Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• ]. Several methods have been developed for site-directed PEGylation. One of the most popular involves the reaction of the thiol group in one or two cysteine residues with appropriate PEG derivatives. The cysteine could be originally present in the protein or introduced by mutagenesis [27][28]. The C-terminus

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

• -terminated SAMs [33], by Diels–Alder reaction of cyclopentadienes and furans on maleimide-terminated SAMs [34], by thiol–ene click reaction of functionalized thiols on alkene-terminated SAMs [35] as well as by strain promoted cycloadditions on azide- and nitriloxide-terminated SAMs [36] using μCP. Homogenous

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs

• Fabrizio Chiodo,
• Marco Marradi,
• Javier Calvo,
• Eloisa Yuste and
• Soledad Penadés

Beilstein J. Org. Chem. 2014, 10, 1339–1346, doi:10.3762/bjoc.10.136

• prodrug candidates. The nucleoside reverse transcriptase inhibitors abacavir and lamivudine have been converted to the corresponding thiol-ending ester derivatives and then conjugated to ~3 nm glucose-coated gold nanoparticles by means of “thiol-for-thiol” ligand place exchange reactions. The drugs

• thioacetate [31], was reacted with ABC and 3TC in DMF in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) to obtain the ester derivative in ~75% yield. After purification, the protecting group of the thiol was removed with hydrazine acetate to give the

• corresponding ester prodrug candidates with a free thiol-ending group fundamental for their gold chemo-adsorption (Figure 1 and Supporting Information File 1). Abacavir (ABC) and lamivudine (3TC) were functionalized at the primary hydroxy groups through an ester bond that will be cleaved by cellular esterase

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• phosphorazidate (DPPA) and diethyl phosphorocyanidate (DEPC) are widely employed as peptide coupling reagents [59][60][61][62]. DPPA was also used in many organic reactions such as the Curtius rearrangement [59], the thiol ester synthesis [63], the azidation of alcohol and phenol [64], and the synthesis of

• . However, as reported in Scheme 32-ii, some chiral phosphoramidates and thiophosphoramidates can be readily synthesized with the AT reaction in high yield (85–88%) from dimethyl phosphite or O,O-dimethyl thiophosphite [106]. When the chiral amine was functionalized with a thiol group (Scheme 32-iii), 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

• ) synthesis. Probably, the same S–S-containing linker could be used in the synthesis of MorGly oligomers, but it should be examined. In our work we propose another approach, which has fewer steps and does not require the additional thiol treatment to cleave the oligomer from the support. In our previous work

End-group-functionalized poly(N,N-diethylacrylamide) via free-radical chain transfer polymerization: Influence of sulfur oxidation and cyclodextrin on self-organization and cloud points in water

• Sebastian Reinelt,
• Daniel Steinke and
• Helmut Ritter

Beilstein J. Org. Chem. 2014, 10, 680–691, doi:10.3762/bjoc.10.61

• synthesis of thermo-, oxidation- and cyclodextrin- (CD) responsive end-group-functionalized polymers, based on N,N-diethylacrylamide (DEAAm). In a classical free-radical chain transfer polymerization, using thiol-functionalized 4-alkylphenols, namely 3-(4-(1,1-dimethylethan-1-yl)phenoxy)propane-1-thiol and

• 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propane-1-thiol, poly(N,N-diethylacrylamide) (PDEAAm) with well-defined hydrophobic end-groups is obtained. These end-group-functionalized polymers show different cloud point values, depending on the degree of polymerization and the presence of randomly

• agents [23][24][25] or (b) indirect by polymer analogous modification of existing end-groups. For the post-modification highly efficient reactions are needed to ensure a high degree of functionalization. For this reason, often “click reactions” [26] such as esterifications [27], azide–alkyne [22], thiol

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• :1 mixture of both 2,3-anti diastereomers 17a and 17b in 57% yield over two steps [22]. Such thiophenol esters readily undergo thiol-exchange reactions and are therefore suitable precursors for SNAc, pantetheine and CoA thioesters [14]. Accordingly, when we treated the mixture of thiophenol esters

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3. Keywords: ansamitocins; antibiotics

• ] were one of the earliest examples of folate disulfide–drug conjugates and after the conjugate is internalized by endocytosis, it was demonstrated that the endosomes exert reductive cleavage. For conjugate 7 we found that disulfide cleavage provided a thiol derivative of ansamitocin P-3 (4, AP-3) 8 with

• order to broaden the opportunities of this approach for the ansamitocins, we now describe alternative accesses towards disulfide linked conjugates that are based on thiol-functionalized AP-3 derivatives. These are planned to be obtained by a combined muta- and semisynthetic strategy using different

