A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

• András György Németh,
• György Miklós Keserű and
• Péter Ábrányi-Balogh

Beilstein J. Org. Chem. 2019, 15, 1523–1533, doi:10.3762/bjoc.15.155

• based on the reaction of amines and the readily available, but toxic and volatile carbon disulfide [42][43][44][45]. Greener methods for the synthesis of thiocarbamates and dithiocarbamates have been developed such as the addition of the amine component to potassium thiocyanate [46][47] or

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• the 1,4-dihydropyridine scaffold. As depicted in Scheme 14, compound 46 was later subjected to a variety of post-MCR cyclizations, including the reaction with carboxylic acids to form the fused steroidal pyridopyrimidinones 47 and with carbon disulfide to form pyridopyrimidinedithione 48 in very good

Understanding the unexpected effect of frequency on the kinetics of a covalent reaction under ball-milling conditions

• Ana M. Belenguer,
• Adam A. L. Michalchuk,
• Giulio I. Lampronti and
• Jeremy K. M. Sanders

Beilstein J. Org. Chem. 2019, 15, 1226–1235, doi:10.3762/bjoc.15.120

• Sciences, University of Cambridge, Downing Street, Cambridge CB2 3EQ, UK 10.3762/bjoc.15.120 Abstract We here explore how ball-mill-grinding frequency affects the kinetics of a disulfide exchange reaction. Our kinetic data show that the reaction progress is similar at all the frequencies studied (15–30 Hz

• of bis(2-nitrophenyl) disulfide and bis(4-chlorophenyl) disulfide in the presence of a small amount of the base catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produce 4-chlorophenyl 2-nitrophenyl disulfide (see Scheme 1). Reliable experimental procedures have already been established for this

• ) conditions with 50 μL of acetonitrile added to 200 mg of powder. The kinetic points prepared for this study are all single point experiments. The reaction under study is a base-catalyzed disulfide exchange reaction starting from equimolar amounts of homodimers using DBU as the base catalyst to result in the

Insertion of [1.1.1]propellane into aromatic disulfides

• Robin M. Bär,
• Gregor Heinrich,
• Martin Nieger,
• Olaf Fuhr and
• Stefan Bräse

Beilstein J. Org. Chem. 2019, 15, 1172–1180, doi:10.3762/bjoc.15.114

• as bioisosters of para-substituted benzene and alkyne moieties. The most promising precursor for BCPs is [1.1.1]propellane (1). The available methods to synthesize BCPs are quite limited and many groups contribute to the development of novel methods. The insertion of 1 into disulfide bonds is known

• , but has never been thoroughly investigated. In this study, we show that an UV initiated radical reaction can be used to synthesize symmetrically and unsymmetrically substituted BCP sulfides by reaction of [1.1.1]propellane (1) with disulfides. Depending on the ratio of 1 to the disulfide, only the BCP

• of the thiol addition [24]. In analogy to this reaction, the insertion of 1 into disulfide bonds has been discovered early, but only very few examples can be found in the literature [10][11][25][26][27][28]. In this work, the insertion of [1.1.1]propellane (1) into disulfide bonds was investigated

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• equivalent of copper(II) acetate, 1.0 equivalent of bipyridine, and 2.0 equivalents of sodium carbonate in dichloroethane at 70 °C for 16 hours provided the desired S-cyclopropylated compound 1a in 86% yield accompanied by only 4% of the diaryl disulfide side-product 26a (Table 1, entry 1, "standard

• disulfide product, suggesting a deleterious effect of oxygen (Table 1, entry 3). Yet, to our surprise, performing the reaction under argon also negatively impacted the yield of the reaction (Table 1, entry 4), showing that air is the ideal (and also most convenient) atmosphere for this reaction. Changing

• ). Attempts at reducing the reaction time led to a minor erosion in the yield of the reaction (Table 1, entry 10). Replacing cyclopropylboronic acid (25) with cyclopropylboronic acid pinacol ester (27) or cyclopropylboronic acid MIDA ester 28 afforded 85% and 96% of the corresponding diaryl disulfide 26a

