Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

• William H. Hersh

Beilstein J. Org. Chem. 2015, 11, 184–191, doi:10.3762/bjoc.11.19

• coupling to give the dinucleoside acylphosphonites proceeded smoothly, but separation of the pure compounds from the nucleoside precursors could not be completely achieved. If the pure acylphosphonites are to be obtained, solid-phase synthesis would probably be required. The chromatography results

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

• aim to facilitate structural modifications in DNA and RNA targeting by oligo-aryl derivatives, new amino acids with phenanthridine attached to the side chain were prepared and the solid phase synthesis of novel peptide-bridged bis-phenanthridine derivatives was developed (Figure 4) [68], whereby the

Versatile synthesis of amino acid functionalized nucleosides via a domino carboxamidation reaction

• Vicky Gheerardijn,
• Jos Van den Begin and
• Annemieke Madder

Beilstein J. Org. Chem. 2014, 10, 2566–2572, doi:10.3762/bjoc.10.268

• enabled by techniques such as solid phase synthesis, post synthetic modifications or enzymatic incorporation of modified analogues. Originating from research into aptamers as strong and selective binders [12][13][14], several research groups are investigating the creation and synthesis of new DNA or RNA

• have a stable and predictable structure allowing the design of engineered active sites through the carefully planned introduction of extra catalytic functionalities via solid phase DNA synthesis. We have further recently shown that the combination of solid phase synthesis and molecular modeling

• of imidazole modified pyrimidine and purine derivatives for solid phase synthesis have been described to date [41][44][45][46][47], we believe that the reactions described here serve as an ideal model system, which can be extended to other commercially available amino acid derivatives and nucleosides

Autonomous assembly of synthetic oligonucleotides built from an expanded DNA alphabet. Total synthesis of a gene encoding kanamycin resistance

• Kristen K. Merritt,
• Kevin M. Bradley,
• Daniel Hutter,
• Mariko F. Matsuura,
• Diane J. Rowold and
• Steven A. Benner

Beilstein J. Org. Chem. 2014, 10, 2348–2360, doi:10.3762/bjoc.10.245

• long DNA (L-DNA) constructs from short synthetic DNA fragments, which are today quite inexpensive because of automated solid-phase synthesis. However, the low information density of DNA built from just four nucleotide “letters”, the presence of strong (G:C) and weak (A:T) nucleobase pairs, the non

• systems; solid-phase DNA synthesis; synthetic biology; Introduction It has been nearly 50 years since the first solid-phase synthesis of DNA by Letsinger and Mahadevan [1][2]. This work laid the platform for new strategies in oligonucleotide synthesis, culminating in the development of phosphoramidite

Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support

• Alejandro Gimenez Molina,
• Amit M. Jabgunde,
• Pasi Virta and
• Harri Lönnberg

Beilstein J. Org. Chem. 2014, 10, 2279–2285, doi:10.3762/bjoc.10.237

• , dynamics of chain invasion and recognition by small molecular entities [6][7][8][9][10]. The quantities of short RNA sequences required for such studies are often larger than what can easily be obtained by lab-scale solid phase synthesis. In other words, there seems to be a need for a straightforward

Synthesis and optical properties of pyrrolidinyl peptide nucleic acid carrying a clicked Nile red label

• Nattawut Yotapan,
• Chayan Charoenpakdee,
• Pawinee Wathanathavorn,
• Boonsong Ditmangklo,
• Hans-Achim Wagenknecht and
• Tirayut Vilaivan

Beilstein J. Org. Chem. 2014, 10, 2166–2174, doi:10.3762/bjoc.10.224

• under different sequence context, were successfully synthesized and characterized by MALDI–TOF MS (Figure 1 and Table 1). Isolated yields in the range of 6–18% were obtained (0.5 μmol scale), which are typical for solid phase synthesis, whereby the majority of material loss occurred during HPLC

Second generation silver(I)-mediated imidazole base pairs

• Susanne Hensel,
• Nicole Megger,
• Kristina Schweizer and
• Jens Müller

Beilstein J. Org. Chem. 2014, 10, 2139–2144, doi:10.3762/bjoc.10.221

• shows silver(I)-mediated methylimidazole homo base pairs involving either 2-methylimidazole (top) or 4-methylimidazole (bottom), resulting in a shielded access to the silver(I) ions from the minor and major groove, respectively. The phosphoramidites required for automated DNA solid-phase synthesis were