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• proceeds through a formation of an enol-containing complex with a metal ion (Scheme 57, Table 14). 3.3. Oxidation of 1,5-dienes in the presence of thiols The co-oxidation of 1,4-dienes and thiols (thiol–olefin co-oxygenation, TOCO reaction) was described for the first time by Beckwith and Wagner as a

Silica: An efficient catalyst for one-pot regioselective synthesis of dithioethers

• Samir Kundu,
• Babli Roy and
• Basudeb Basu

Beilstein J. Org. Chem. 2014, 10, 26–33, doi:10.3762/bjoc.10.5

• allyl bromide with excess thiol at room temperature is described. The choice of silica gel, either pre-calcined or moistened with water, exhibited notable regioselectivity in the formation of dithioethers. Plausible mechanistic routes were explored and postulated. Keywords: allyl halide; dithioether

• ; silica gel; tandem reactions; thiol; Introduction Organosulfur compounds are important building blocks for the synthesis of various biologically active molecules [1][2][3]. Versatile applications of organosulfur compounds are known in fields such as the pharmaceutical, the polymer, the pesticide and the

• showed varying results under conditions A or B, and allyl acetate did not undergo any desired reaction, but merely produced the disulfide from oxidative dimerization of the thiol (Table 1, entries 6–8). Allyl tosylate, however, produced the desired thioethers in a regioselective manner, but with

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

• 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

• [20]. Carbohydrate conjugation was achieved by copper-catalyzed azide alkyne cycloaddtion (CuAAC) of carbohydrate ligands on alkyne presenting oligomers [21]. As an alternative conjugation approach to CuAAc, a very efficient thiol–ene coupling (TEC) [22][23][24][25] protocol in a continuous flow

• removal of the desired product minimizes unwanted secondary reaction pathways [27][28][29][30][31][32][33][34][35][36][37][38][39]. We also introduced the so-called building block approach in the context of thiol–ene coupling via the continuous-flow technique. A first example involved conjugating a

Stereoselective synthesis of the C79–C97 fragment of symbiodinolide

• Hiroyoshi Takamura,
• Takayuki Fujiwara,
• Isao Kadota and
• Daisuke Uemura

Beilstein J. Org. Chem. 2013, 9, 1931–1935, doi:10.3762/bjoc.9.228

• (Scheme 4). The synthesis started from commercially available methyl (S)-3-hydroxy-2-methylpropanoate (21), which was converted to alcohol 22 by the known method [22]. Alcohol 22 was treated with 1-phenyl-1H-tetrazole-5-thiol/DEAD/PPh3 to furnish the corresponding PT-sulfide, which was oxidized with H2O2

Polymeric redox-responsive delivery systems bearing ammonium salts cross-linked via disulfides

• Christian Dollendorf,
• Martin Hetzer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 1652–1662, doi:10.3762/bjoc.9.189

• circulation and extracellular milieus, but are prone to cleavage in a reductive environment through dithiol–disulfide exchange reactions forming two corresponding thiol end-group bearing moieties [27][28]. The cleavage reaction is relatively fast and can take place within minutes to hours. This is

• transition temperature (Tg), swelling behavior, and cloud points (Tc) of the thiol-bearing copolymers after cleavage were investigated. Although our results show only preliminary investigations, this hydrogel system with its redox-responsive behavior and polycationic structure could be a promising system for

• disulfide bonds to thiol side-chains (Scheme 1b). The dissolved polymers were cross-linked again by the oxidation of the thiol groups to reform disulfide bonds using oxygen under basic conditions at 60 °C. As described above, it was crucial to use concentrated solutions, because only thiol groups of

Re₂O₇-catalyzed reaction of hemiacetals and aldehydes with O-, S-, and C-nucleophiles

• Wantanee Sittiwong,
• Michael W. Richardson,
• Charles E. Schiaffo,
• Thomas J. Fisher and
• Patrick H. Dussault

Beilstein J. Org. Chem. 2013, 9, 1526–1532, doi:10.3762/bjoc.9.174

• ions [21][22]. As illustrated in Table 5, tetrahydrofuranol and tetrahydropyranol both undergo condensation with a simple thiol in the presence of Re2O7 to provide the monothioacetal in good yield; only traces of the S,S-dithioacetal were observed. The same reaction, when catalyzed by a Brønsted acid

• , required a higher catalyst loading and provided a lower yield of product accompanied by a greater amount of dithioacetal. Re(VII)-promoted reaction with thioacetic acid proceeded in much lower yield. As illustrated in Scheme 2, Re2O7 also promotes the reaction of an aldehyde with a thiol or a dithiol to

