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

• synthesis of (2S,3S)-5,5,5-trifluoroisoleucine (L-5-F3Ile) and (2R,3S)-5,5,5-trifluoro-allo-isoleucine (D-5-F3-allo-Ile) was developed. The hydrophobicity of L-5-F3Ile was examined and it was incorporated into a model peptide via solid phase peptide synthesis to determine its α-helix propensity. The α-helix

• [14][15]. Therefore, the preparation of enantiomerically pure fluorinated isoleucine analogues with retained α-helix propensity is of general interest for site-specific modification of coiled-coil positions in parallel packing arrangements, especially when solid phase peptide synthesis is employed

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• chemistry [1], colloidal science [2], natural product chemistry [3], medicinal chemistry [4][5][6], solid-phase peptide synthesis [7] and in the biosciences [8]. Despite the many advantages of this heating method, and the introduction of a wide range of instrumentation [1], the scale up of microwave

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

• introduced the concept of solid-phase peptide synthesis in 1963 [1], synthesis on solid supports has evolved as a powerful tool for organic chemists [2]. Over the past fifty years this strategy has been successfully applied to the synthesis of other biopolymers, such as oligonucleotides [3] and

• 30 min, eluents: H2O and MeCN, detection at 254 nm; the double peak for 39 is caused by an anomeric mixture). Solid-phase synthesis of biopolymers. X represents a reactive site such as an amino group for peptide synthesis or a hydroxy group for oligonucleotide and oligosaccharide synthesis. Design of

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• ]. This is an attractive concept, because it can be combined with solid-phase peptide synthesis (SPPS) [4][5], as well as with native chemical ligation (NCL) utilizing an S→N acyl shift [3][6][7][8][9][10]. In addition, glycocysteine derivatives can be easily converted into the corresponding dimers by

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

• to a significant improvement of the antimicrobial activity. Experimental General methods The synthesis of Boc2-Aoa-OH was described in an earlier publication from our laboratories [23]. It is now available from Polypeptide Laboratories (NeoMPS, Strassbourg, France). Automated peptide synthesis was

• carried out on a fully automated Syro II peptide synthesizer (MultiSynTech). Manual peptide synthesis was performed in polypropylene syringes fitted with a polyethylene porous disk. Solvents and soluble reagents were removed by suction. Chemicals were purchased from commercial suppliers Sigma–Aldrich

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

• , 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

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• . Peptide synthesis The peptides used were synthesized as described previously [30] by automated solid-phase peptide synthesis (SPPS) on a multiple Syro II peptide synthesizer (MultiSynTech, Witten, Germany) following Fmoc/t-Bu-strategy utilizing a double-coupling procedure and in situ activation with Oxyma

• -2,6-dioxocyclohex-1-ylidene)ethyl; SPPS: solid-phase peptide synthesis; TFA: trifluoroacetic acid; TIS: triisopropylsilane; HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DIPEA: diisopropylethylamine; TA: thioanisole; TC: p-thiocresol. Peptide sequences.a Analytical

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• , peptides containing monosaccharide-substituted allo-L- and D-threonine building blocks were assembled by solid-phase peptide synthesis (SPPS). The retro-inverso AFGP analogue contained all amino acids in D-configuration, while the allo-L-diastereomer was composed of L-amino acids, like native AFGPs, with

• subsequent step the pure α-product 3A/3B was subjected to tert-butyl ester cleavage with TFA. Peptide synthesis was accomplished under microwave heating in a semi-automated fashion, as previously published by us [16][23], by employing 2-chlorotrityl resin loaded with Fmoc-L-Ala-OH or Fmoc-D-Ala-OH. After

• purchased from Iris Biotech (Marktredwitz, Germany), Orpegen (Heidelberg, Germany) and Molekula (Gillingham, Dorset, UK). Peptide synthesis was executed on a Liberty Automated Microwave Peptide Synthesizer (CEM, Kamp-Lintfort, Germany). For preparative RP-HPLC a Thermo Separation Products system equipped

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

• ; cyclic β-tripeptide scaffold; orthogonal protection groups; peptide synthesis; template-assembled synthetic proteins (TASP); Introduction Cyclic β-tripeptides form structurally well-defined secondary structures with the potential for alignment of the rings to form intermolecular aggregates [1]. Due to

