Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• kynurenine pathway starting from tryptophan or by anthranilate synthases from the PqsR-controlled phnAB operon starting using chorismic acid as a source [24]. Either way, the ligase PqsA starts PQS synthesis by condensing anthranilic acid with coenzyme A [25]. The resulting activated thioester (anthraniloyl

• -CoA) is then transferred to an active-site cysteine of the β-ketoacyl-ACP synthase III (FabH)-type enzyme PqsD [26][27]. Subsequently, another CoA-activated substrate comes into play. In analogy to fatty acid synthesis, malonyl-CoA is reacted with the enzyme-bound thioester to yield 2

• formed by action of the heterodimeric complex PqsBC. This time, CoA-activated octanoic acid is used to preload an active-site cysteine of PqsC with the fatty acid via a thioester linkage [30][31]. The previously produced 2-ABA is then consumed to from HHQ under decarboxylative condensation [30]. Finally

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

• by substitution of the good leaving group 5’-deoxy-5’-thiomethyladenosine (5) of the thioester group, leading to homoserine lactone 4 formation (Scheme 1). Recently a LuxI-homolog, BjaI [20] preferring acyl-coenzyme A (CoA) substrates instead of the common ACP precursors, was characterized [21]. The

Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

• Dan Liu,
• Ya-Li Guo,
• Jin Qu and
• Chi Zhang

Beilstein J. Org. Chem. 2018, 14, 1112–1119, doi:10.3762/bjoc.14.97

• the p-nitrophenyl ester method (Scheme 4, method A). The other one was described by Agrigento and co-workers, the cyclization was completed via the p-chlorophenyl thioester method with peptide-thioester being the precursor (Scheme 4, method B) [39]. Herein, we realized the synthesis of pseudostellarin

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

• (for A and C) or isopropylphenoxyacetyl (for G) groups on exocylic amines. These deprotection conditions prevent base-mediated phosphotriester cleavage. Finally, to address the synthetic issue completely, they stabilized the thioester bond to diisopropylamine/methanol by substituting electron-donating

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

• Sergii V. Melnykov,
• Andrii S. Pataman,
• Yurii V. Dmytriv,
• Svitlana V. Shishkina,
• Mykhailo V. Vovk and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2017, 13, 2617–2625, doi:10.3762/bjoc.13.259

• -dihydroquinazolin-2(1H)-ones and the anti-HIV drug DPC 083 [28]. No examples of any ketimines reacting directly with malonic acid have been reported so far. Here we present the results of the decarboxylative addition of malonic acid, malonic monoester 1a and thioester 1b to 4-trifluoromethylpyrimidin-2(1H)-ones 2

• exclusively Michael-type adducts 6 regardless of the reaction conditions used. Likewise, the more reactive malonic mono thioester 1b, when reacted with a broader scope of substrates 2 under milder conditions, gives rise only to analogous Michael-type products 8. In general, the reactivity of substrates 2 can

• decarboxylative addition of malonic acid mono-4-methoxyphenyl thioester (1b) to 4-trifluoromethylpyrimidin-2(1H)-ones 2a–m. Supporting Information Supporting Information File 481: Experimental procedures, characterization data and X-ray structure determination for compound 11b. Supporting Information File 482

Block copolymers from ionic liquids for the preparation of thin carbonaceous shells

• Sadaf Hanif,
• Bernd Oschmann,
• Dmitri Spetter,
• Muhammad Nawaz Tahir,
• Wolfgang Tremel and
• Rudolf Zentel

Beilstein J. Org. Chem. 2017, 13, 1693–1701, doi:10.3762/bjoc.13.163

• (see Figure S5, Supporting Information File 1). In the last step the aminolysis of the reactive ester block with dopamine was performed, which leads also to a partial removal of the thioester end group. For this purpose a large excess of dopamine was applied. The 1H NMR spectrum in Figure 3 proves the

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• synthesis, and a phosphate as a charged group) has the remarkable role of a swinging arm transporting a variety of thioester substrates between sulfhydryl catalytic sites (Figure 2). It could well have been involved in its own synthesis as well as that of diverse compounds involving acyl groups (lipids

• convincing way [31]. Other coenzymes, possibly generated by such a swinging-arm thioester-dependent catalysis, may have been precursors of nucleotides, the essential building blocks of nucleic acids. As a matter of fact, extant biosynthesis of nucleotides (built on purine and pyrimidine carbon–nitrogen

