DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• programmability of the assemblies lends itself to a combinatorial display of multiple ligands. Recent efforts in the synthesis and applications of such conjugates are discussed. Keywords: glycan; glycoconjugate; DNA display; multivalency; nucleic acid conjugates; oligomeric interaction; Introduction Cell

• hybridization instructions (Figure 1). This hybridization can be used to rigidify a nucleic acid strand containing multiple glycans at variable positions, to generate oligomers through half-slide hybridization and to combinatorial pair multiple ligands. The flexibility of the template can be further tuned with

• ][42]. Since these methods are compatible with the powerful scheme of mix and split combinatorial chemistry the synthesis of libraries is easily performed wherein each library member is tagged with a unique sequence. Conjugation of glycans at different positions within a PNA oligomer has been achieved

Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach

• Martin C. N. Brauer,
• Ricardo A. W. Neves Filho,
• Bernhard Westermann,
• Ramona Heinke and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2015, 11, 25–30, doi:10.3762/bjoc.11.4

• synthesized through an Ugi four-component reaction (U-4CR) followed by a copper-catalysed alkyne homocoupling (Glaser reaction). The short and chemoselective reaction sequence allows generating diverse (pseudo) dimeric peptoids. A combinatorial version allows the one-pot preparation of, e.g., six-compound

• -libraries of homo- and heterodimers verified by ESI-MS and HPLC. In a preliminary evaluation, some compounds display moderate activity against the Gram-positive bacterium Bacillus subtilis. Keywords: antibacterial; combinatorial; diynes; homodimerization; multicomponent reactions; peptoids; Ugi reaction

• development of a combinatorial version of the copper-catalysed homodimerization. In this strategy two or more alkyne peptoids should couple simultaneously in the same reaction vessel in order to generate small libraries of dimers. In contrast to parallel synthesis, the combinatorial approach easily generates

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• anode and a platinum wire coil is used as the cathode; the flow cell is placed into a dry ice bath to maintain the −78 °C temperature required. Cation flow systems can be used to prepare individual molecules and combined with the concept of combinatorial chemistry to generate libraries of compounds. A

• spatially addressable electrolysis platform’s (SAEP) [56]. This technique has been used to prepare both parallel and combinatorial libraries using Shono-type oxidation on a microarray. Some technical aspects of anodic alkoxylation have been patented [57]. The use of the Shono-type electrooxidation in

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• design of analogous peptide libraries for combinatorial approach to recognition of various DNA and RNA targets. A structure–activity search revealed several phenanthridinium derivatives as promising binders to DNA:RNA hybrid structures [78]. Based on their previous work [79], Arya and coworkers designed

Synthesis of aromatic glycoconjugates. Building blocks for the construction of combinatorial glycopeptide libraries

• Markus Nörrlinger and
• Thomas Ziegler

Beilstein J. Org. Chem. 2014, 10, 2453–2460, doi:10.3762/bjoc.10.256

• linked to the backbone by a malonyl moiety were prepared via peptide coupling. The orthogonally protected glycoconjugates, bearing an acetyl-protected glycoside, were converted into their corresponding acids which are suitable building blocks for combinatorial glycopeptide synthesis. Keywords: amino

• interactions. Recently our group has prepared a series of trifunctional glycopeptide building blocks with aliphatic backbones, which allow for the automated construction of combinatorial libraries of highly divers glycopeptides suitable for studying carbohydrate–protein interactions [5][6][7][8]. Hitherto, our

• were used for combinatorial solid phase or automated spot synthesis of libraries of highly glycosylated peptides and shown to specifically bind to lectins [5][8][10]. Here, we now describe the preparation of a series of glycopeptide building blocks which allow for the construction of glycopeptide

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• accomplished using conventional chiral phosphines lacking hydrogen bonding moieties. Such multifunctional phosphines are readily accessible from simple chiral starting materials through a molecular building block approach, allowing combinatorial syntheses of new multifunctional chiral phosphines with diversity

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• afforded an initial product Ph-CH(NH2)-CN of configurational instability[5]. In the following, Sigman and Jacobsen used a parallel combinatorial library synthesis for the discovery and optimization of a chiral catalyst for the reaction of imines and HCN [6]. From then on, various catalytic asymmetric

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• -nucleoside substrates, the ones dealing with the construction of a non-natural nucleobase predominated (18 examples). Interestingly, a combinatorial solid-phase approach has not been extensively exploited (2 examples). The findings concerning the syntheses of nucleoside antibiotic analogs or 1'-aza-analogs