• functionalization by amide bond formation. To protect the lysine side chain for selective and orthogonal amide-bond formation following the solid-phase peptide synthesis (SPPS), the protection groups fluorenylmethoxycarbonyl (Fmoc) and carbobenzyloxy (Cbz) were applied. Alteration of the amine in the third β

• ). Standard reagents, protocols and procedures were used for deprotection (20% piperidine in NMP, 210 s, 50 °C, 20 W) and coupling (HBTU/HOBt/DIEA/NMP, 300 s, 50 °C, 20 W). Double couplings were performed for arginine. No final Fmoc deprotection step was used. After the automated peptide synthesis, the

Approaches to α-amino acids via rearrangement to electron-deficient nitrogen: Beckmann and Hofmann rearrangements of appropriate carboxyl-protected substrates

• Sosale Chandrasekhar and
• V. Mohana Rao

Beilstein J. Org. Chem. 2012, 8, 1393–1399, doi:10.3762/bjoc.8.161

• confirmation of final products was conducted with X-ray diffraction in selected cases. The final N-benzoyl and N-(methoxycarbonyl) products are α-amino acids with both carboxyl and amino protection; hence, they are of great interest in peptide synthesis. Keywords: amino acid; Beckmann rearrangement; Hofmann

• 2,4,10-trioxaadamantyl group may be cleaved with acid as reported previously [16]; alternatively, selective cleavage of the N-benzoyl group in base would furnish carboxyl-protected amino acids with a free amine function: all attractive tactical elaborations vis-à-vis peptide synthesis. Moreover, the

• carbamates are clearly less robust than the BOC analogues which are frequently employed in peptide synthesis. However, the former do offer a measure of protection that can be selectively relinquished in base. The trioxaadamantyl group would stay unaffected under these conditions, but may be cleaved off with

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• epimers (Scheme 1). While macrocyclization to give the core 2 could be performed at any of the amide or ester bonds [10], we chose to use a macrolactonization approach to enable ready access to analogues of the LI-F04a core through straightforward Fmoc solid-phase peptide synthesis of the linear

• which the D-allo-Thr protecting group was either tert-butyl or ΨMe,Me'Pro, respectively, to investigate whether a turn-inducer might assist the macrolactonization reaction. Linear peptides 5 and 6 were prepared by standard Fmoc solid-phase peptide synthesis protocols using PyBOP/Hünigs base as the

• of the crude peptide, so obtained, to authentic samples of both 5 and the C-terminal epimer 9 (which was independently prepared by solid-phase peptide synthesis), indicated that the major product obtained upon macrolactonization of 5 under the Corey–Nicolaou conditions was the undesired cyclic

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

• starting point to create a potent AMP. Experimental Peptide synthesis and chemical reagents Gp41w, gp41w-4R, gp41w-KA, gp41w-FKA were synthesized by Anaspec Inc. (Fremont, CA) to >95% purity. Peptide concentrations were determined from absorbance measurements at 280 nm and theoretical extinction

Partial thioamide scan on the lipopeptaibiotic trichogin GA IV. Effects on folding and bioactivity

• Marta De Zotti,
• Barbara Biondi,
• Cristina Peggion,
• Matteo De Poli,
• Haleh Fathi,
• Simona Oancea,
• Claudio Toniolo and
• Fernando Formaggio

Beilstein J. Org. Chem. 2012, 8, 1161–1171, doi:10.3762/bjoc.8.129

• backbone modification is compatible with the preservation of its typical membrane leakage and antibiotic properties, although somewhat attenuated. Keywords: bioactivity; conformation; peptaibiotic; peptide synthesis; peptides; thiopeptides; Introduction Since their first incorporation into peptides [1

• (CD), FT-IR absorption, and NMR. Finally, we carried out fluorescence leakage experiments in model membranes and antibacterial assays on a large set of both Gram-positive and Gram-negative strains. Results and Discussion Peptide synthesis The total syntheses of the three monothionated ψ[CS-NH

