Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• ]. In this review, we describe synthetic sequences involving repetitive or consecutive IMCRs that have provided molecules with even more structural diversity. By “repetitive” we mean processes in which two or more IMCRs are occurring in the same reaction vessel using polyfunctionalized compounds. In

• points of diversity. In this strategy, intermediates 26 and 27 were formed through Ugi-type reactions and then mixed together with benzylamine and isobutyraldehyde to furnish the final product in 24% yield as a mixture of diastereomers (Scheme 7). Other examples of 5- and 6CRs involving Passerini and Ugi

• paraformaldehyde (Scheme 31a). Subsequently, it was observed that varying the amine component (C-protected amino acids) allowed the obtention of exocyclic elements of diversity as observed in macrocycles 162a and b (Scheme 31b). The process allows the increase of the peptide sequence as well as the inclusion of

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• practiced in supramolecular chemistry to produce complex molecules with topological diversity [81]. Therefore, organic transformations through subcomponent synthesis under mechano-milling conditions might be considered as a useful tool for performing a chemical reaction in a greener fashion. The

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• molecules using multicomponent reactions (MCRs). MCRs transform three or more starting materials into a single product in an atom- and step-economical way in diversity- and target-oriented syntheses in modern organic synthesis. In addition, MCRs are characterized by high yields, time efficiency, low waste

Synthesis of acylglycerol derivatives by mechanochemistry

• Karen J. Ardila-Fierro,
• Andrij Pich,
• Marc Spehr,
• José G. Hernández and
• Carsten Bolm

Beilstein J. Org. Chem. 2019, 15, 811–817, doi:10.3762/bjoc.15.78

• (Figure 2). Biological routes that lead to the formation of DAGs include enzymatic degradation of glycerophospholipids and lipolysis of triacylglycerols (TAGs) [22][25]. However, due to the structural diversity of fatty acids present in acylglycerols and to the small structural differences among these

Hoveyda–Grubbs catalysts with an N→Ru coordinate bond in a six-membered ring. Synthesis of stable, industrially scalable, highly efficient ruthenium metathesis catalysts and 2-vinylbenzylamine ligands as their precursors

• Kirill B. Polyanskii,
• Kseniia A. Alekseeva,
• Pavel V. Raspertov,
• Pavel A. Kumandin,
• Eugeniya V. Nikitina,
• Atash V. Gurbanov and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2019, 15, 769–779, doi:10.3762/bjoc.15.73

• substituent) reduces the potential diversity of the chemical environment of the catalytic centre [18][19][20][21]. In our opinion, replacing the oxygen atom by the nitrogen atom in the lower part of the catalyst would enhance the variability for both steric and electronic effects of the substituents (Figure 1

Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety

• Iteng Ng-Choi,
• Àngel Oliveras,
• Lidia Feliu and
• Marta Planas

Beilstein J. Org. Chem. 2019, 15, 761–768, doi:10.3762/bjoc.15.72

• resulting biaryl monocyclic peptidyl resin leading to the formation of the expected biaryl bicyclic peptide. This study provides the first solid-phase synthesis of this type of bicyclic compounds being amenable to prepare a diversity of synthetic or natural biaryl bicyclic peptides. Keywords: borylation

• macrolactamization step. This work constitutes the first solid-phase synthetic approach to biaryl bicyclic peptides. The method described is general and allows access to a diversity of novel Phe- and Tyr-containing biaryl bicyclic peptides. Structure of biaryl bicyclic peptides 1–3. Retrosynthetic analysis for the

New sesquiterpenoids from the South China Sea soft corals Clavularia viridis and Lemnalia flava

• Qihao Wu,
• Yuan Gao,
• Meng-Meng Zhang,
• Li Sheng,
• Jia Li,
• Xu-Wen Li,
• Hong Wang and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2019, 15, 695–702, doi:10.3762/bjoc.15.64

• , eight sesquiterpenoids (1–8), belonging to four different structural types, were isolated from two South China Sea soft corals (C. viridis and L. flava) for the first time. The discovery of these metabolites extended the structural diversity and complexity of sesquiterpenoids derived from soft corals C

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• degree of structural diversity that should be of interest in drug synthesis or material science. The versatility of alkoxyallenes [11][12][13][14][15][16][17][18][19][20][65][66] as easily available C3 building blocks is key for this prosperousness. Discovery of the LANCA three-component reaction. The

Catalyst-free assembly of giant tris(heteroaryl)methanes: synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts

• Rodrigo Abonia,
• Luisa F. Gutiérrez,
• Braulio Insuasty,
• Jairo Quiroga,
• Kenneth K. Laali,
• Chunqing Zhao,
• Gabriela L. Borosky,
• Samantha M. Horwitz and
• Scott D. Bunge

Beilstein J. Org. Chem. 2019, 15, 642–654, doi:10.3762/bjoc.15.60

• . [52] and by Mousavizadeh et al. [53] through the three-component reactions of indole and coumarin, but in all cases, ordinary aliphatic and aromatic aldehydes as the third partner, mediated by a catalyst or by a biphasic system as solvent, respectively, were used. The lack of structural diversity in

