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

Synthesis of novel multifunctional carbazole-based molecules and their thermal, electrochemical and optical properties

• Nuray Altinolcek,
• Ahmet Battal,
• Mustafa Tavasli,
• William J. Peveler,
• Holly A. Yu and
• Peter J. Skabara

Beilstein J. Org. Chem. 2020, 16, 1066–1074, doi:10.3762/bjoc.16.93

• homoleptic or heteroleptic iridium(III) complexes were also reported in the construction of different OLEDs [10][11][12][13]. In OPVs, carbazole derivatives are frequently used as small molecule p-type (electron-donating) materials or electron-accepting (n-type) materials with a variety of donor–acceptor

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• copper complex 22 in as fast as two minutes, and therefore, it exhibits a strong increase in reactivity when compared to its unstrained analogue [40]. This example of a bioinspired small-molecule synthetic system combines two reactivity-enhancing features from metalloenzymes: entasis and redox cofactors

Opening up connectivity between documents, structures and bioactivity

• Christopher Southan

Beilstein J. Org. Chem. 2020, 16, 596–606, doi:10.3762/bjoc.16.54

• Google and indexed for chemistry searching [4][5]. Structures: A necessary focus of this article will be traditional small-molecule chemistry that is not too far outside the rule-of-five lead-like property space. In terms of connectivity antibodies, other protein biotherapeutics, as well as large

• peptides or polynucleotides, are also important to encompass. However, capture into structured records is more challenging for these larger therapeutic modalities than for small-molecules that can be merged on the basis of chemistry rules. Notwithstanding, space limitations mean that non-small molecule

• collection of small-molecule structures extracted from papers, patents and other sources. A presentation from 2016 declared that in the first 7 months of that year ≈10.5 million substances were extracted from ≈0.5 million patents and ≈1.0 million documents. In addition, ≈75% of current novel structures are

Room-temperature Pd/Ag direct arylation enabled by a radical pathway

• Amy L. Mayhugh and
• Christine K. Luscombe

Beilstein J. Org. Chem. 2020, 16, 384–390, doi:10.3762/bjoc.16.36

• number average molecular weight of 14 kg/mol, although in 9% yield [7]. Room-temperature DArP would improve the simplicity of conjugated polymer synthesis, and reduce the energy requirements. Small molecule reactions can help predict a method’s utility in polymerizations, as DArP proceeds through a step

• -growth polymerization mechanism. Generically, a small molecule reaction is a candidate for adaptation to a polymerization when it is highly regioselective, and high yielding. Under step-growth conditions a high yielding reaction is essential for producing a high molecular weight material [8], which

• paper, we investigated the mechanism of room-temperature direct arylation and DArP by extending the method reported by Larrosa to synthesize a conjugated polymer, polyindole (PIn). Small molecule mechanistic studies were undertaken that will help future development of mild, efficient DArP conditions

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• ; chemoinformatics; Cu-catalysis; cycloadditions; molecular scaffolds; multicomponent reactions; Introduction The screening of small molecule libraries is a well-established approach in early-stage drug discovery to identify hit candidates for the development of drug leads. The application of unconventional

• generation of high-quality small molecule collections, taking advantage of the stereochemical diversity, and of their three-dimensional shape and structural bias to develop lead compounds, specifically in the field of protein–protein interactions [3][4][5][6]. Spiranic rings such as spiroketals are present

• molecular platforms for the generation of high-quality small molecule collections, taking advantage of their three-dimensional shape and structural bias to develop lead compounds. The combination of multicomponent KA2 and Pauson–Khand reactions using representative cyclic ketones, allylamine and

Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo

• Alexander Sailer,
• Franziska Ermer,
• Yvonne Kraus,
• Rebekkah Bingham,
• Ferdinand H. Lutter,
• Julia Ahlfeld and
• Oliver Thorn-Seshold

Beilstein J. Org. Chem. 2020, 16, 125–134, doi:10.3762/bjoc.16.14

• understanding MT biology; and optogenetic modifications of tubulin have never succeeded. Instead, studies of the roles of MTs in these processes overwhelmingly rely on small molecule tubulin inhibitors [1]. Due to the non-invasiveness and high spatiotemporal precision with which optical stimulation can be

• development beyond classical small molecule inhibitors; since the spatiotemporal complexity inherent to the diversity of tubulin-dependent cellular processes may finally yield to studies that can leverage high-spatiotemporal-specificity optical control to deliver cell-specific, time-reversible modulation of

• colchicine. It is not the case that colchicine (or any other small-molecule inhibitor) represents an ideal structure that colchicine domain inhibitors (CDIs) should reproduce. Thus, our design focus was to introduce reversible photoresponse to a CDI rather than developing compounds with high similarity to