Synthesis of phosphoramidites of isoGNA, an isomer of glycerol nucleic acid

• Keunsoo Kim,
• Venkateshwarlu Punna,
• Phaneendrasai Karri and
• Ramanarayanan Krishnamurthy

Beilstein J. Org. Chem. 2014, 10, 2131–2138, doi:10.3762/bjoc.10.220

• triethylamine·HF complex instead of TBAF was preferable at room temperature. The free alcohols 12, 18, 21 and 24 were phosphitylated under standard conditions to obtain the phosphoramidites suitable for the automated solid phase synthesis. Conclusion We have described herein improvements to and the optimization of

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

• ). Complete deprotection of 43 was accomplished in methanolic HCl to yield products 44 as mixtures of diastereoisomers. The Ugi reaction has been often used in solid-phase synthesis of compound libraries [83]. Suda et al. developed the optimal reaction conditions of the solid-phase Ugi reaction involving Rink

• (IC50 = 4.78 µM) was significantly lower than that of nikkomycin Z (IC50 = 0.06 µM). The remaining compounds 46 were inactive toward Candida albicans chitin synthase 2. Another approach to the solid-phase synthesis of nucleoside analogs was developed by Sun and Lee (Scheme 19) [85]. The library of 1344

Photoswitchable precision glycooligomers and their lectin binding

• Daniela Ponader,
• Sinaida Igde,
• Marko Wehle,
• Katharina Märker,
• Mark Santer,
• David Bléger and
• Laura Hartmann

Beilstein J. Org. Chem. 2014, 10, 1603–1612, doi:10.3762/bjoc.10.166

• ethylenediamine linker and used as resin for solid phase synthesis. 0.0125 mmol of resin were swollen in DCM for 15 min. The initial coupling to the ethylenediamine linker was performed with a 0.1 mmol building block solution (8 equiv, TDS, EDS or AZO) in DMF (0.5 mL), followed by the addition of a 0.1 mmol PyBOP

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• incorporated SIINFEKL epitope on MHC-I molecules. However, stimulation of the NOD2 receptor in DCs was not sufficient to provide a strong immunostimulatory signal. Keywords: automated synthesis; glycopeptide; innate immunity; muramyl dipeptide; NOD2 receptor; solid phase synthesis; Introduction In recent

• application of advanced building block 16 (Scheme 1). En route to 4, peptide 21 was elongated with 16 in a coupling cycle using HATU as a coupling reagent (Scheme 2). The solid-phase synthesis scheme was concluded with the removal of the Fmoc protective group resulting in the partially protected immobilized

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

• immobilized peptides can finally be tested for specific enzyme reactions (peptide arrays [65]). All these methods are variations of the solid-phase synthesis concept [63]. But Bruce Merrifield had another vision. He wanted peptide synthesis to be performed in single reaction vessels that are placed in a

• . Thus, solid-phase synthesis is presently, besides the solution technique, one of the major procedures for peptide manufacturing [10]. The great efforts in improving linkers, protecting groups, resins etc. provided access for the synthesis of larger peptides and even proteins. But nevertheless, the

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

• Tatyana V. Abramova,
• Sergey S. Belov,
• Yulia V. Tarasenko and
• Vladimir N. Silnikov

Beilstein J. Org. Chem. 2014, 10, 1151–1158, doi:10.3762/bjoc.10.115

• nucleobases can be performed simultaneously by treatment with aqueous ammonia as in the solid phase synthesis of native oligonucleotides (ODN) [21]. The oxalyl-mediated attachment of the growing chain to the solid support is usual in the synthesis of base sensitive ODN derivatives [22]. Figure 3 indicates the

A new building block for DNA network formation by self-assembly and polymerase chain reaction

• Holger Bußkamp,
• Sascha Keller,
• Marta Robotta,
• Malte Drescher and
• Andreas Marx

Beilstein J. Org. Chem. 2014, 10, 1037–1046, doi:10.3762/bjoc.10.104

• °C, 84%. Stepwise solid-phase synthesis for branched oligonucleotides. (I): The first oligonucleotide branch is synthesized in 3'–5' direction using standard phosphoramidites. (II): Incorporation of the branching point by usage of 6. (III): Simultaneous synthesis of the two remaining oligonucleotide