• , appeared after an (iso)peptide-based metabolism was commonplace. Cofactors such as pterins and riboflavin are ubiquitously present in living organisms. Precursors of these essential compounds may have been synthesised by a thioester swinging-arm pathway and phosphorylated by polyphosphate. Remarkably, in

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• substrate used was the synthetically accessible (2RS)-2-methyl-3-oxopentanoic acid N-acetylcysteamine (NAC) thioester (‘β-keto diketide’) 17 – a racemic analogue of the diketide generated by condensation of a propionyl starter unit and a (2S)-methylmalonyl extender unit. NAC was chosen as the activating

• in fact, epimerizing KRs bind their substrates in two distinct modes. In the first, which is only available to the substrate bearing the non-epimerized methyl center, the thioester and C-3-keto groups are aligned so that the pKa of the C-2 proton is suitably depressed, allowing facile catalysis by KR

• ). This is apparently the first example of such reversal of diastereospecificity due to the nature of the thioester conjugate. Taken together, these results agree with a common syn dehydration mechanism for PKS DHs, but the requirement that the abstracted proton be positioned equivalently relative to the

Solution-phase automated synthesis of an α-amino aldehyde as a versatile intermediate

• Hisashi Masui,
• Sae Yosugi,
• Shinichiro Fuse and
• Takashi Takahashi

Beilstein J. Org. Chem. 2017, 13, 106–110, doi:10.3762/bjoc.13.13

• serine, and the subsequent reduction of carboxylic acid derivatives such as ester [20][21][22][23][24][25][26][27], thioester [28], or Weinreb amide [29][30] to the aldehyde. In addition, Burke and co-workers reported an asymmetric hydroformylation of 2,2-dimethyl-2,3-dihydrooxazole for the synthesis of

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• catalyzes the condensation with malonyl-CoA to form 2-aminobenzoylacetyl-CoA. The thioesterase PqsE hydrolyses the thioester to produce 2-aminobenzoylacetate (2-ABA) [13]. The PqsBC complex finally generates HHQ or other AQs in a decarboxylative condensation reaction of 2-ABA with fatty acids loaded on PqsC

• (Figure 1B) [14]. For the condensation step of an anthraniloyl residue with malonyl-CoA by PqsD, a cysteine residue (Cys112) is involved in the formation of a covalent thioester intermediate. We were speculating that activity-based electrophilic probes may be applicable to target this enzyme in vitro

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• and thioester compounds [8][30] and the CD thiouronium salt intermediates are not isolated [8] despite their good crystallization properties, while the excess/residual TU and used solvents are removed upon the conversion to thiols only. However, the easy crystallization of these salts is a nice

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• outcome of reductive processing of the newly-formed β-ketoacyl thioester. Finally, the extended chain is passed on to the following module. This processive assembly-line operation, in which all intermediates remain covalently attached to the multienzyme, helps to explain the efficiency of the process. It

• -ketoacyl–ACP is then reduced by the action of KR and DH but the ER domain is "skipped" so an enoyl thioester is produced. In the second cycle, condensation with a second malonyl–ACP is followed by full reduction, and then the triketide chain is transferred to the KS of the following module, module 2

• . Module 2 is predicted to catalyse addition of a methylmalonate extension unit and reduction to an enoyl thioester (the module lacks an ER domain). Puzzlingly, the structure of azalomycin requires full reduction at this stage. There is precedent for this, for example in the PKS for the anticancer compound

DNA functionalization by dynamic chemistry

• Zeynep Kanlidere,
• Oleg Jochim,
• Marta Cal and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2016, 12, 2136–2144, doi:10.3762/bjoc.12.203

• metal ligands or fluorophores. Functional molecules of interest can be tethered post-synthetically in an irreversible manner as amide or reversibly as imine or thioester. Recent advances in dynamic combinatorial chemistry [29][30][31][32][33][34][35][36][37][38][39][40] have enabled the utilization of

• of nucleobase monomers. In case of an amine group on the backbone, a reversible imine exchange reaction with aldehyde modified nucleobases was performed (Figure 1a). In the presence of a thiol group on the backbone, a thioester exchange reaction with thioester modified nucleobases was expected

• functionalized by imine or thioester formation. In principle this concept allows dynamic DNA functionalization with all kind of functional or recognition units at positions that were modified with the threoninol deoxyribose analogous by solid phase synthesis. As proof of principle the 13mer oligonucleotide