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• differences in the crystal packing in the solid state. The products 32 were obtained via thermodynamic control (Figure 18) from a dynamic combinatorial library [53][88]. In 2010, Otto and co-workers observed unprecedented product selectivity for the formation of disulfide macromolecules based on mechanical

• shaking and stirring [89]. Peptide-chain containing distal thiol groups underwent an aerial oxidation process to give different disulfide-containing macromolecules. They observed that under mechanical shaking conditions preferentially the cyclic hexamer 33 is formed, whereas stirring resulted in formation

An efficient and concise access to 2-amino-4H-benzothiopyran-4-one derivatives

• Peng Li,
• Yongqi Wu,
• Tingting Zhang,
• Chen Ma,
• Ziyun Lin,
• Gang Li and
• Haihong Huang

Beilstein J. Org. Chem. 2019, 15, 703–709, doi:10.3762/bjoc.15.65

• from 2’-chloroacetophenone as the starting material through treatment with carbon disulfide in the presence of sodium hydride [23], followed by alkylation using iodoethane according to the literature procedures [13][16][17][19]. The oxidation of 1 with 1.2 or 5 equiv of H2O2 yielded ethyl sulfoxide 2

Thiol-free chemoenzymatic synthesis of β-ketosulfides

• Adrián A. Heredia,
• Martín G. López-Vidal,
• Marcela Kurina-Sanz,
• Fabricio R. Bisogno and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2019, 15, 378–387, doi:10.3762/bjoc.15.34

• ][4], however, there are certain negative aspects of thiols that need to be taken into account (i.e., foul smell, easy oxidation into disulfide, participation as donors in one-electron events, reaction with olefins through ene-type reactions, etc) [5][6][7][8]. Hence, the development of thiol-free

Metal-free C–H mercaptalization of benzothiazoles and benzoxazoles using 1,3-propanedithiol as thiol source

• Yan Xiao,
• Bing Jing,
• Xiaoxia Liu,
• Hongyu Xue and
• Yajun Liu

Beilstein J. Org. Chem. 2019, 15, 279–284, doi:10.3762/bjoc.15.24

• -catalyzed C–S coupling reactions [13]. Conventional methods for the synthesis of 2-mercaptobenzoxazoles and 2-mercaptobenzothiazoles include the interaction of 2-aminophenol or 2-haloanilines with carbon disulfide [14][15][16], or potassium ethyl xanthate [17][18] (Scheme 1). In 2017, the Dong group

• reported a new method for the synthesis of 2-mercaptobenzoxazoles and 2-mercaptobenzothiazoles by cyclization of 2-aminothiophenols or 2-aminophenols with tetramethylthiuram disulfide in water [19]. Very recently, the Liu group developed a novel protocol for the synthesis of 2-mercaptobenzothiazoles via a

• -catalyzed C–H thiolation of benzothiazole or benzoxazole with a disulfide and a thiol provides easy access to the corresponding sulfides [26][27][28][29][30][31][32][33][34]. However, the examples using C–H functionalization for preparing 2-mercaptobenzoxazoles or 2-mercaptobenzothiazoles are still rare. In

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• Pharmaceuticals GmbH, Leberstr. 20, A-1110 Vienna, Austria 10.3762/bjoc.15.11 Abstract Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY

• )-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from

• of linkers are unsuitable, as they rendered the peptide inactive (results not shown). However, disulfide-bonded linkers retained activity, presumably by cleavage in the reductive milieu of cancer cells, if connected via a short ester or amide linkage at the C-terminus. The retrosynthetic analysis

Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

• Miriam Schehr,
• Daniel Hugenbusch,
• Tobias Moje,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2018, 14, 2799–2804, doi:10.3762/bjoc.14.257

• discovered by Baeyer in 1874 [24] and further investigated by Mills [25] and Bamberger [26]. The S-diazocines 1–5 were obtained using a 2–3 step synthesis (Scheme 1). To synthesize the nitro and amino-substituted precursors 13–16, disulfide 12 was reduced with sodium borohydride and in situ reacted with

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• ) operon; PefI negatively regulates the pef operon and SrgA is a disulfide oxidoreductase involved in correctly folding PefA, a fimbrial subunit [33]. The functions of SrgB-D are unknown [28]. SrgE is a type III secreted effector, but its target is unknown [19]. Lastly, rck (resistance to complement