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

• Huisgen’s azide–alkyne cycloaddition (CuAAC reaction). In fact, the catalytic effect of copper ions had first been mentioned by L’Abbé in 1984 [7], but had henceforth been overlooked until Meldal presented a copper(I)-catalyzed solid-phase synthesis of 1,2,3-triazoles. In this procedure, the terminal alkyne

• structure of the catalytically active species is unknown. For the solid-phase synthesis of peptidotriazoles, the group of Meldal used copper(I) iodide in combination with DIPEA (Scheme 5). The author pointed out that albeit copper(I) iodide was used in stoichiometric amounts (2 equivalents), this was only

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• , 14195 Berlin, Germany 10.3762/bjoc.9.276 Abstract We present the solid phase synthesis of carbohydrate-functionalized oligo(amidoamines) with different functionalization patterns utilizing a novel alphabet of six differently glycosylated building blocks. Highly efficient in flow conjugation of

• thioglycosides to a double-bond presenting diethylentriamine precursor is the key step to prepare these building blocks suitable for fully automated solid-phase synthesis. Introduction of the sugar ligands via functionalized building blocks rather than postfunctionalization of the oligomeric backbone allows for

• heteromultivalent glycosylation patterns by combining building blocks presenting different mono- and disaccharides. Keywords: continuous flow; flow chemistry: flow synthesis; glycoligands; multivalency; photochemistry; solid-phase synthesis; thiol–ene; thioglycosides; Introduction Multivalent carbohydrate ligand

Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

• Holger Erdbrink,
• Elisabeth K. Nyakatura,
• Susanne Huhmann,
• Ulla I. M. Gerling,
• Dieter Lentz,
• Beate Koksch and
• Constantin Czekelius

Beilstein J. Org. Chem. 2013, 9, 2009–2014, doi:10.3762/bjoc.9.236

• peptide (KX), its α-helix propensity can be calculated from circular dichroism (CD) spectroscopy [8][9]. Therefore, 5-F3Ile was converted into its Fmoc analogue and subsequently used in solid-phase synthesis of K-5-F3Ile applying standard Fmoc-based chemistry (see Supporting Information File 1) [30]. The

Glycosylation efficiencies on different solid supports using a hydrogenolysis-labile linker

• Mayeul Collot,
• Steffen Eller,
• Markus Weishaupt and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 97–105, doi:10.3762/bjoc.9.13

• cleavage efficiencies on these functionalized solid supports were investigated, and restrictions for the choice of solid support for oligosaccharide synthesis were found. Keywords: glycosylation; hydrogenolysis; linkers; oligosaccharides; resins; solid-phase synthesis; Findings Since Bruce Merrifield

• oligosaccharides [4]. Solid-phase synthesis is performed on insoluble supports that are functionalized with a linker that connects the growing molecule with the resin (Scheme 1). Once the target molecule has been assembled, it is cleaved from the solid support. The solid-phase paradigm allows for the use of excess

• . In order to be suitable for automated solid-phase synthesis the resins have to be stable, chemically and mechanically, have to be permeable for the reagents, have to allow for reproducible loadings, and must exhibit good swelling behavior in a wide range of solvents. Mindful of these requirements

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• either polyamines or peptoids. In addition, functionalized nucleic acids were attached to polyamines via the same route. Based on a modular solid-phase synthesis of peralkynylated peptoids with up to six alkyne groups, the latter were modified with azidosugar building blocks by using copper-catalyzed

• functionalities. For peptoids, CuAAC has already been used successfully to introduce diverse side-chain functionalities directly during solid-phase synthesis of peptoids starting from both, azido- and alkyne-functionalized side chains [41][42]. In addition CuAAC has also been used in order to constrain peptoid

• secondary structures [43]. CuAAC reactions for the attachment of sugar residues to peptoid backbones have been reported for some cases [44][45]; however, a fully glycosylated structure is unknown (for glycodendrons see [46]). In this study, we describe the first solid-phase synthesis of glycosylated

Multivalent display of the antimicrobial peptides BP100 and BP143

• Imma Güell,
• Rafael Ferre,
• Kasper K. Sørensen,
• Esther Badosa,
• Iteng Ng-Choi,
• Emilio Montesinos,
• Eduard Bardají,
• Lidia Feliu,
• Knud J. Jensen and
• Marta Planas

