Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

Breakdown of 3-(allylsulfonio)propanoates in bacteria from the Roseobacter group yields garlic oil constituents

• Anuj Kumar Chhalodia and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 569–580, doi:10.3762/bjoc.17.51

• ]. Compound 17 can be transformed into the coenzyme A thioester 18 by the CoA ligase DmdB, followed by FAD-dependent oxidation to the α,β-unsaturated compound 19 by DmdC. The attack of water to the Michael acceptor catalyzed by the enoyl-CoA hydratase DmdD yields the hemithioacetal 20 that spontaneously

• collapses to methanethiol (MeSH) and malonyl-CoA semialdehyde (21). This compound further degrades to acetaldehyde (22) through the thioester hydrolysis and decarboxylation [27]. Feeding of (methyl-2H6)DMSP to Phaeobacter inhibens DSM 17395 and Ruegeria pomeroyi DSM 15171 resulted in the efficient uptake of

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• biosynthesis start at FclJ (the Figures were adapted and modified from [20] and [22]. KS: ketosynthase, AT: acyltransferase, T: thiolation domain, KR: ketoreductase, CLF: chain length factor domain, DH: dehydratase, Ox: 2-nitropropane dioxygenase (enoyl reductase), AMT: aminotransferase, TR: thioester

• . stockiae, g: KK7.4, h: KJ12.1, i: X. bovienii, j: P. temperata. KS: ketosynthase, AT: acyltransferase, T: thiolation domain, KR: ketoreductase, CLF: chain length factor domain, DH: dehydratase, Ox: 2-nitropropane dioxygenase (enoyl reductase), AMT: aminotransferase, TR: thioester reductase, Nit: nitrilase

Synthesis of disparlure and monachalure enantiomers from 2,3-butanediacetals

• Adam Drop,
• Hubert Wojtasek and
• Bożena Frąckowiak-Wojtasek

Beilstein J. Org. Chem. 2020, 16, 616–620, doi:10.3762/bjoc.16.57

• efficient method for the isomerization of trans-disubstituted butanediacetal derivative 11 with two different substituents (one ester group and one thioester group) to its cis derivative 14 which proceeded with 94% yield [37]. The cis-2,3-butanediacetals 12–14 have the appropriate configuration of the

• 19 instead. This compound was obtained from both aldehyde 15 and its precursor ethyl thioester methyl ester 14, respectively (Scheme 3). Both substrates 14 and 15 were reduced to the corresponding diol 17 with lithium aluminum hydride with 73% or 83% yield, respectively. Next, the selective

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• accomplished in this stimulating field. Keywords: acylimidazole; N-acyloxazolidinone; N-acylpyrrole; N-acylpyrrolidinone; aldehyde; amide; copper catalysis; electron-deficient alkenes; enantioselective conjugate addition; Michael acceptor; thioester; Introduction Generating high molecular complexity and

• report the ECA of Grignard reagents to α,β-unsaturated thioesters [25]. Advantageously, the latter were also readily accessible but significantly more reactive than α,β-unsaturated esters. Indeed, the thioester fragments featured a reduced electron delocalization compared to oxoesters, which resulted in

• CuBr∙SMe2/(R,S)-Josiphos (L9). However, the catalytic system was poorly selective toward sterically hindered organomagnesium nucleophiles (15–25% ee). The synthetic versatility of the thioester function was illustrated in the synthesis of (−)-lardolure (26% overall yield over 12 steps) via a relevant

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide. Keywords: antibiotic; argyrin

• derivatives upon incorporation of synthetically provided tripeptide thioester intermediates, the so called mutasynthons. Mutasynthons are synthesized as SNAc thioesters which mimic the phosphopantetheine (PPant) moiety normally present on the PCP domain of the NRPS. It has been shown by several mutasynthesis

• . This fact provides the opportunity to chemically substitute the initial tripeptide thioester accepted by module 4 on the Arg3 subunit and replace the natural construct in biosynthesis. By feeding the block mutant with synthetic analogs, derivatives should be accessible without the need for full total

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• thioester. Using the technology, the sensitive groups can be installed at any location within the ODN sequences without using any sequence- or functionality-specific conditions and procedures. Keywords: Dmoc; electrophilic; oligonucleotides; protecting group; solid-phase synthesis; Introduction After over

• incorporating electrophilic groups, we also needed phosphoramidite monomers 26a–c, which contained the sensitive functionalities ester, α-chloroacetamide and thioester, respectively (Figure 2). The synthesis of 26b,c has been reported [40]. Scheme 3 shows the synthesis of 26a. The required 1,2-diol 28 was

• under non-nucleophilic conditions using the dM-Dmoc technology, studying the feasibility of the technology for the synthesis of modified ODNs containing ester, α-chloroacetamide and thioester groups was pursued. These groups are sensitive to nucleophiles and cannot survive the commonly used concentrated

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• tetraketide intermediate that can be cyclised by aldol condensation, followed by elimination of water to result in the aromatic ring system. Thioester hydrolysis and decarboxylation produce 29a that can be converted by SAM-dependent O-methylation into 24. In summary, this hypothetical biosynthetic mechanism

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