]. Firstly, a reaction mixture is prepared consisting of monomers/small molecule precursors, polymeric precursors, or a combination of the two (Figure 1) and solvent (e.g., water). ). It is worth noting that while we refer to water as the solvent here

• and in Figure 1, other solvents can be used, providing they have an appropriate melting/freezing temperature. Typically, the reagents will comprise only 5–20% of the reaction mixture. Often an initiator may also be required to initiate the polymerisation of the monomers/small molecule precursors. The

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• challenging to design small molecule catalysts that resemble anion-binding properties of enzymes. Hence, a major challenge of small organic receptors to mimic nature’s capability of binding to the targeted anions resides in the supramolecular properties of enzymes and co-factors to form exact matching binding

• the concepts and implementation of natural principles of anion recognition by small molecule catalysts. Review Hydrogen bonding to neutral substrates or anion binding? In the early stages of anion-binding-catalysis development, some reactions might have potentially been mistaken to be hydrogen-bond

• examples, and the advance of anion-binding-catalyzed strategies involving more complex H-bonding networks clearly highlight that it is indeed possible to mimic enzyme-like structures with small-molecule catalysts for asymmetric synthesis. Conclusion In the past two decades, tremendous advances in the field

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• stereogenic centers. Review A plethora of highly effective small‐molecule organocatalysts have enriched the field of organic synthesis [27], including chiral proline derivatives, N‐heterocyclic carbenes, chiral thioureas and Brønsted acids as well as phase‐transfer catalysts (PTC), such as the quaternary

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• regioselectivity is absent (ratio 75:76 and 77:78 ≈ 1:1, Table 6, entries 7–9) under conditions B, most likely due to solvent-separated ion pair formation. Conclusion Both 1H- and 2H-indazoles represent a core heterocyclic motif in many therapeutic small molecule drugs. Thus, from a synthetic perspective, the

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• iron-based small molecule catalyst and hydrogen peroxide as oxidizing agent (Scheme 25A and B) [156]. This pioneering methodology changed the way how complex molecules and pharmaceuticals are synthesized, by using the steric and electronic properties of the substrates to achieve selectivity, without

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• through complementary Watson–Crick base-pairing, the sequence options of ASO lead compounds can be rationalized based on a knowledge of the endogenetic gene sequence to be targeted, thus further offering a potential against targets which are considered undruggable using conventional small-molecule drugs

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• candidates with tailored physical and biological properties [47]. For example, ampicillin, an analogue of benzylpenicillin (penicillin G), also used as an antibiotic, contains an amine group at the benzylic position [48]. Likewise, other commercially available small-molecule drugs, such as Plavix

• constitute an important structural modality in small-molecule drugs, such as levonorgestrel (birth control drug), efavirenz (HIV/AIDS treatment), and erlotinib (anticancer). Although step-economical C–H alkynylations have been investigated with 4d and 5d transition metals, 3d metal-catalyzed late-stage C–H

• =NTces were used. Mn-catalyzed C–H methylation of heterocyclic scaffolds commonly found in small-molecule drugs. aDAST activation. bBF3⋅OEt2 activation. c1 mol % of (S,S)-Mn(CF3–PDP) was used. Examples of late-stage C–H methylation of bioactive molecules. aDAST activation. bFor insoluble substrates

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• production of proteins, enzymes and receptors that may be inhibited by small-molecule and antibody therapeutics. However, native RNA oligonucleotides do not possess sufficient metabolic stability for in vivo applications. Therefore, chemical modification is absolutely essential to re-engineer RNA into a

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• -protected phosphonodepsitetrapeptides 63 were obtained and further transformed to the N-protected phosphonodepsipeptide ester lithium salts 58 after aminolysis with tertiary butylamine and treatment with Dowex-Li+ (Scheme 10) [26]. Synthesis of β-phosphonodepsipeptides To develop iminocyclitol-based small

• molecule libraries against a bacterial TGase, an iminocyclitol was conjugated with a pyrophosphate mimic. After in situ screening, the first potent iminocyclitol-based inhibitor against bacterial TGases was efficiently developed [27]. The synthesis of N-pyrrolidine-derived β-phosphonodepsipeptides 64 is

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• proteins. It has also become a widely adopted method for ligand screening, enabling the evaluation of small molecule–protein interactions over a wide range of affinities. In protein-observed fluorine NMR experiments (PrOF) binding events can be readily monitored using simple 1D techniques, and the

• , protein folding, and potentially small-molecule library screening, as it can broaden the accessibility of quantitative NMR spectroscopy to a wider range of laboratories. Ligand-observed protein binding interactions In addition to protein-observed fluorine (PrOF) NMR spectroscopy, ligand-observed fluorine

Multiswitchable photoacid–hydroxyflavylium–polyelectrolyte nano-assemblies

• Alexander Zika and
• Franziska Gröhn

Beilstein J. Org. Chem. 2021, 17, 166–185, doi:10.3762/bjoc.17.17

• composition when studying these effects, two ratios were introduced. The loading ratio l describes the small molecule to polyelectrolyte stoichiometry: It is defined as the molar concentration of the negative charges of the photoacid plus the molar concentration of formal Flavy binding sites – formally set to