Synthesis of aryl sulfides via radical–radical cross coupling of electron-rich arenes using visible light photoredox catalysis

• Amrita Das,
• Mitasree Maity,
• Simon Malcherek,
• Burkhard König and
• Julia Rehbein

Beilstein J. Org. Chem. 2018, 14, 2520–2528, doi:10.3762/bjoc.14.228

• -Trimethoxybenzene and diphenyl disulfide were employed as the model substrates to test our proposal and to optimize the reaction conditions. Our developed photocatalytic method allows the activation of electron-rich alkoxyarenes for the direct C–H sulfenylation reaction using visible light and [Ir(dF(CF3)ppy)2

• ). The organic dye 9-mesityl-10-phenylacridinium tetrafluoroborate completely decomposed in the presence of excess disulfide within 30 minutes of irradiation. [Ir(dF(CF3)ppy)2(dtbpy)]PF6 was found to be the best photocatalyst and in this case, CH3CN was the best solvent compared to DMF, DMSO and DCE

• . When thiophenol was used as the sulfur source, diphenyl disulfide was obtained as a major side product, which in turn hindered the arylation process and resulted in several other oxidized products of thiophenol. So, the readily available diphenyl disulfide was added as the thiolating agent. Addition of

Synthesis and post-functionalization of alternate-linked-meta-para-[2ⁿ.1ⁿ]thiacyclophanes

• Wout De Leger,
• Koen Adriaensen,
• Koen Robeyns,
• Luc Van Meervelt,
• Joice Thomas,
• Björn Meijers,
• Mario Smet and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2190–2197, doi:10.3762/bjoc.14.192

• structure [15][16][17]. Wang et al. were the first to report a one-pot procedure towards the synthesis of various thiapillararenes [18][19][20]. Our group reported a disulfide-bridged [2n] pillararene-like molecule in a two-step procedure [21]. In contrast to meta-para-bridged azacyclophanes [22][23][24][25

Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• “molecular muscles” can accumulate their force and consequently deform a material by concerted switching. In rotaxane 21, the two macrocycles are attached by disulfide anchors to the gold surface of microcantilever beams (500 × 100 × 1 µm) and form a self-assembled monolayer. Chemical oxidation leads to a

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• )disulfide (empirical name – dichlorodiphenyl disulfide, abbreviated as DDDS), 2,6-lutidine and acridinium salts under blue LED irradiation, providing access to precious, non-commercially available and multifunctional amine building blocks in one step (Scheme 2) [40]. The group demonstrated the synthesis of

• structural characteristic of peptides is the disulfide bridge formed by cysteines. This functional group is much more prevalent in peptide medicinal chemistry. Noël et al. have published a protocol for the aerobic oxidation of thiols to disulfides, using Eosin Y photocatalysis and TMEDA (Scheme 3) [43]. The

• , in a similar manner to the amide coupling by Leow. The demonstrated oxidation of the free thiols to a disulfide to afford oxytocin (3c) as the product in quantitative yield shows the value of this procedure. Medicinal chemists who specialise in creating artificial peptides could find much use for

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• resolution observed at m/z of 13 for FimHtr) and an elemental composition of truncated and his-tagged FimH with a disulfide bond (C803H1213O242N217S2). The relative peak abundances were extracted and compared to the theoretical spectra. A change in molecular composition upon addition of the diazirine 3

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• since sulfur, in the form of the sulfate ion, is the second most abundant anion in sea water after chloride. As part of natural products, sulfur can appear in a multitude of combinations and oxidation states: thiol, sulfide (acyclic or heterocyclic), disulfide, sulfoxide, sulfonate, thioaminal

• , sulfide (acyclic or heterocyclic), disulfide, sulfoxide, sulfonate, thioaminal, hemithioacetal, various thioesters, thiocarbamate and isothiocyanate [3]. The three simplest sulfur-containing natural products are perhaps, (E)-2-butene-1-thiol (1), the principal ingredient of the repulsively malodorous

