Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• helped to pave the way of combinatorial chemistry and its applications for the fast generation of pharmacological hits through library deconvolution. The reactivity of the system led to complex product mixtures, with no practical substrate selectivity. However, if in analogous experiments several

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• synthesis was accomplished by a rapid, one-pot synthesis of indole-based macrocycles based on Ugi macrocyclization. The reaction of 12 different α,ω-amino acids and different indole-3-carboxaldehyde derivatives afforded a unique library of macrocycles otherwise difficult to access. Screening of the library

• -pocket as shown by our docking studies (Figure 1A,B, Figure S4 in Supporting Information File 1). Thus, extending our previous work [13], the Leu26 subpocket was probed by utilizing the different ring sizes and the different heteroatoms (oxygen or sulfur) of our macrocyclic library. In addition, the

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• synthesis of a novel library of 9-alkyl-2-amino-6-triazolylpurine derivatives. Thus, copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition reaction of compounds 6a–c with different para-substituted phenylacetylenes produced the expected compounds 7a–f, 8a–f and 9 (Scheme 1). The yields of 1,3-dipolar

• biocompatibility could be applied for the cell staining in fluorescence microscopy. Applications in the cell studies The newly prepared compound library with purine and 7-deazapurine derivatives was submitted to the screening of their biological activity. The compounds of interest were studied on two cancer cell

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• combinatorial library [88]. The work carried out by Davis and co-workers led to the metabolic incorporation of unnatural amino acids (uAAs) bearing a terminal alkene as CM substrates for protein modification [89]. The authors investigated the possibility to incorporate methionine (Met) analogues in a Met

Annulation of 1H-pyrrole-2,3-diones by thioacetamide: an approach to 5-azaisatins

• Aleksandr I. Kobelev,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2019, 15, 364–370, doi:10.3762/bjoc.15.32

• heterocycles; thioamides; Introduction Omnipresent among natural compounds and drugs, the indole core is a privileged scaffold for library design and drug discovery [1]. Its dioxo derivative, isatin (1H-indole-2,3-dione), is an important building block for the construction of diverse indole-based compounds

Ruthenium-based olefin metathesis catalysts with monodentate unsymmetrical NHC ligands

• Veronica Paradiso,
• Chiara Costabile and
• Fabia Grisi

Beilstein J. Org. Chem. 2018, 14, 3122–3149, doi:10.3762/bjoc.14.292

• olefin metathesis, a small library of indenylidene and Hoveyda-type complexes bearing unsaturated unsymmetrical NHCs combining a flexible cycloalkyl moiety and a mesityl unit as N-substituents (85–89, Figure 18) was synthesized by Mauduit and co-workers [34]. These systems were tested in the RCM of

Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins

• Christiane Schultze and
• Bernd Schmidt

Beilstein J. Org. Chem. 2018, 14, 2991–2998, doi:10.3762/bjoc.14.278

• these established methods necessary. Examples from the past 15 years include transition metal-catalyzed transformations [21][22][23], solid-phase synthesis directed at combinatorial library design [24] and organocatalytic annellation reactions [25][26]. Sparked by our interest in the development and

Synthesis of indole–cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

• Muthumani Muthu,
• Rakkappan Vishnu Priya,
• Abdulrahman I. Almansour,
• Raju Suresh Kumar and
• Raju Ranjith Kumar

Beilstein J. Org. Chem. 2018, 14, 2907–2915, doi:10.3762/bjoc.14.269

• -carbonitrile hybrids 15–18 were isolated (Table 4). The structure of all the hybrid heterocycles 15–18 was elucidated using NMR spectroscopy and in the case of 16f the structure was further confirmed from single crystal X-ray studies (Figure 4) [74]. Conclusion The syntheses of a library of novel indole

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• the peptide-binding pocket of the β-clamp, they carried out a fluorescence anisotropy titration screening of the Rockefeller University chemical library containing 30,600 polar organic compounds which led to the discovery of RU7 (9, Figure 3) with an inhibition constant of 10 μM. Pleasingly, it was

• ECSC 10 (Figure 3), which displayed an IC50 in the low micromolar range (IC50 = 40 μM). X-ray crystallography studies revealed that this biphenyl oxime derivative 10 also occupies subsite I of the β-clamp [61]. In 2014, the Zenobia’s First Pass Screen fragment library containing more than 350 fragments

• was screened by X-ray crystallography leading to the identification of four fragment hits. In an attempt to improve their binding affinities, another library was searched for compounds displaying similarity to these initial hits. After a docking-based screening followed by a fluorescence polarization