Building photoswitchable 3,4'-AMPB peptides: Probing chemical ligation methods with reducible azobenzene thioesters

• Gehad Zeyat and
• Karola Rück-Braun

Beilstein J. Org. Chem. 2012, 8, 890–896, doi:10.3762/bjoc.8.101

• by manual Fmoc-based peptide synthesis using standard amino-acid building blocks (Scheme 2) [4]. Commercially available preloaded Wang resin was used, and HBTU was applied as the coupling reagent in the presence of DIPEA in NMP. Removal of the temporary Fmoc-protecting group was achieved by using 20

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• backbones, or mimics thereof, offer further possibilities to study protein-binding events. Keywords: glycopeptide binding; glycopeptides; glycoprotein synthesis; solid-phase peptide synthesis; synthetic vaccines; Introduction The majority of human proteins are co- or post-translationally modified by mono

• sialyl-T MUC1 glycopeptides (2, 11, 12) were prepared and fully deprotected. Peptide synthesis was followed by fragment condensation employing HATU and HOAt and after additional deprotection steps, resulting in the formation of the lipopeptide vaccine constructs 14–16. Immunization of the vaccines in

• cysteine, followed by a S→N acyl shift. The development of a variant of NCL, namely expressed protein ligation (EPL), has further made it possible to efficiently prepare large proteins without the size limitations set by ordinary peptide synthesis [45]. Bertozzi and co-workers introduced the NCL and EPL

Investigation of the network of preferred interactions in an artificial coiled-coil association using the peptide array technique

• Raheleh Rezaei Araghi,
• Carsten C. Mahrenholz,
• Rudolf Volkmer and
• Beate Koksch

Beilstein J. Org. Chem. 2012, 8, 640–649, doi:10.3762/bjoc.8.71

• three β- and two γ-amino acids, was synthesized by standard solid-phase peptide synthesis and labeled at the N-terminus with the fluorophore 5(6)-tetramethylrhodamine (TAMRA). As described above, the chimera has a modified pentad (β- and γ-amino acids) at the center of its 31-residue sequence (positions

• background-corrected mean value over three replica spots for each sequence. TAMRA was measured at 645 nm. The aforementioned wavelength was chosen to detect TAMRA at lower background noise. Peptide synthesis and characterization (analogous to [18]): Peptides were synthesized by using standard, automated Fmoc

Synthesis of szentiamide, a depsipeptide from entomopathogenic Xenorhabdus szentirmaii with activity against Plasmodium falciparum

• Friederike I. Nollmann,
• Andrea Dowling,
• Marcel Kaiser,
• Klaus Deckmann,
• Sabine Grösch,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 528–533, doi:10.3762/bjoc.8.60

• synthesized using solid-phase peptide synthesis, followed by esterification and subsequent cleavage from the resin, deprotection and cyclization to yield 1, assisted by microwave irradiation at every stage with the exception of the esterification (Scheme 1). In detail, a preloaded 2-chlorotrityl chloride

• protists in order to also understand its molecular function. Experimental Synthesis Unless otherwise stated, we used the chemicals in their highest available purity. The progress of the synthesis was monitored with MALDI–MS as well as RP-UPLC coupled with ESI–MS. Solid-phase peptide synthesis. The linear

Azobenzene dye-coupled quadruply hydrogen-bonding modules as colorimetric indicators for supramolecular interactions

• Yagang Zhang and
• Steven C. Zimmerman

Beilstein J. Org. Chem. 2012, 8, 486–495, doi:10.3762/bjoc.8.55

• (DeUG) is described. The coupling of azobenzene dye 2 to mono-amido DAN units 4, 7, and 9 was effected by classic 4-(dimethylamino)pyridine (DMAP)-catalyzed peptide synthesis with N-(3-dimethylaminopropyl)-N’-ethyl carbodiimide hydrochloride (EDC) as activating agent, affording the respective amide

A straightforward approach towards combined α-amino and α-hydroxy acids based on Passerini reactions