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• ) domains as well as ketoreductase (KR), dehydratase (DH), enoyl reductase (ER) and thioesterase (TE) domains [6][8]. The PKS intermediates remain tethered to the megaenzyme via a thioester linkage during the whole process. Among these domains, only TE domains participate in cyclisation reactions as part of

• their standard catalytic repertoire (Scheme 1). They transacylate the thioester of a PKS-bound polyketide onto a nucleophile. If the nucleophile is water, this leads to carboxylic acids. The reactions of backbone hydroxy groups or amines consequently give lactones and lactams. TE domains mostly form

• thioester to a hydroxy group (d in Scheme 2). A Michael addition–lactonisation cascade leads to pyranones with a substituent in the 4-position 16 (e in Scheme 2). 3-Acylfuran-2-ones (19, 3-acyltetronates) are formed by acylation–Dieckmann condensation between 2-hydroxythioesters 18 and β-ketothioesters 17

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• macrocyclisation found in NRP biosynthesis, although the energetic demands of breaking an amide bond versus a thioester bond are notably different. PatG may have synthetic utility, as studies with unnatural substrates have shown that macrocycles of between 5–22 residues can be produced [108], despite it naturally

• cysteine protease-like mechanism [118]. In vivo, this staphylococcal protein ligates proteins with a C-terminal LPXTG motif to the peptidoglycan, via the formation of an enzyme bound thioester on the threonine residue, and has been used widely as an enzymatic tool for ligation to proteins with an LPXTG tag

• thioester acyl–enzyme intermediate that is then attacked by Cys28 of AgrD to generate a 16-membered thiolactone [120] (Figure 9). Radical SAM-catalysed oxidative cross-linking The majority of characterised cyclic RiPPs are generated by standard ionic reactions. In contrast, radical mechanisms permit

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• ). Building on their addition of benzylic and aromatic thiols to N-acryloyloxazolidinones, Singh and colleagues demonstrated that thiourea 102b catalyzes the addition of thioacetic acid to N-acryloyloxazolidinones in high yields and enantioselectivity to provide thioester 101b [48]. In a related

• could be achieved, the saturated ester product 146 could not be obtained in greater than 50% yield. In contrast, the unsaturated thioester 145 (X = S) provided the product in high yield and enantioselectivity. By switching to samarium catalyst (R)-Sm-143, the catalyst loading could be halved and a

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• . Transformation of 104 with the thioester-activated peptide moiety 105 then gives muraymycin C2 (Scheme 10), which is speculated to serve as an intermediate en route to other muraymycins, in particular towards O-lipidated congeners of the A and B series (see Figure 2). A fragmented non-ribosomal peptide

• closure to furnish L-epicapreomycidine ((2S,3S)-capreomycidine, 108), that is then activated as thioester 109 (Scheme 10). This proposal is based on the elucidated formation of the epimeric amino acid L-capreomycidine ((2S,3R)-capreomycidine) as part of viomycin biosynthesis in Streptomyces vinaceus. In

• thioester 109 is proposed to be converted into the urea dipeptide motif with valine derivative 110 and possibly hydrogen carbonate as a C1-building block for urea formation, thus furnishing 111. The 3-hydroxy-L-leucine moiety might be obtained by stereoselective enzymatic β-hydroxylation of thioester

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• the catalytic cysteine residue. Subsequently, the thioester bond is cleaved by the nucleophilic water molecule, which itself is activated through hydrogen bonding to the catalytic cysteine and a histidine residue. Thereby, the β-keto acid intermediate is generated. This intermediate is proposed to be

• reaction to form the α-pyrone, while CysB should first generate a β-keto acid intermediate by hydrolysis of the thioester bond. Then the starter of the second chain is loaded onto the free catalytic cysteine, gets elongated by a malonyl-CoA before the nucleophilic attack of the first chain. In that way the

• thioester bond is cleaved and subsequently lactonization takes place, yielding in the final product (Figure 24 B). In Photorhabdus luminescens it was shown that α-pyrones act as bacterial signaling molecules at low nanomolar concentrations [14]. A similar mechanism for the biosynthesis of these photopyrones

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• malonyl moiety to the α,β-unsaturated thioester bound to the keto-synthase domain (KS). After this reaction, the polyketide chain is bound to the KS and the acyl carrier protein (ACP). The following lactonization to generate the δ-lactone structure in 4 can either proceed via nucleophilic attack of the δ

