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

• ; sulfoxide; thiol-free; Introduction Throughout the years, several strategies have been developed to build up organic compounds bearing a sulfide moiety [1][2]. Often, thiols (or the corresponding thiolate anions) are employed as nucleophilic sulfur reagents in order to react with a suitable electrophile [3

• ][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

• further preparation of valuable ketosulfoxides and ketosulfones. Selected examples of valuable β-ketosulfides. A: bioactive synthetic compounds, B: natural products. Time-course plot for the CAL-B catalysed hydrolysis of 1a. Different strategies for the preparation of β-ketosulfides. 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–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

• 2009, the Daugulis group reported that benzoxazole was converted to 2-mercaptobenzoxazoles in the presence of sulfur and potassium tert-butoxide, but only one example was shown [35]. In 2017, the Lei group reported a copper catalyzed C–H mercaptalization strategy using elementary sulfur as thiol source

• benzoxazoles to the corresponding thiols through direct C–H mercaptalization using 1,3-propanedithiol as thiol source. Results and Discussion Previous studies in our group revealed that small aliphatic diols and dithiols are promising reagents for the synthesis of phenols and arylthiols, respectively [23][37

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

• )-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

• potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide–toxin conjugate. The conjugate shows toxic selectivity to tumor cell lines overexpressing the hY1R receptor subtype like, e.g., the hard to treat

• -1)-βA),F7,L17,P34]-hNPY (8), was synthesized by reacting the tubugi-1-SSPy (3) with the free thiol function of a β-alanine–cysteine dipeptide (βAC) linked to the side chain of Lys4 of the targeting peptide. For this purpose, 1 mol equiv of the tubugi-1-SSPy building block 3 and one molar equivalent

Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents

• Mingjun Yuan,
• Song Lin Chua,
• Yang Liu,
• Daniela I. Drautz-Moses,
• Joey Kuok Hoong Yam,
• Thet Tun Aung,
• Roger W. Beuerman,
• May Margarette Santillan Salido,
• Stephan C. Schuster,
• Choon-Hong Tan,
• Michael Givskov,
• Liang Yang and
• Thomas E. Nielsen

Beilstein J. Org. Chem. 2018, 14, 3059–3069, doi:10.3762/bjoc.14.284

• established biofilm [44]. In addition, the gold-containing drug, auranofin, was found to be a broad-spectrum bactericidal compound, that targets the thiol-redox homeostasis of a range of Gram-positive bacteria [45]. Further studies will be carried out to better understand the resistance mechanism and

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• NHC ligand. The conjugation was performed via maleimide-thiol “click” reaction under slightly basic (pH 7.5) conditions. Within the small cavity of NB4, only the GH-type catalyst Ru-6 with the longest spacer was able to undergo conjugation; however, the conjugational yield was very low (25%). Within

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• afford rhodamine B conjugated polypeptide chain 12. Amino acid protecting groups such as Boc, tert-butyl and Trt of diaminopropionic acid, aspartic acid and cysteine thiol moieties, respectively, in 12 were cleaved traceless using a cocktail of trifluoroacetic acid, triisopropylsilane, ethanedithiol in

• such as Boc, tert-butyl and Trt present in diaminopropionic acid, aspartic acid and cysteine thiol aminoacids, respectively, were cleaved using a cocktail of trifluoroacetic acid, triisopropyl silane, ethanedithiol in water to give folate receptor targeted chelating rhodamine B conjugate 17 in high

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• infections [61]. While not typically classed as toxins, bacterial proteolytic enzymes, such as collagenases or elastases, often account for host cell damage and immune evasion. Janda and co-workers developed thiol-based small molecules targeting the active site zinc ion in P. aeruginosa elastase LasB showing

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• -250TM, ChemoMetec A/S, Lillerød, Denmark) using Vitabright-48™ (ChemoMetec A/S, Lillerød, Denmark), a cell permeable dye that reacts with thiol groups to form a fluorescent product. An inverse correlation has been shown between the concentration of thiols and progression of apoptosis; the level of

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• simplified n-pentyl and cyclohexylmethyl model compounds towards thiol and amine nucleophiles as well as their reactivity towards a model protein target, lysozyme. Results and Discussion Preliminary studies of the reactivity of onchidal (6) towards 1-pentanethiol or 1-pentylamine were undertaken in CDCl3

• solvent in an NMR tube. Somewhat to our surprise, no reaction was observed with 1-pentanethiol, even with incubation in the presence of excess thiol for one week [14]. In contrast, incubation with excess 1-pentylamine rapidly afforded a mixture of products, as identified by changes in the 1H NMR spectrum

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

• deprotonation of the OH group and subsequent chloride loss of 4 an o-quinoid structure 9 is formed in situ, that quickly reacts with the deprotonated thiol 10 via Michael addition (Scheme 3, route A) [28][29][30]. However, as aromatic thiols at the benzylic position are good leaving groups, conversely β

A switchable [2]rotaxane with two active alkenyl groups

• Xiu-Li Zheng,
• Rong-Rong Tao,
• Rui-Rui Gu,
• Wen-Zhi Wang and
• Da-Hui Qu

Beilstein J. Org. Chem. 2018, 14, 2074–2081, doi:10.3762/bjoc.14.181

• and thiol functional groups. The reversible shuttling movement of the macrocycle between two different recognition sites on the molecular thread can be driven by external acid and base. This kind of rotaxane bearing functional groups provides a powerful platform for preparing stimuli-responsive

• the presence of Grubbs’ catalyst and thiol groups irradiated by UV light. Besides, the shuttling movement of the DB24C8 macrocyclic ring was confirmed by 1H NMR spectroscopy. Results and Discussion The structures of the two states of [2]rotaxane R1 are shown in Scheme 1. In the target structure [2