Photocatalyic Appel reaction enabled by copper-based complexes in continuous flow

• Clémentine Minozzi,
• Jean-Christophe Grenier-Petel,
• Shawn Parisien-Collette and
• Shawn K. Collins

Beilstein J. Org. Chem. 2018, 14, 2730–2736, doi:10.3762/bjoc.14.251

• conversion of an alcohol to bromide involved screening a wide variety of structurally varied complexes. Our group has previously demonstrated that the nature of each ligand influences the physical and photophysical properties as well as catalytic activity of the resulting catalyst (Figure 2) [27]. A library

• adapted to continuous flow using purple LED reactors. The batch and continuous flow processes were all made possible due to the ability to screen highly modular copper-based complexes for photocatalysis. Alcohol→bromide functional group transformations. Ligands used in the library generation of

• heteroleptic copper(I)-based complexes for photocatalysis. Evaluation of the library of copper-based complexes in photocatalytic alcohol→bromide conversion. Reactions irradiated with 394 nm light (pink) or 450 nm (blue). Front entries without an indicated phosphine ligand pertain to homoleptic Cu(diamine)2BF4

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• product 6. As variation of the substituents on the three different starting materials is necessary to obtain a diverse library, there is one main limitation to overcome. The first step of the reaction relies on the fluidity of salicylaldehyde (1a) to liquefy the reaction mixture. Salicylaldehyde analogs

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• , traditionally considered to be challenging scaffolds. Screening of the library provided valuable insights into the structure–activity relationship of the bacterial growth defects, and suggested that selectivity between bacterial species should be attainable. Furthermore, a structurally related series of

• substituent in our previous study, for which these copper-catalysed conditions resulted in dimerization [11]. Following the discovery of this substrate-dependent dichotomy with respect to optimal reaction conditions, the entire library of compounds was successfully cyclised. Whilst the yields ranged from low

• heterocyclisation with concomitant N–>N’ methyl transfer. With the library of natural products and analogues in hand, our attention turned to their biological activity. It was desired to further explore the growth defects which had been previously noted for natural products 1–4 against E. coli and S. aureus, and so

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• identify an expanded range of synthetic ligands for SdiA. Herein, we report the screening of a focused library of AHL analogs for activity in the SdiA receptor from S. Typhimurium. Compound efficacies and potencies were measured in agonism and antagonism assays using an SdiA luminescence reporter system

• Selection of the AHL library for screening. We sought to examine a range of AHL-type scaffolds for activity in SdiA. We selected a series of sub-libraries from our in-house compound collections for analysis with demonstrated activities in other LuxR-type receptors, including TraR from Agrobacterium

• tested is shown in Supporting Information File 1. An overview of the structures in each sub-library is provided below. Sub-libraries A and H contained AHLs with differing acyl tail lengths and oxidation levels at the tail β-carbon, including many naturally occurring AHLs [51][55]. The B and D sub

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• chelating groups of the siderophore. The synthesis is readily amenable to the preparation of analogues whereby the siderophore component of the conjugate can be modified. The route will be used to prepare a library of siderophore–phenothiazine conjugates for full biological evaluation of much needed new

• antibiotic delivery. A library of mono-, bis- and tris-catechol phenothiazine–siderophore conjugates are currently being prepared using this route. Their synthesis and MIC values against pathogenic mycobacteria, Gram-negative bacteria and Gram-positive bacteria, along with compound 11, will be reported in

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• showed activity in the nanomolar range (Figure 8). Furthermore, a tetrazolopyrimidinone scaffold 19 has been reported to inhibit PqsD through a putative blockade of the CoA binding site [61]. The Böttcher group used a library of HHQ as well as PQS analogues to screen for PqsD inhibition [62]. To this end

• . In order to block the thioesterase activity of the enzyme, a library of 500 fragments was screened via differential scanning fluorimetry (DSF) and the hit fragments 24–26 (Figure 11) were further validated using isothermal titration calorimetry (ITC) [66]. Binding to PqsE could be confirmed with KD

• the same group used docking studies to select compounds from a quinolone-based compound library (Figure 17). The best fitting compounds 37–40 were then evaluated in a whole bacterial cell-based P. aeruginosa screening with IC50 values in the low micromolar range. Additionally, they showed that

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• heterocyclization. In order to enlarge the compound library available for pharmacological studies, the 3β-OH analogs 7a–j of the primary products 6a–j were also synthesized through simple alkaline deacetylation (Scheme 2, Table 1). The structures of all synthesized compounds were characterized by 1H and 13C NMR