Incorporation of a metal-mediated base pair into an ATP aptamer – using silver(I) ions to modulate aptamer function

• Marius H. Heddinga and
• Jens Müller

Beilstein J. Org. Chem. 2020, 16, 2870–2879, doi:10.3762/bjoc.16.236

• quadruplex, so that metal-mediated base pairs can be introduced. 3) It is a short oligonucleotide, so the modified aptamers can easily be synthesized using automated solid-phase synthesis. 4) The target molecule of this aptamer is a small molecule, facilitating the binding assays. 5) The aptamer also binds

NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• signal intensities (tau bound by 14-3-3 compared to free tau) show a decrease for tau residues that are part of the 14-3-3 binding epitopes due to line broadening. In the presence of chimeric inhibitors, in which a small molecule was fused to a 14-3-3 binding peptide, the inhibitors target the unlabeled

• described in [110] and was employed to protein–protein interactions and binding of small molecule inhibitors of the kelch-like ECH-associated protein 1 (Keap1) kelch domain. This labeling scheme will be interesting for supramolecular binders selective for arginine, but, to our knowledge, has not yet been

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

• Daniela Rodrigues Silva,
• Joyce K. Daré and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2020, 16, 2469–2476, doi:10.3762/bjoc.16.200

• also a dependence between the calculated dipole moment and lipophilicity for small molecules. The considerably lower correlation may be explained by the fact that, in a small molecule, subtle structural changes strongly influence the overall molecular dipole and, sometimes, the introduction of a polar

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• ][6]. Among many strategies to achieve novel dye properties, one is based on combining two or more DNA/RNA binding modes in one small molecule (dye), thus building elaborate constructs which are able to recognise and report between slightly different DNA/RNA structures [2][7]. For the recognition

• balanced ratio of GC-(48%) and AT-(52%) base pairs, as well as synthetic alternating polynucleotide poly(dAdT)2 with also B-helix structure but with a fully available minor groove for small molecule binding. As alternative we used poly(dGdC)2 differing significantly in the secondary structure as well as in

• the availability of the minor groove for small molecule binding (the guanine amino group sterically hinders deep molecule penetration). Homopolynucleotide poly(dA)–poly(dT) is characterised by a peculiar twisted C-DNA structure with a minor groove only half-width of the minor groove of the alternating

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• . One exciting development in C–F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this

• the yields of gram-scale photosensitized C(sp3)–H fluorinations (Scheme 8 and Scheme 10) did not decrease indicates a fundamental advantage of PS TTET chemistry vs PRC; the low extinction coefficients of small-molecule PSCats in the near-UV to visible region (380–420 nm). In this respect, PS TTET

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

• Annike Weißenstein,
• Myroslav O. Vysotsky,
• Ivo Piantanida and
• Frank Würthner

Beilstein J. Org. Chem. 2020, 16, 2032–2045, doi:10.3762/bjoc.16.170

• stability of the ds-polynucleotide, consequently causing an increase of the denaturation temperature (∆Tm). This ∆Tm value can be related to the various binding modes of a small molecule to DNA/RNA [39]. The studies with poly(dG-dC)2 were not possible due to the high melting temperature of >100 °C. As shown

• commonly attributed to nucleobase pairs. However, since it is not likely that the chirality of the double helix will strongly increase upon binding of a small molecule, the most prominent changes at 300 nm and above are most likely attributable to ICD bands of the NDI core bound to the polynucleotide in a

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• fluorine as a powerful physicochemical modulator in small-molecule drug discovery is a compelling argument for the importance of sustained innovation to facilitate this form of structural editing [1][2][3][4]. Routinely employed as a bioisostere of hydrogen or hydroxy [5][6], substitution may enable

• substrate specificity in small-molecule catalysis. It is envisaged that this organocatalytic variant of the venerable Kucherov reaction will find application in contemporary organofluorine chemistry [61] and contributes to the current interest in alkyne functionalisation via I(I)/I(III) catalysis [62][63

• Jessica Neufeld Constantin G. Daniliuc Ryan Gilmour Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany 10.3762/bjoc.16.135 Abstract Substrate specificity is ubiquitous in biological catalysis, but less pervasive in the realm of small

A smart deoxyribozyme-based fluorescent sensor for in vitro detection of androgen receptor mRNA

• Ekaterina A. Bryushkova,
• Erik R. Gandalipov and
• Julia V. Nuzhina

Beilstein J. Org. Chem. 2020, 16, 1135–1141, doi:10.3762/bjoc.16.100

• different levels, including DNA, RNA, proteins, and small molecule metabolites. Today, along with other methods in clinical diagnosis biosensors are ubiquitously used in the biomedical field. The first prototype of a biosensor was invented by Leland Clark and Champ Lyons in 1962 as an amperometric Clark