• -hydroxy function at the KS-bound (A) or at the ACP-bound thioester (B) with subsequent loading of the polyketide onto the ACP. To distinguish both mechanisms, 13C-labeled malonyl-CoA and an N-acetylcysteamine (SNAC) thioester as synthetic analogon were used as substrates for an in vitro construct of the

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• “intermediate” addition products (1,6-adducts when n = 1 and 1,6- and 1,8-adducts when n = 2) was detected in all cases. The nature of the substrate seemed to also have an influence since better results were obtained when the thioester was used as a starting material, in both 1,8- (63% yield, 72% ee) and 1,10

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• oxidation to CO2. Acyl-CoA pathways A number of recently elucidated cyclic pathways that exist primarily in archaea initiate through the fixation of CO2 onto acetyl-CoA (10) [51][70], and end with the generation of two equivalents of the starting substrate 10 (Scheme 4). One equivalent of the CoA thioester

Lewis acid-promoted hydrofluorination of alkynyl sulfides to generate α-fluorovinyl thioethers

• Davide Bello and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 1902–1909, doi:10.3762/bjoc.11.205

• thioester enols and enolates, important intermediates in enzymatic C–C bond forming reactions. The method opens access to appropriate analogues for investigations in this direction. Keywords: alkynyl sulfides; α-fluorovinyl thioethers; hydrofluorination; Lewis acids; organofluorine; Introduction

• 5% yield. However, when 1i was reacted with the BF3·Et2O, the starting material was completely consumed in 16 hours, but only traces of the desired compound 2i could be detected, with thioester 5 being the main reaction product (45% yield). An explanation for this behaviour can be drawn from the

• fact that the 4-nitrophenyl group surely must increase the triple bond electrophilicity, hence any trace of water present in the reaction mixture could lead to an intermediate enol thioester which would in turn readily convert to the stable thioester 5. Nonetheless, ensuring rigorously anhydrous

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• using stable isotope labeled precursors [7] suggested a two-chain biosynthesis mechanism for photopyrone biosynthesis (Scheme 1): First, thioester-activated 9-methyldecanoic acid 14 is covalently bound to an active site cysteine. Deprotonation of the α-carbon of 14 results in the formation of a

• nucleophile, which subsequently attacks the carbonyl carbon of a 5-methyl-3-oxohexanoyl thioester 15, formed by BkdABC [18] to form a new C–C bond. After an additional deprotonation of the bound intermediate 16 the α-pyrone ring is formed and 4 is released from PpyS. The two substrates 14 and 15 might be

One-pot odourless synthesis of thioesters via in situ generation of thiobenzoic acids using benzoic anhydrides and thiourea

• Mohammad Abbasi and
• Reza Khalifeh

Beilstein J. Org. Chem. 2015, 11, 1265–1273, doi:10.3762/bjoc.11.141

• reaction of thiourea with benzoic anhydrides, which were subjected to conjugate addition with electron-deficient alkenes or a nucleophilic displacement reaction with alkyl halides. Keywords: benzoic anhydride; Michael addition; nucleophilic displacement; thioester; thiourea; Introduction Thioesters have

• aqueous Triton X-100 micelle [53]. Alternatively, the thioester could be synthesized from the reaction of the alkyl halide with the thioacid in situ generated from the reaction of thiourea and benzoyl chlorides (Scheme 1, path b). In order to explore this possibility, the alkyl halide was removed from the

• the thioester product cannot be produced through generation of the thioacid from thiourea and benzoyl chloride. To establish a protocol for the one-pot synthesis of thioacid derivatives via in situ generation of thioacids, considerable preliminary tests were accomplished using thiourea and carboxylic

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• -hydroxypropyl)methacrylamide) (pHPMA) possesses a C2 repeating unit with three fully rotatable bonds, which should convey – compared to the other polymers employed in this study – high backbone flexibility to this carrier. Reactive pHPMA was prepared in a copolymerization of HPMA and the thioester-containing

• building block N-methacryloyl-β-alaninyl-S-benzyl thioester under reversible addition–fragmentation chain-transfer (RAFT) conditions yielding a thioester-containing copolymer with 13.3 kDa and polydispersity of 1.2, which we denominated as NCL-polymer [10]. NCL-polymer was converted into multivalent