Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• potent and isoform selective HDAC inhibitor. Here we report our preliminary studies on thioester HDAC inhibitors derived from the active monomeric (thiol) form of psammaplin A, as a means to improve compound delivery into cells. We have discovered that such compounds exhibit both potent cytotoxicity and

• enzymatic inhibitory activity against recombinant HDAC1. The latter effect is surprising since previous SAR suggested that modification of the thiol functionality should detrimentally affect HDAC potency. We therefore also report our preliminary studies on the mechanism of action of this observed effect

• unambiguously demonstrated that, similarly to the natural product and clinically approved romidepsin, psammaplin A is a prodrug, requiring reduction of its disulfide functionality to the corresponding thiol monomer 4 (X = OH), in order to potently inhibit HDACs (Scheme 1, right). The resulting thiol moiety acts

Stereoselective synthesis of tetrasubstituted alkenes via a sequential carbocupration and a new sulfur–lithium exchange

• Andreas Unsinn,
• Cora Dunst and
• Paul Knochel

Beilstein J. Org. Chem. 2012, 8, 2202–2206, doi:10.3762/bjoc.8.248

• starting from 2,2’-dibromobiphenyl. Thus, the performance of a double bromine–lithium exchange with BuLi (1.1 equiv, −78 °C, 0.25 h) followed by a quenching with tetramethylthiuram disulfide (1.1 equiv, −78 to 25 °C, 12 h) furnishes the dithiocarbamate 13 in 82% yield. Since the reduction to the free thiol

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

• oxidation of the intermediate free thiol in good yield. As O-acetylated building blocks are often advantageous over the OH-free analogues for SPPS [2][3][4], our next step was to apply the synthesis outlined in Scheme 1 to the O-acetylated glycoamino acid derivative 4 (Scheme 2). The O-acetylated

• , when the trityl group in 4 was removed first, thiol 7 was obtained as expected, but the following Fmoc deprotection under standard conditions [14], employing 6 equiv of morpholine in DMF, unexpectedly led to the S-fluorenylmethyl (Fm)-protected glycoamino acid 8 in 77% yield (Scheme 2). The anticipated

• HMBC NMR spectrum of 8 (Figure 1) clearly indicates that the formerly unprotected thiol group of the cysteine side chain of 7 became protected by a fluorenylmethyl (Fm) moiety. This is indicated by the respective cross peaks between C-β and the Fm-CH2 protons on one hand and between Fm-CH and the H-βa

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• disulfide-containing linkers, which would be reduced inside the cell so as to release a defined thiol derivative of phalloidin (Table 1). Actin binding All phalloidin derivatives were tested for their affinity to muscle actin (α-actin), which is used as a model for β-actin present in nonmuscle cells. This

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

• heteroaromatic thiol 64 provides the sulfur-substituted bisallene derivative 65 in good yields. Likewise, the stable diallenes 66 carrying phosphorus-containing substituents were obtained by heating the diols 63 with R52PCl [51][52][53][54]. How critically the substituents in the 3- and 4-position determine the

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

• containing 0.1% TFA) in 40 min and UV detection at 216 nm). Disulfide bridges were formed by oxidizing the peptides (0.25 mg/mL in 50% ACN in 0.1 M ammonium acetate, pH 8) at room temperature with slight shaking until free thiol groups were no longer detectable by Ellman’s reagent. Oxidized peptides were

Imidazolinium and amidinium salts as Lewis acid organocatalysts

• Oksana Sereda,
• Nicole Clemens,
• Tatjana Heckel and
• René Wilhelm

Beilstein J. Org. Chem. 2012, 8, 1798–1803, doi:10.3762/bjoc.8.205

• desulfurization of the products containing a thiol or thiocarbonyl group. Keywords: Diels–Alder; ionic liquids; organocatalysis; soft Lewis acids; thiiranes; thioesters; Introduction Salts with melting points below 100 °C are known as ionic liquids and are often used as novel solvents for reactions and

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• of 2-aminobenzaldehydes with acyclic α,β-unsaturated compounds The asymmetric organocatalytic Michael conjugate addition of an amine to an electron-deficient α,β-unsaturated system provides a unique reaction process because of the weaker nucleophilic character of the amine compared to a thiol or an