The search for new amphiphiles: synthesis of a modular, high-throughput library

• George C. Feast,
• Thomas Lepitre,
• Xavier Mulet,
• Charlotte E. Conn,
• Oliver E. Hutt,
• G. Paul Savage and
• Calum J. Drummond

Beilstein J. Org. Chem. 2014, 10, 1578–1588, doi:10.3762/bjoc.10.163

• amphiphilic species, the synthesis of a combinatorial library of amphiphilic compounds would allow the factors that drive self-assembly and liquid-crystalline phase formation to be analysed. Such studies are critical to the further development and design of new amphiphiles tailored for a specific application

• library of amphiphiles, with ammonium head groups and single-chain saturated tails, can be synthesised in a combinatorial approach, using this chemistry [26]. Amphiphiles and self-assembled nanoparticles have been synthesised using CuAAC chemistry previously [27][28][29], however to our knowledge, this

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• application in combinatorial and medicinal chemistry [23][24][25][26][27][28], to the best of our knowledge a synthesis of 3,3-disubstituted 3-aminooxindoles which relies on isocyanide-based multicomponent reactions has not been unexplored yet. Although in this kind of reaction a new stereogenic center is

Molecular recognition of surface-immobilized carbohydrates by a synthetic lectin

• Melanie Rauschenberg,
• Eva-Corrina Fritz,
• Christian Schulz,
• Tobias Kaufmann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 1354–1364, doi:10.3762/bjoc.10.138

• water with excellent selectivity versus other simple carbohydrates (for example, ~50:1 versus galactose) which also has sufficient affinity for glucose sensing at the concentrations found in blood [38]. On the other hand, we have described a dynamic combinatorial approach to the identification of

• biomimetic carbohydrate receptors [39]. To this end, we explored a dynamic combinatorial library of cyclic peptides to select receptors that are assembled from tripeptides under thermodynamic equilibrium. Amongst others, we identified a synthetic lectin (HisHis) that binds N-acetylneuraminic acid (NANA) [18

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

• Anna M. Bogazkaya,
• Clemens J. von Bühler,
• Sebastian Kriening,
• Alexandrine Busch,
• Alexander Seifert,
• Jürgen Pleiss,
• Sabine Laschat and
• Vlada B. Urlacher

Beilstein J. Org. Chem. 2014, 10, 1347–1353, doi:10.3762/bjoc.10.137

• have been made in this field. By using an iterative mutagenesis approach “combinatorial active-site saturation test (CAST)” Reetz and colleagues constructed several variants of CYP102A1 which demonstrate high regio- and stereoselectivity for testosterone and progesterone oxidation [42]. The parent F87A

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• combinatorial methods. Whilst the rational procedure is a lead structure-oriented process, there is typically little knowledge about the evaluated biological system in combinatorial methods. In order to identify a lead compound of a relative unknown system, numerous molecules (peptides) have to be produced in

Olefin cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

• Bernd Schmidt and
• Sylvia Hauke

Beilstein J. Org. Chem. 2014, 10, 1023–1031, doi:10.3762/bjoc.10.102

• -benzyloxyhex-5-enal [30], oxidative degradation of aromatics and subsequent lactonization [31], and a two-carbon homologation of an enantiopure C4-building block with a metallated sulfone [32]. A combinatorial biosynthetic approach to D- and L-amicetose has also recently been established by combining different

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• in combinatorial synthesis [40][41][42][43] and can be used strategically for the synthesis of depsipeptoids. By analogy to peptides and peptoids, a depsipeptoid would be a peptoid bearing an ester group instead of an amide group. Differences between peptide, peptoid, depsipeptide and depsipeptoid

The Ugi four-component reaction as a concise modular synthetic tool for photo-induced electron transfer donor-anthraquinone dyads

• Sarah Bay,
• Gamall Makhloufi,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 1006–1016, doi:10.3762/bjoc.10.100

• -aminoacylamide backbone in one step and with high diversity. Therefore, it is also extensively used in medicinal and combinatorial chemistry for lead finding and optimization [61]. We have recently employed the Ugi 4CR as a one-step process to simultaneously introduce a phenothiazine-functionalized amine and an