Back to the future: Why we need enzymology to build a synthetic metabolism of the future

• Tobias J. Erb

Beilstein J. Org. Chem. 2019, 15, 551–557, doi:10.3762/bjoc.15.49

• 200,000 different molecules that have been isolated from different biological systems so far [9]. This diversity has inspired generations of biologists to use living cells as small chemical factories for the production of chemicals. In the past, many efforts centered on manipulating the metabolism of

• diversity of enzymatic scaffolds [36][37][38][39]. One example is formaldehyde lyase (or “formolase”) – the key enzyme of the formolase pathway – that was crafted from a benzaldehyde lyase, which showed initially some side reactivity with formaldehyde [17][24]. Other examples are propionyl-CoA oxidase and

• were developed recently to analyze the diversity of enzyme (super)families in respect to new functions [53][54][55]. While these tools have been successfully used to identify and discover new metabolic pathways (Balskus, etc.), they might as well be used to identify interesting candidate enzymes to be

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

• [21], supramolecular structures (cryptands, cages, cryptophanes, podands, etc.) [22][23][24], cyclic/macrocyclic peptides [25] and other complex structures in a straightforward manner (Scheme 5). The diversity in these systems arises not only from combining a variety of building blocks (from simple

• -based MCRs. In this way, the selective formation of intermediate B, leads to the following MCR processes based in different isocyanide MCRs. This approach made possible a remarkable 8-CR process for the one-pot synthesis of compounds with up to 11 diversity points. A conceptually distinct approach for

• the following transformation. Several examples use this approach with the same set of reagents leading to MMCRs, with limited structural variability (Scheme 9B and C) [36][37]. However, in some occasions the two processes are split up and higher levels of diversity can be achieved. In these cases, the

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

• -pot procedure with one purification step), much better yields, no need of expensive catalysts as in ring-closing metathesis (RCM) reaction and higher complexity/diversity on the macrocyclic ring, e.g., insertion of heteroatoms that could improve the ADMET properties (Scheme 1) [4]. Results and

• bear a heteroatom in the 4-position as oxygen or sulfur (Y = O, S, Scheme 2) were employed in order to enhance the diversity of our macrocycles [4]. Thus, in a parallel way, we readily synthesized 12 different amino acids which were subsequently subjected to the Ugi macrocyclization. After quite some

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

• ) = 100 μM, B and D passed separately through filter (365 ± 20 nm)). General synthetic routes for the compounds 5, 7–9, 10 and 11. Method A: alkyl halogenide, MeCN or DMF, NaH, 1–3 days, 20–55 °C; method B: alcohol, Ph3P, THF, DIAD, 1 h, 0→20 °C. Diversity of 9-alkyl-2-pyrrolidino-6-triazolylpurine 7 and

• 7-deazapurine 10 derivatives obtained in reactions 6a→7a–f and 3→10a–f according to Scheme 1. Diversity of 9-alkyl-2-piperidino-6-triazolylpurine 8 and 7-deazapurine 11 derivatives obtained in reactions 6b→8a–f and 3→11a–f according to Scheme 1. Photophysical properties of 6-triazolyl compounds 7a–f

Thiol-free chemoenzymatic synthesis of β-ketosulfides

• Adrián A. Heredia,
• Martín G. López-Vidal,
• Marcela Kurina-Sanz,
• Fabricio R. Bisogno and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2019, 15, 378–387, doi:10.3762/bjoc.15.34

• developed in order to obtain high chemical diversity employing a single sulfur donor. This methodology for the selective synthesis of a set of β-ketosulfides is performed under mild conditions and can be set up in one-pot two-step and on a gram-scale. Keywords: ketosulfides; lipase; multicomponent

• isolation of intermediates and creating chemical diversity with high atom economy [33][34][35][36]. In the last two decades, enzymes have found a privileged place in organic chemistry by virtue of its inherent selectivity and eco-friendly reaction conditions. Such properties, among other, make them

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• substrate scope and some applications of the products arising from those reactions, are presented in this review. Keywords: alkylidenecyclopropanes; cyclopropanes; cyclopropenes; sigmatropic rearrangements; strained rings; Introduction Among the ever expanding diversity of chemical transformations

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• than for HQNO (5). The investigation of AQ levels in cultures of P. aeruginosa revealed quorum sensing activity for the two PQS derivatives 11 and 12, suggesting once more that AQ-based quorum sensing in P. aeruginosa tolerates significant structural diversity on the signaling molecule [27][28][29

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• -galactopyranosides, L-fucopyranosides and sialic acids) that comprise the most terminal, and therefore most accessible for lectin recognition, oligosaccharide regions contribute to a vast diversity of possible glycocalyx structures [40][41][42]. It is known, for example, that the carbohydrate composition of the

Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• special emphasis to the tolerance to a wide range of nucleophiles, despite high proximity of the nucleophilic and reductive properties. We presume the transformation finds its place in the diversity-oriented synthesis toolbox to produce libraries of chromenoimidazoles with complex substitution and

Organometallic vs organic photoredox catalysts for photocuring reactions in the visible region

• Aude-Héloise Bonardi,
• Frédéric Dumur,
• Guillaume Noirbent,
• Jacques Lalevée and
• Didier Gigmes

Beilstein J. Org. Chem. 2018, 14, 3025–3046, doi:10.3762/bjoc.14.282

• small part of the wide diversity of possible photoredox catalyst has been presented here. Moreover, wavelength of irradiation is here restricted from 300 to 500 nm. In the recent literature, free radical polymerization using a photoredox catalyst has for example been presented using NIR light with both

• cycles involved with iodonium salt and (A) (TMS)3SiH, (B) NVK and (C) EDB. Structures of additives involved in the photoredox catalytic cycles. Structures of photoredox metal-based catalysts. Photocatalytical cycle for the Ru complex. Structures of photoredox organocatalysts. Diversity of the chemical

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step

• Pierre-Antoine Nocquet,
• Aurélie Macé,
• Frédéric Legros,
• Jacques Lebreton,
• Gilles Dujardin,
• Sylvain Collet,
• Arnaud Martel,
• Bertrand Carboni and
• François Carreaux

Beilstein J. Org. Chem. 2018, 14, 2949–2955, doi:10.3762/bjoc.14.274

• glycal scaffolds are versatile building blocks with multiple applications in the field of natural product synthesis [6], the development of new asymmetric synthetic sequences with stereochemical diversity is still of high interest. Different approaches have been reported for the asymmetric synthesis of

• -protected aldehyde should afford the desired aldol adduct with a syn relative configuration between the two newly created chiral centers [29][30]. Moreover, the boron-mediated stereoselective aldol reaction is all the more interesting for our synthetic plan as stereochemical diversity can be generated

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

• fluorescence polarization assay of 50,400 compounds from the Chemical Diversity, Maybridge and Chembridge chemical libraries, and subsequent dose-dependent evaluation of the disruption of the SSB/ExoI complex, led to the discovery of four inhibitors, CFAM, BCBP, BOTP and MPTA (24–27, Figure 6), with IC50

An overview on recent advances in the synthesis of sulfonated organic materials, sulfonated silica materials, and sulfonated carbon materials and their catalytic applications in chemical processes

• Hashem Sharghi,
• Pezhman Shiri and
• Mahdi Aberi

Beilstein J. Org. Chem. 2018, 14, 2745–2770, doi:10.3762/bjoc.14.253

• silica supported imidazole derivative, it was sulfonated by the reaction of supported imidazole with ClSO3H in cold chloroform to give new -SO3H functionalized SiO2. To screen the scope and diversity of this catalyst, several aldehydes containing electron-donating and electron-withdrawing substitutions 7

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• powerful and widely applied methodology for the synthesis of such derivatives, including alkenylated molecular scaffolds with multiple stereogenic centers [14][15][16] and references cited therein. Diversity-oriented synthesis (DOS), with the aim of the preparation of structurally diverse elements of small

• -lactams [24], shown to be highly important precursors for the access of various structures (e.g., amino acids, azido esters, hydroxylated amino esters, fluorinated amino esters, etc.) with various functional groups as well as stereochemical and skeletal diversity [21][22][23]. Results and Discussion

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

• -based reporter strain for agonism and antagonism of the LuxR homolog, SdiA, from S. Typhimurium. This AHL library contained many scaffolds with demonstrated agonism and antagonism activity in other LuxR-type receptors. Despite the relative structural diversity of the library, nearly 80% of the compounds

Gold-catalyzed post-Ugi alkyne hydroarylation for the synthesis of 2-quinolones

• Xiaochen Du,
• Jianjun Huang,
• Anton A. Nechaev,
• Ruwei Yao,
• Jing Gong,
• Erik V. Van der Eycken,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2018, 14, 2572–2579, doi:10.3762/bjoc.14.234

• procedures, two asymmetric versions were designed to provide access to axially chiral 2-quinolone-based heterobiaryls such as 2e (Scheme 1c) [45][46]. One substantial drawbacks of the previous methodologies is that they do lack an exploration of the substituent diversity on the nitrogen atom. We decided to

• –Crafts-type cyclizations involving attack of electron-rich arenes on the triple bonds, leading to the formation of a great number of fused [50][51][52][53] and spirocyclic structures [54][55][56][57][58][59]. In addition, Ugi adducts have already been successfully utilized for the diversity-oriented

• fact that the resulting cyclized products 8r and 8r’ were essentially inseparable. The best 8r/8r’ ratio could be obtained using hexafluoro-2-methylpropan-2-ol while the best overall yield was obtained using HFIP (Table 4, entry 2 versus entry 4). Conclusion We have elaborated a fast and diversity