Beilstein J. Org. Chem. 2012, 8, 2106–2117, doi:10.3762/bjoc.8.237

• , USA) at 25 °C. Spectra were obtained in a fused quartz cell with 1 mm path length over a wavelength range 190–260 nm at 0.1 nm intervals, 50 nm/min speed, 0.5 s response time, and 1 nm bandwidth. Solid-phase synthesis of peptides BP100 and BP143 Peptides were synthesized manually by the solid-phase

• % purity); ESIMS (m/z): 1420.87 [M + H]+. Solid-phase synthesis of peptide aldehydes 4 and 5 TentaGel S NH2 (TG) resin (0.27 mmol/g) was placed in a syringe and swelled with CH2Cl2 (3 × 10 min) and DMF (3 × 10 min). The ortho backbone amide linker (o-BAL) was incorporated by treating the resin twice with 5

• phosphate buffer at pH 7.4 (broken dotted line, ··−··−). Solid-phase synthesis of the peptide aldehydes 4 and 5. Synthesis of the carbopeptides 1–3. Antibacterial activity (MIC) and cytotoxicity of parent peptides and carbopeptides. Supporting Information Supporting Information File 248: HPLC, ESIMS of

Acylsulfonamide safety-catch linker: promise and limitations for solid–phase oligosaccharide synthesis

• Jian Yin,
• Steffen Eller,
• Mayeul Collot and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2012, 8, 2067–2071, doi:10.3762/bjoc.8.232

• cleavage products revealed shortcomings for oligosaccharide synthesis. Keywords: glycosaminoglycans (GAGs); glycosylation; resins; safety-catch linker; solid-phase synthesis; Findings Solid-phase oligosaccharide synthesis [1][2] has been automated [3][4][5] to rapidly assemble complex oligosaccharides

• employed in the successful synthesis of a sialyl LewisX tetrasaccharide [15] and a sialyl Tn antigen [16]. In the search for a linker suitable for the solid-phase synthesis of complex glycosaminoglycans (GAGs) [17][18], we designed a new acylsulfonamide safety-catch linker that combined the advantageous

• , the amount of glycosylating agent was decreased during a reaction, which resulted in the production of glycosylated linkers 21 and 22. It was evident that two unexpected reactions had occurred. First, the use of excess glycosylating agent, common practice for solid-phase-synthesis protocols, leads to

Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

• Julia Meier,
• Kristin Kassler,
• Heinrich Sticht and
• Jutta Eichler

Beilstein J. Org. Chem. 2012, 8, 1858–1866, doi:10.3762/bjoc.8.214

• additional cysteine residues in CD4-M5, CD4-M6 and CD4-M7, was separated from the CD4 sequences by the spacer amino acids ε-aminohexanoic acid (X) and β-alanine (B). All peptides were generated through solid-phase synthesis and purified by preparative HPLC (Figure 2 and Experimental section). Peptide binding

• , which in turn will increase their affinity to the complementary protein, and, consequently, their ability to interfere with the native protein–protein interaction. Experimental Peptide synthesis Peptides were synthesized as C-terminal amides by Fmoc/t-Bu-based solid-phase synthesis on 100 mg TentaGel S

Automated synthesis of sialylated oligosaccharides

• Davide Esposito,
• Mattan Hurevich,
• Bastien Castagner,
• Cheng-Chung Wang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2012, 8, 1601–1609, doi:10.3762/bjoc.8.183

• sialyl α-(2→3) and α-(2→6) galactosyl imidates, which, used in combination with the automated platform, provided rapid access to a small library of conjugation-ready sialosides of biological relevance. Keywords: automated synthesis; disaccharide building blocks; solid-phase synthesis; sialic acid

• disaccharide building block approach is an attractive possibility for solid-phase synthesis, since it avoids performing a low yielding and unselective sialylation on a solid support. Here, we describe a method for the rapid preparation of different sialosides relying on a new automated solid-phase synthesis

• the solid-phase synthesis of sialosides we undertook a model solution-phase synthesis of the glycan portion of GM3 ganglioside 16 (Scheme 2). GM3 serves as an important receptor for viral infection [24][25] and contains the common sialyl α-(2→3) galactose motif. The key step en route to compound 16

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• protection of the primary α-amino group. Therefore, tert-butyloxycarbonyl (Boc) protection was used to mask all α-amino groups during solid-phase synthesis of the tripeptide. Synthesis of the cyclo-β-peptide scaffold The Boc protected β-amino acid building blocks for SPPS of the cyclic β-tripeptide were