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• spirooxindoles. Recently, this route has become significant in combinatorial chemistry due to its process simplicity, mild conditions, atomic economy and extension of the scope of substrates. A large number of focused libraries of spirooxindolo pyrrolidines and pyrrolizidines containing a wide set of natural and

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• , combinatorial chemistry techniques have been used to generate large compound libraries in the hope that high-throughput screenings would identify new structures worthy of further development [21]. Unfortunately, these efforts have not resulted in a net increase in the number of new pyridine containing drug

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks

• Sushil K. Maurya,
• Mark Dow,
• Stuart Warriner and
• Adam Nelson

Beilstein J. Org. Chem. 2013, 9, 775–785, doi:10.3762/bjoc.9.88

• ][15][16][17]. The approach enabled the combinatorial variation of molecular scaffolds, and was exploited in the synthesis of natural-product-like small molecules with unprecedented scaffold diversity (over 80 distinct scaffolds). Although powerful, this general approach to skeletally diverse molecules

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• compounds related to LLW62 was developed on Rink resin as part of a “one-bead, one-compound” combinatorial approach for on-bead screening purposes. The current synthesis is carried out in solution and is amenable to scale-up for follow-up studies on LLW62 and investigations of related structures. The key

• the discovery of new small-molecule probes that modulate biological phenomena [1]. Although the use of solid-phase, split-pool combinatorial synthesis for the preparation of solutions of small-molecule libraries has declined, the use of these compounds for on-bead screening has resulted in recent

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• of pharmacophore-based combinatorial libraries [26] and identification of new peptidomimetic scaffolds of potential interest in drug discovery [27][28][29][30], we evaluated the THBC-DKP-based scaffold as a potential suitable motif for the creation of unusual reverse-turn nucleators. Reverse turns

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

• Nikolay T. Tzvetkov,
• Harald Euler and
• Christa E. Müller

Beilstein J. Org. Chem. 2012, 8, 1584–1593, doi:10.3762/bjoc.8.181

• to be introduced. Several synthetic strategies involving combinatorial and sequential approaches, in particular intramolecular cyclocondensation reactions of functionalized 1,2,4-triazole and imidazole precursors, have been developed [5][6][12]. We have been interested in expanding the medicinal

Photochemistry with laser radiation in condensed phase using miniaturized photoreactors

• Elke Bremus-Köbberling,
• Arnold Gillner,
• Frank Avemaria,
• Céline Réthoré and
• Stefan Bräse

Beilstein J. Org. Chem. 2012, 8, 1213–1218, doi:10.3762/bjoc.8.135

• . Keywords: azides; chemical diversity; flow chemistry; heterocycles; laser; micro reactor; Introduction Classical combinatorial chemistry [1][2] approaches usually aim at the synthesis of multi-milligram amounts of new compounds to extend screening decks used in multiple screening campaigns [3]. An

• combinatorial flow chemistry in lab-on-a-chip applications. Photochemical processes are in this case particularly interesting because of their enhanced molecular activation [8]. Photochemistry in microreactors is an emerging research area [9], and especially photocatalytic reactions have been investigated in

• this study have four reaction chambers with varying volumes of the chambers due to increasing depth, and different connections for the reagent entrance (Figure 1). Photochemistry The combinatorial synthesis of heterocycles and among them of carbazole is of particular interest since they are potential

Synthesis of diverse indole libraries on polystyrene resin – Scope and limitations of an organometallic reaction on solid supports

• Kerstin Knepper,
• Sylvia Vanderheiden and
• Stefan Bräse

Beilstein J. Org. Chem. 2012, 8, 1191–1199, doi:10.3762/bjoc.8.132

• indoles. Despite the interest in new indoles [3][4][5] and in particular for libraries of combinatorial compounds [2][6][7][8][9][10][11][12][13][14][15][16][17], there has only been one report for the application of the Bartoli reaction [18][19][20][21][22][23] on solid supports so far [24

Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41

• Evan F. Haney,
• Leonard T. Nguyen,
• David J. Schibli and
• Hans J. Vogel

Beilstein J. Org. Chem. 2012, 8, 1172–1184, doi:10.3762/bjoc.8.130

• . Arginine residues seem to be preferred over Lys residues in short Trp- and Arg-rich AMPs obtained through combinatorial chemistry [29]. Interestingly, the gp41w-4R peptide did not show any increased antimicrobial activity despite the high content of Trp and cationic residues. Instead, the gp41w-4R peptide