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• cyanohydrin-hydrolysis route (10f→19) and an umpolung acyl addition strategy (10f→21). The development of a library of quinoline scaffolds is currently underway within our lab utilizing this synthetic process [34][35]. Experimental General procedure for isatoic anhydride synthesis 6-Bromo-2H-benzo[d][1,3

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• conclusions drawn attributing bioactivities such as antifeedant activity to this chemical reactivity [1][11][12][13]. In an effort to ascertain whether the mollusc metabolite onchidal is susceptible to nucleophilic attack in a similar manner, herein we report on the reactivity of onchidal and a library of

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• various molecules involving multiple chemical transformations (homogeneous or reactions involving multiple phases) at various optimal conditions including work-up/purification in continuous mode. Screening: Rapid screening of operating conditions and development of a library of molecules from similar

• speed up the overall process to truly harness the advantages of flow synthesis. Based on different objectives viz. reaction screening, library generation, bench/pilot scale synthesis for various molecules we have shown three approaches to make a unified multistep flow synthesis platform which can be

Host–guest complexes of conformationally flexible C-hexyl-2-bromoresorcinarene and aromatic N-oxides: solid-state, solution and computational studies

• Rakesh Puttreddy,
• Ngong Kodiah Beyeh,
• S. Maryamdokht Taimoory,
• Daniel Meister,
• John F. Trant and
• Kari Rissanen

Beilstein J. Org. Chem. 2018, 14, 1723–1733, doi:10.3762/bjoc.14.146

• Rakesh Puttreddy Ngong Kodiah Beyeh S. Maryamdokht Taimoory Daniel Meister John F. Trant Kari Rissanen University of Jyvaskyla, Department of Chemistry, P. O. Box 35, 40014 Jyväskylä, Finland Department of Chemistry, Oakland University, 146 Library Drive, Rochester, Michigan 48309-4479, USA

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• derivatives. This relayed strategy can therefore be applied to non-symmetrical cyclic diaryliodonium species, thereby affording a library of functionalized benzoxazoles 58 with complete regiocontrol. The group of Zhang has developed a one-pot procedure for the sequential difunctionalization of cyclic diaryl

• -λ3-iodanes (Scheme 23) [63]. The first step relies on the copper-catalyzed coupling between an anthranilic acid derivative and the biphenyl moiety. The resulting iodoarene product is then submitted to a Sonogashira coupling reaction, allowing the one-pot preparation of a library of biphenyl products

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• advances, the involvement of other types of organocatalysts and metal ligands will have to be investigated in these transformations along with the use of other nucleophiles to even more extend the library of chiral 3-substituted 3-amino-2-oxindoles available for drug discovery. Mannich reaction of N-Boc

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• sequence-specific DNA binding, the lack of viable strategies for facile synthesis of library of structural variants of these classes of conjugates remains a huge challenge for the researchers. In order to resolve this issue, Dervan et al. recently published a modular microwave-assisted Fmoc-based solid

• phase synthetic approach for the syntheses of cyclic Py/Im polyamides [84]. This group previously optimized and reported a machine-assisted Fmoc solid phase synthesis of simpler polyamides to afford high step-wise coupling yield [85]. A seven-member library of cyclic polyamides targeting androgen

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• hypoxanthine but cytosine remained untransformed. In situ deprotection of 2′,3′,5′-tri-O-acetyladenosine was also claimed. This chemistry has also been applied to the preparation of a library of ribosylated nicotinamide and nicotinic acid ester derivatives in a mortar grinder or using mixer or planetary ball

• ) and adenosine diphosphate ribose (ADPR) was also described. Subsequently, this methodology was applied to the preparation of a library of six ADPR carbonate derivatives in 23–68% yields (e.g., Scheme 14) and tested as sirtuin inhibitors [54]. The efficiency of phosphate coupling under mechanochemical

An efficient and facile access to highly functionalized pyrrole derivatives

• Meng Gao,
• Wenting Zhao,
• Hongyi Zhao,
• Ziyun Lin,
• Dongfeng Zhang and
• Haihong Huang

Beilstein J. Org. Chem. 2018, 14, 884–890, doi:10.3762/bjoc.14.75

• considerable efforts have been expended to build stereogenic centers of pyrrolidine derivatives using chiral catalysts [7]. As our aim was to construct a small library of polysubstituted pyrroles for antibacterial screening, it prompted us to develop a concise and efficient synthesis of pyrrolo[3,4-c]pyrrole

• could meet our requirement to basically construct a small library of highly functionalized pyrrole derivatives for antibacterial screening or for further chemical manipulations to get more promising compounds. Conclusion In summary, we have developed an efficient, operationally simple protocol to afford