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition

• Kim A. Fredriksen,
• Tor E. Kristensen and
• Tore Hansen

Beilstein J. Org. Chem. 2012, 8, 1126–1133, doi:10.3762/bjoc.8.125

• immobilization of Cinchona organocatalysts using thiol–ene chemistry, in which catalyst immobilization and bead polymerization is combined in a single step. A solution of azo initiator, polyfunctional thiol, polyfunctional alkene and an unmodified Cinchona-derived organocatalyst in a solvent is suspended in

• water and copolymerized on heating by thiol–ene additions. The resultant spherical and gel-type polymer beads have been evaluated as organocatalysts in catalytic asymmetric transformations. Keywords: asymmetric catalysis; Cinchona derivatives; organocatalysis; polymerization; thiol–ene reaction

• transformations based on radical intermediates [1]. As a result, polymeric immobilization of Cinchona derivatives by using thiol–ene addition has a substantial history, founded on procedures developed already in the early 1970s [1]. Cinchona derivatives are either copolymerized with certain comonomers, such as

Control over molecular motion using the cis–trans photoisomerization of the azo group

• Estíbaliz Merino and
• María Ribagorda

Beilstein J. Org. Chem. 2012, 8, 1071–1090, doi:10.3762/bjoc.8.119

• residues were intramolecularly cross-linked with thiol reactive azobenzene-based photoswitches. Photoisomerization of the azobenzene changes the conformation of the peptide depending on the location of the cysteine. When the azo group of polypeptide 2 is in its trans form, it retains its affinity for DNA

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

• Boc-3,4'-AMPB 1a and Boc-4,4'-AMPB 2a may result in an in-depth analysis of the redox-stability of these building blocks under the reducing conditions of thiol-based ligation methods. Generally, native chemical ligation allows the coupling of two unprotected peptides in neutral aqueous solution: a C

• . Peptide 9 with a protected thiol moiety was treated with Hg(OAc)2 in TFA, followed by DTT according to the literature [8], and the deprotected peptide 5 was purified by preparative RP-HPLC and isolated in 64% yield. All attempts to ligate azobenzene ω-amino acid thioester 1b in phosphate buffer in the

• '-AMPB-derived thioester 2b and its ligation peptides, may be rationalized by the following considerations [19][20]: The initial addition of a thiol to an electron-poor diazene double bond is a reversible reaction, furnishing a zwitterionic adduct intermediate A en route to an N-sulfenohydrazodiarene B

Intramolecular bridges formed by photoswitchable click amino acids

• Christian Hoppmann,
• Ronald Kühne and
• Michael Beyermann

Beilstein J. Org. Chem. 2012, 8, 884–889, doi:10.3762/bjoc.8.100

• a photoswitchable unit elongated with a functional group that allows for a specific click reaction, such as an alkene that can react with the thiol group of a cysteine residue. An intramolecular click reaction results in the formation of a photoswitchable bridge, which can be used for controlling

• a model peptide without a preferred conformation, it was seen that the thiol–ene click reaction takes place efficiently in both cases. Upon induction of an α-helical structure by the addition of trifluoroethanol, the thiol click reaction occurs preferentially with the i,i+4 spacing. Even in the

• presence of glutathione as an additional thiol the click reaction of the PSCaa occurs intramolecularly with the cysteine rather than with the glutathione, indicating that the click reaction may be used even under reducing conditions occurring in living cells. Keywords: azobenzene; helical conformation

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

• ., auxiliary based protocols, desulfurization methods or sugar-assisted chemical ligation (SAL) are all examples of expanded NCL techniques [70][71][72][73][74][75][76][77]. According to the auxiliary-based ligation strategy, a thiol-containing mimic replaces the N-terminal cysteine; the mimic group is then

• rearranges, forming a C-terminal thioester, followed by coupling to the N-terminal peptide fragment containing a thiol auxiliary. After coupling, the Tmb auxiliary could be removed by treatment with 95% trifluoroacetic acid (TFA). In spite of the strong-acid treatment required, the glycosidic bonds were

• amine group is reduced resulting in longer coupling times and lower yields. Therefore, the auxiliary method is mainly applied when the ligation site contains a glycine residue. To avoid these limitations, a ligation methodology has been developed with the thiol group linked to the amino-acid side-chain

Formation of carbohydrate-functionalised polystyrene and glass slides and their analysis by MALDI-TOF MS

• Martin J. Weissenborn,
• Johannes W. Wehner,
• Christopher J. Gray,
• Robert Šardzík,
• Claire E. Eyers,
• Thisbe K. Lindhorst and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2012, 8, 753–762, doi:10.3762/bjoc.8.86