• Ameer F. Zahoor,
• Sarah Thies and
• Uli Kazmaier

Beilstein J. Org. Chem. 2011, 7, 1299–1303, doi:10.3762/bjoc.7.151

• reactions together have made the IMCR highly popular in combinatorial chemistry [7][8]. Our group has been involved in amino acid and peptide synthesis for nearly two decades [12][13], and multicomponent reactions are known to play a dominant role [14][15]. In particular, the Ugi reaction has so far been

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• groups such as Cbz and Pht. The use of phosphorus pentaoxide for peptide synthesis was also reported, but racemization could occur under these reaction conditions [10][11]. Phosphorus oxychloride was another condensing agent used to synthesize various N-protected aminoacyl-pNAs in yields between 70% and

Synthesis of glycosylated β³-homo-threonine conjugates for mucin-like glycopeptide antigen analogues

• Florian Karch and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2010, 6, No. 47, doi:10.3762/bjoc.6.47

• solid-phase peptide synthesis. By appropriate conjugation, the resulting α/β-hybrid glycopeptide conjugate could be used as an antigen surrogate to elucidate the effects of chemically modified antibody determinants on the immunological properties of glycopeptide antigen analogues. Experimental General

• remarks: DMF (amine-free, for peptide synthesis) and NMP were purchased from Roth and Ac2O in p.a. quality from Acros. Fmoc-protected amino acids were purchased from Orpegen Pharma. For solid-phase synthesis, pre-loaded TentaGel S resin (Rapp Polymere) was employed. Reactions were monitored by TLC with

Synthesis and binding studies of two new macrocyclic receptors for the stereoselective recognition of dipeptides

• Ana Maria Castilla,
• M. Morgan Conn and
• Pablo Ballester

Beilstein J. Org. Chem. 2010, 6, No. 5, doi:10.3762/bjoc.6.5

• phenylalanine iodides 4 (Scheme 1). The mild reaction conditions used in the carbonylative cross-coupling permit the use of common protecting groups of peptide synthesis [24]. This characteristic of the carbonylative cross-coupling reaction allowed us to achieve the differential protection of the two amino acid

2-Phenyl- tetrahydropyrimidine- 4(1H)-ones – cyclic benzaldehyde aminals as precursors for functionalised β²-amino acids

• Markus Nahrwold,
• Arvydas Stončius,
• Anna Penner,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2009, 5, No. 43, doi:10.3762/bjoc.5.43

• containing e.g. tert-butyl protected side chain functions. Amino acids protected like that are particularly suitable for solid phase peptide synthesis and are thus highly desirable. Our novel ring cleavage concept includes the protection of both ring-nitrogen atoms as carbamates (Scheme 1C). Similar to the

Synthesis of novel photochromic pyrans via palladium- mediated reactions

• Christoph Böttcher,
• Gehad Zeyat,
• Saleh A. Ahmed,
• Elisabeth Irran,
• Thorben Cordes,
• Cord Elsner,
• Wolfgang Zinth and
• Karola Rueck-Braun

Beilstein J. Org. Chem. 2009, 5, No. 25, doi:10.3762/bjoc.5.25

• cyanation, carbonylation and Sonogashira cross-coupling starting from bromo-substituted naphthopyran 1 and benzopyrans 2a/b. A novel photoswitchable benzopyran-based ω-amino acid 6 for Fmoc-based solid-phase peptide synthesis is presented. The photochromic behaviour of the 3-cyano-substituted benzopyran 5a

The first preparative solution phase synthesis of melanotan II

• Vladimir V. Ryakhovsky,
• Georgy A. Khachiyan,
• Nina F. Kosovova,
• Elena F. Isamiddinova and
• Andrey S. Ivanov

Beilstein J. Org. Chem. 2008, 4, No. 39, doi:10.3762/bjoc.4.39

• accomplished in 12 steps with 2.6% overall yield, affording >90% pure peptide without using preparative chromatography. Keywords: melanotan II; solution phase synthesis; peptide synthesis; Introduction Development of solid phase peptide synthesis methodology [1], recombinant techniques for expressing

• 8-fold excess of DCC as the coupling agent and 1-hydroxybenzotriazole (HOBt) as a racemization suppressant. The yield of the cyclized product 12 was 31%, very close to the reported 30% yield for solution-phase cyclization of a related linear heptapeptide obtained by solid phase peptide synthesis [18