• transparent light yellow solution (Figure S1, Supporting Information File 1), addition of thiol to a mixture of Re2O7 and hemiacetal produces an opaque, black, solution that gradually becomes translucent but remains very dark (Figure S2, Supporting Information File 1). Attempted reaction with nitrogen

A³-Coupling catalyzed by robust Au nanoparticles covalently bonded to HS-functionalized cellulose nanocrystalline films

• Jian-Lin Huang,
• Derek G. Gray and
• Chao-Jun Li

Beilstein J. Org. Chem. 2013, 9, 1388–1396, doi:10.3762/bjoc.9.155

• novel nanocomposite catalyst AuNPs@HS-CNC. The uniform, fine AuNPs were made by the reduction of HAuCl4 solution with thiol (HS-) group-functionalized CNC films. The AuNPs@HS-CNC nanocomposites were examined by X-ray photoelectron spectroscopy (XPS), TEM, ATR-IR and solid-state NMR. Characterizations

• synthesized by using a modified procedure reported by Tingaut et al. Only the method of thiol functionalized CNC support (HS-CNC) is different from that reported by MacLachlan et al. (see Methods for the details about the catalyst preparation). Structure characterizations The XPS spectra (Figure 1

Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives into thioglycosides and glycosyl thiols

• Tamashree Ghosh,
• Abhishek Santra and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2013, 9, 974–982, doi:10.3762/bjoc.9.112

• thiols in a one-pot two-step reaction sequence mediated by Appel reagent (carbon tetrabromide and triphenylphosphine). 1,2-trans-Thioglycosides and β-glycosyl thiol derivatives were stereoselectively formed by the reaction of the in situ generated glycosyl bromides with thiols and sodium

• carbonotrithioate. The reaction conditions are reasonably simple and yields were very good. Keywords: Appel reagent; carbon tetrabromide; glycosyl hemiacetal; glycosyl thiol; thioglycoside; triphenylphosphine; Introduction Thioglycosides (1-thiosugar) are widely used glycosyl donors in glycosylation reactions [1

• , instability of the starting materials (glycosyl bromides, etc.), multiple steps, unsatisfactory yields, use of metallic salts, use of expensive reagents, pregeneration of glycosyl isothiouronium salts, etc. Similar to thioglycosides, glycosyl thiol derivatives are useful intermediates for the synthesis of

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• purification with crotylamine under microwave heating conditions to provide 15. Reaction of 15 with potassium ethyl xanthogenate, again under microwave heating conditions, led to the bicyclic thiol 16. Without purification, 16 was added to 1-bromo-3-phenylpropane in the presence of potassium carbonate to

Synthesis of 2,3-dihydronaphtho[2,3-d][1,3]thiazole-4,9-diones and 2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones and novel ring contraction and fusion reaction of 3H-spiro[1,3-thiazole-2,1'-cyclohexanes] into 2,3,4,5-tetrahydro-1H-carbazole-6,11-diones

• Lidia S. Konstantinova,
• Kirill A. Lysov,
• Ljudmila I. Souvorova and
• Oleg A. Rakitin

Beilstein J. Org. Chem. 2013, 9, 577–584, doi:10.3762/bjoc.9.62

• formation of thiol 17 followed by the dihydropyrrole ring closure under the impact of both quinone and amine groups and the generation of the aromatic pyrrole cycle with hydrogen sulfide extrusion by the action of base (triethylamine). Although, to the best of our knowledge, the transformation of 3H-spiro

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• remaining fluorine to introduce different substituents, as shown by the simple formation of trifluoroethoxy derivative 64. The adducts derived from xanthate 61 can be used in yet another way. Gentle aminolysis of the xanthate frees a thiol, which, under more basic conditions, displaces the ortho-fluorine to

Efficient Cu-catalyzed base-free C–S coupling under conventional and microwave heating. A simple access to S-heterocycles and sulfides

• Silvia M. Soria-Castro and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2013, 9, 467–475, doi:10.3762/bjoc.9.50

• the reactions of KSCOMe (1) with aryl iodides under a Cu/ligand/base-free system to afford S-aryl thioacetates 2 as thiol surrogates in good to excellent yields, under conventional heating and microwave irradiation as an efficient access to a variety of sulfur compounds. Results and Discussion

• finally affords heterocycle 6. The free thiol 7 can be also generated by acyl transfer from 2-mercaptoanhydride 11 (Scheme 5). By optimizing the reaction conditions, it was possible to improve the yield of 6. Hence, the copper-catalyzed reaction between iodide 9 and 1 in a ratio of 1:2 rendered only

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