• MALDI-TOF MS analysis. Results and Discussion The hydrophobic trityl tethers chosen for our studies consisted of S-tritylated instead of N-tritylated groups, which were used previously [7]. This followed the idea of “orthogonal” surface functionalisation. Thus, a thiol group would make the tethers

Synthesis and antiviral activities of spacer-linked 1-thioglucuronide analogues of glycyrrhizin

• Christian Stanetty,
• Andrea Wolkerstorfer,
• Hassan Amer,
• Andreas Hofinger,
• Ulrich Jordis,
• Dirk Claßen-Houben and
• Paul Kosma

Beilstein J. Org. Chem. 2012, 8, 705–711, doi:10.3762/bjoc.8.79

• corresponding glucuronyl 1-thiol 3 in 89% yield [17][18]. Reaction of 3 with an excess of 1,2-dibromoethane (3–4 equiv) in DMF in the presence of sodium hydride, with the strict exclusion of oxygen, afforded the 2-bromoethyl 1-thioglycoside 4 in 80% yield. Under these conditions formation of the bis

• -substitution product 5 (3%) and the disulfide oxidation product of 1-thiol 3 was observed in only very minor quanities. The corresponding 2-iodoethyl derivative 6 was prepared by a Finkelstein reaction from the bromoethyl 1-thioglycoside 4 in 95% yield (Scheme 1). The previously reported 3β-amino derivative of

• spacer elongation [14]. The previously reported 1,2-dehydro-3-thiol derivative 20 was subjected to alkylation with the 2-iodoethyl 1-thioglucuronide compound 6 in the presence of K2CO3 to furnish the thioether-bridged glucuronide triterpene 21 in 60% yield. Deprotection of 21 was performed in two steps

2-Allylphenyl glycosides as complementary building blocks for oligosaccharide and glycoconjugate synthesis

• Hemali D. Premathilake and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2012, 8, 597–605, doi:10.3762/bjoc.8.66

• can be reverted as needed (active–latent strategy). Direct conjugation of the AP moiety to biomolecules, monolayers, arrays, etc., should be possible by executing thiol–ene chemistry [43], ozonolysis/reductive amination [44][45][46], or other ligation protocols [47][48]. Experimental General remarks

Mutational analysis of a phenazine biosynthetic gene cluster in Streptomyces anulatus 9663

• Orwah Saleh,
• Katrin Flinspach,
• Lucia Westrich,
• Andreas Kulik,
• Bertolt Gust,
• Hans-Peter Fiedler and
• Lutz Heide

Beilstein J. Org. Chem. 2012, 8, 501–513, doi:10.3762/bjoc.8.57

• as = +16.8 (c = 0.33, MeOH). Endophenazine E is a new natural product. The conjugation of a phenazine to N-acetylcysteine has been described previously [17]. In that case, conjugation occurred through the thiol group of cysteine and led to the loss of the antibacterial activity of the phenazine. A

Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry

• Teruo Umemoto,
• Lloyd M. Garrick and
• Norimichi Saito

Beilstein J. Org. Chem. 2012, 8, 461–471, doi:10.3762/bjoc.8.53

• the production of various arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides), from the corresponding diaryl disulfides or aryl thiols. The method consists of two steps: (Step 1) treatment of a diaryl disulfide or an aryl thiol with chlorine in the presence of

• ) between 7 and 8. The reaction of aryl thiol as a starting material is similar to that of the disulfide 1 since aryl thiol reacts with Cl2 to form disulfide 1. The arylsulfur chlorotetrafluorides 2a–j and bis(sulfur chlorotetrafluorides) 2p′ and 2q′ obtained were trans-isomers, while the polyfluorinated 2k

Syntheses and applications of furanyl-functionalised 2,2’:6’,2’’-terpyridines

• Jérôme Husson and
• Michael Knorr

Beilstein J. Org. Chem. 2012, 8, 379–389, doi:10.3762/bjoc.8.41

• electrophilic thiocyanato group and a nucleophilic residue present on the biomolecule (amine, thiol, for example) should allow anchorage of 62. Another approach that was envisioned for the linking of fluorescent europium–terpyridine complexes to biomolecules is the use of click chemistry [54]. Again, 54 was