• substituent (electron donating/withdrawing) on the aromatic ring of the disulfide was reported to have no effect on the reaction (Scheme 23). Despite using a very reactive metal, the advantage of this method is that there is no use of any extra acidic catalyst for activating the epoxide ring, and moderate to

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• compare the influence of sequence modification, the presence or absence of a spacer as well as the type of spacers on toxicity. Disulfide dimers were also developed based on conjugates 4, 6 and 8, resulting in compounds 9, 10 and 11. Four conjugates with two identical (Dau) or different (Dau and Mtx) drug

• conjugates with two different drug molecules or Lys(Ac) in position 4, orthogonal protecting schemes were applied during the SPPS. For the preparation of the disulfide dimers, an additional Cys was attached to the ε-amino group of 8Lys of the GnRH-III derivatives. First, Dau was linked to the aminooxyacetyl

Acyl-group specificity of AHL synthases involved in quorum-sensing in Roseobacter group bacteria

• Lisa Ziesche,
• Jan Rinkel,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 1309–1316, doi:10.3762/bjoc.14.112

• addition. The location of the double bond of the major acids was determined by dimethyl disulfide (DMDS) derivatization [32][34]. The fragment ions at m/z 145 and 161 of the DMDS-derivative and the secondary fragments obtained by loss of the methyl ester group (m/z 129) located the position of the double

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• reaction mechanism starts with the oxidative addition of the diaryliodonium salt 1 to copper(I) iodide affording the Cu(III) species A, releasing aryl iodide 2. Coordination of the disulfide 6 to the metal centre leads to complex B, followed by the base-induced formation of arylcopper sulfide complex C and

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• which may cyclize through the formation of intramolecular disulfide bonds [39]. The most commonly used linear peptides and cyclic peptides that can be delivered inside cancer cells via endocytosis and one that smuggles into glioma tissues via transcytosis (angiopep-2) are presented below: Arginine

• /or in the acidic cellular compartments of cancer cells and consequently release the active drug. Additionally, disulfide linkers are often adopted in PDCs, since they are cleaved by reducing agents like cysteine and glutathione, present in high concentrations in malignant cells. Linkers bearing

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• polypeptide chain which is cleaved by a protease to give two subunits, A1 and A2, remain held together by extensive non-covalent forces and a single interchain disulfide bond [16]. The A2-subunit acts as a linker between the toxic A1-subunit and CTB which is the delivery vehicle that can transport the complex

• the cytosol. Following arrival in the ER, protein disulfide bond isomerase can reduce the disulfide bond between A13 and A2, releasing the A1 protein and causing the A12 and A13 domains to unfold [17]. The protein is then recognised by the cell as a misfolded protein and is exported into the cytolsol

• to come. a) Ribbon and b) surface depictions of the cholera toxin: A11 domain in light blue; A12 domain in dark blue; A13 domain in purple; cystine disulfide in orange; A2 peptide in green and B-subunit in red. Figure prepared using the PyMOL programme from Protein Data Bank file 1XTC.pdb. a

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• intracellular abundant GSH. In this context, two classes of reduction-responsive units, disulfide-bond and benzyl-containing groups, were mainly introduced in prodrug-based ONs. Modifications at the internucleotide linkage Masking the negative charges of native phosphates typically improves cell penetration of

• internucleotide linkage [13]. It was shown that the stability in aqueous buffer and deprotection rates in the presence of GSH were influenced by the nature of substituents (Cl, NO2) on the benzene ring. More recently, Urata et al. reported a reduction-responsive modification containing a typical disulfide bond

• within a robust cyclic disulfide moiety [14]. Several modified ONs containing the cyclic disulfide trans-5-benzyl-1,2-dithiane-4-yl moiety have been synthesized using the corresponding thymidine phosphoramidite. Although they exhibited strong stability in serum and penetrated cells more efficiently

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• disulfide linker in the cytoplasm. In another example, Perrin and co-workers conjugated the N-propargylasparagine of an amanitin analog to a cycloRGD integrin ligand (cyclo[RGDfK]) using a copper-catalyzed azide–alkyne cycloaddition [8]. The conjugates were tested in the U87 glioblastoma cell line, but only