• . The naked alkenyl groups could react with other functional groups such as alkenyl and thiol groups to prepare stimuli-responsive polymers. Besides, the introduction of long alkyl chains makes the polymers easier to form gels. This kind of functional rotaxane enriches the species of building blocks to

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

• photocatalysts in cooperation with a disulfide cocatalyst, which is converted to the corresponding thiol and serves as a source of hydrogen atoms for the reduction of the double bond (Scheme 17) [62]. The scope of the reaction is not particularly broad; electron-withdrawing groups such as pyridyl or

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• synthesis, otherwise subsequent steps are complicated. Synthetic chemists, armed with various elegant artificial orthogonal bond formations, including alkyne–azide cycloaddition [27][28][29][30][31][32][33][34], thiol–ene ligation [35][36][37][38], Staudinger ligation [39][40], inverse-electron-demand Diels

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

• organic compounds are, like all natural products/secondary metabolites, staggeringly diverse with respect to their natural source and their level of structural complexity. As part of their molecular architecture, sulfur can appear in the form of various functional groups and oxidation states: thiol

• , 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

Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA

• Timo Weinrich,
• Eva A. Jaumann,
• Ute M. Scheffer,
• Thomas F. Prisner and
• Michael W. Göbel

Beilstein J. Org. Chem. 2018, 14, 1563–1569, doi:10.3762/bjoc.14.133

• -labeled adenosine tends to be sluggish and incomplete [25]. Furthermore, the protection group present in 22a–27a also shields the nitroxide precursor if subsequent enzymatic ligation steps in thiol containing buffers are required [43]. A single case has been reported earlier of an O-acetyl protected TEMPO

Recent advances in phosphorescent platinum complexes for organic light-emitting diodes

• Cristina Cebrián and
• Matteo Mauro

Beilstein J. Org. Chem. 2018, 14, 1459–1481, doi:10.3762/bjoc.14.124

• -thiol as bridging ligands coordinating two Pt(II) centers in a monodentate fashion, Zhu and co-workers have reported on dimeric structures, namely 2 and 3, exhibiting an interaction between the two metallic centres (Pt···Pt distance of ca. 3 Å) (Figure 2). The appearance of a triplet metal–metal-to

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

• with cysteamine into the protected thiol 8 [39]. Steglich esterification [40] with different free acids led to nine saturated PCEs 10a–i, four monounsaturated acids (11a–d), 3-OH-C10:0-HSL PCE (12), and 2E,11Z-C18:2-PCE (13) after deprotection with acetic acid [41]. Although compounds 10–13 can be

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• ]. Thiol functionalized PEG blocks were immobilized on Au NPs. PS segments improved the stability of the system and provided the necessary hydrophobic environment that is required to undertake the reduction reaction in water. The outcome of using Au@PEG-PS as nanoreactors was compared to those resulting

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

• ’-O-acetylthiomethyl-containing RNA, produces various 2’-O-alkyldithiomethyl (RSSM)-modified RNAs bearing lipophilic or polar groups through a thiol disulfide exchange reaction with alkyldisulfanyl-pyridine derivatives (Scheme 3). In a preliminary evaluation, the RSSM modifications were shown to

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• preparation of sulfides. Non-photocatalytic procedures apply the so-called radical thiol–ene or radical thiol–yne reactions for efficient cross-coupling of thiols with olefins [24][29][30]. In 2013, Yoon and co-workers developed a photoredox-catalyzed version of the radical thiol–ene reaction (Scheme 2) [31

• of 4 equivalents of the thiol is needed for the reaction. The authors addressed this limitation in a later report (vide infra). Functional groups like alcohols, Boc-protected amines, carbonyls, esters and halides are tolerated. One year later, Yoon and co-workers described a redox mediator concept

• , which was applied to their photocatalytic radical thiol-ene reaction (Scheme 3) [32]. While the photooxidation of aliphatic thiols by excited [Ru(bpz)3](PF6)2 is thermodynamically feasible, this process is kinetically hindered. Therefore, relatively low yields are observed or the amount of thiol has to

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• comprised of AuNPs with the surface Au atoms covalently attached to thiols of thiol-terminated oligosaccharides [8]. It was found that GAuNPs could be used as mimics of the glycocalyx to study both carbohydrate–carbohydrate and carbohydrate–protein interactions [9][10]. Other applications of GAuNPs, as

• thiol end group, which is generally attached to the reducing terminus by a linker (Figure 1a) [8][14][17][18][19][20][21][22][23][24][25][26][27]. The second method is a ligand exchange reaction involving the replacement of the ligands on pre-formed AuNPs with thiol-linked carbohydrate derivatives

• (Figure 1b). The most frequently employed approach here is to first synthesize citrate-stabilized AuNPs (Cit-AuNPs) [28], and then to replace the citrate ligands with the desired thiol-linked carbohydrate derivatives [29][30]. Ligand exchange on the AuNP surface is driven by the higher binding affinity of

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• cycloaddition, CuAAC and RuAAC), the thiol–yne reaction, Diels–Alder reactions and the Sonogashira cross-coupling. While amino acids with a terminal alkyne in the side chain are well-known, the synthesis of their correlates where the carboxy group is replaced by a terminal alkyne is still tedious. Nevertheless

• propargylamines without an acidifying Cα-substituent. Synthesis of propargylamines containing polar or acidic functional groups The synthesis of propargylamines with polar substituents to mimic polar amino acids such as serine (alcohol), cysteine (thiol) or glutamine (carboxamide) requires special protective