Liquid-crystalline nanoparticles: Hybrid design and mesophase structures

• Gareth L. Nealon,
• Romain Greget,
• Cristina Dominguez,
• Zsuzsanna T. Nagy,
• Daniel Guillon,
• Jean-Louis Gallani and
• Bertrand Donnio

Beilstein J. Org. Chem. 2012, 8, 349–370, doi:10.3762/bjoc.8.39

• LCNPs, and the first such report involved the direct synthesis of 3 nm Au NPs in the presence of a calamitic (cyclohexyl)phenoxy thiol (5, Figure 3) to give a densely packed surface coating (Figure 4a) [60]. The ligand showed both smectic and nematic phases, and the authors claimed that the Au@5 hybrid

• moiety (612, Figure 4b) [61]. The thiol ligand exhibited a nematic phase, and the hybrids displayed a mesophase between 110 °C and 130 °C, but no distinct texture could be observed with POM (Table 1). Interestingly, direct observation of the possible arrangement of the NPs was obtained through annealing

• -mesogenic ligands: Side-on attachment The first assignment of a nematic phase for a pseudospherical NP was realised through the use of a laterally substituted rodlike mesogenic thiol (12, Figure 13) [69]. In this study, Au-NPs of diameters 1.6 ± 0.4 nm were targeted because of their small size and low

Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca

• Jeroen S. Dickschat,
• Hilke Bruns and
• Ramona Riclea

Beilstein J. Org. Chem. 2011, 7, 1697–1712, doi:10.3762/bjoc.7.200

• with equal functions to the individual and respective megasynthase domains. In both cases a starter unit, usually acetyl-CoA, is selected by the acetyl transferase (AT) and loaded onto an acyl-carrier-protein (ACP), or, more precisely, onto the thiol end of a phosphopantetheinyl linker that is attached

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• corresponding PKS module was found to activate malonyl-CoA, which is expected to be transferred to the thiol group of the adjacent ACP domain via the embedded GNAT domain. However, only an acetyl group could be detected on the ACP, supporting an additional decarboxylase activity for the GNAT domain [46

Ratiometric fluorescent probe for enantioselective detection of D-cysteine in aqueous solution

• Xiao-bo Zhou,
• Wing-Hong Chan,
• Albert W. M. Lee and
• Chi-Chung Yeung

Beilstein J. Org. Chem. 2011, 7, 1508–1515, doi:10.3762/bjoc.7.176

• ]. The facile cyclization of β- or γ-aminothiols with aldehydes containing fluorescent probes forms the basis for the development of several fluorescent probes [12][13][14][15][16][17]. In addition, cleavage of disulfide-based probes by thiols [18][19][20][21] and other thiol-sensing tactics have been

• , it becomes apparent that the presence of free amine and thiol groups is essential for the effective interaction with the cadmium metal centre of the sensor. Interestingly, Hcy bearing a β-mercaptoamino moiety is far less effective at binding with the cadmium of the probe in comparison with the α

• -mercaptoamino group present in Cys. When the thiol group in Hcy is methylated, as in methionine, its power to bind to the sensor is completely lost. As none of the bifunctional α-amino acids caused any fluorescence quenching of the probe, the presence of β-mercaptoamino moiety in cysteine may confer a

The Eschenmoser coupling reaction under continuous-flow conditions

• Sukhdeep Singh,
• J. Michael Köhler,
• Andreas Schober and
• G. Alexander Groß

Beilstein J. Org. Chem. 2011, 7, 1164–1172, doi:10.3762/bjoc.7.135

• the mercapto hydantoin derivative 2g underwent the two step reaction smoothly and yielded the desired product 4ag in good quantity. In case of the 1H-benzoimidazole-2-thiol (2h), the selective S-alkylation failed. The utilized alkylation conditions favor the bis-alkylation, and hence the S-alkylated

Advances in synthetic approach to and antifungal activity of triazoles

• Kumari Shalini,
• Nitin Kumar,
• Sushma Drabu and
• Pramod Kumar Sharma

Beilstein J. Org. Chem. 2011, 7, 668–677, doi:10.3762/bjoc.7.79

• , phenoxyacetic acid derivatives and carbon disulfide, respectively. Their antifungal activity was investigated against Aspergillus niger and Fusarium oxysporum. Among the series of synthesized compounds, 7-(3-chlorophenyl)-6,7-dihydro-5H-imidazo[2,1-c][1,2,4]triazole-3-thiol (8, Figure 6) showed the most