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

• approach where simpler and fully synthetic intermediates of the natural product’s biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a

• synthetase (NRPS), mutasynthons often carry thioesters to mimic the natural phosphopantetheinyl conjugate [20]. For the argyrins, the Müller group identified the corresponding biosynthetic gene cluster from Cystobacter sp. SBCb004 [21], studied the biosynthesis (Figure 2) and established a heterologous

• 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

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• acids. In 2014, a Cu(I/II)-catalyzed α-trifluoromethylation of α,β-unsaturated carbonyl compounds were unfolded by the Bi group (Scheme 77) [140]. The reaction was applied to a broad range of carbonyl compounds, including enones, α,β-unsaturated esters, thioesters, and amides. Notably, the authors

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

• best using aromatic aldehydes with both electron-withdrawing and donating substituents in ortho, meta and para-positions. In addition, not only acetoacetates can be employed, but the reaction can be extended to ketones, thioesters, benzoylacetic esters, acetoacetamides, alkylic or cyclic β-diketones

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

• protected with the 2-cyanoethyl group. These protecting groups and the linker have to be cleaved under strongly basic and nucleophilic conditions. As a result, many sensitive groups including acetal, hemiacetal, vinyl ethers, enol ethers, aldehydes, esters, activated esters, thioesters, aziridines, epoxides

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• (III) form of 1 has recently been found to catalyze atom transfer radical addition of alkyl halides to olefins (phenyl vinyl sulfone and acrylates) in the presence of NaBH4 [115]. In addition, a new light-driven method for generating acyl radicals from 2-S-pyridyl thioesters was developed through the

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

• , hemithioacetal, various thioesters, thiocarbamate and isothiocyanate. This review article focuses on β-hydroxy sulfides and analogs; their presence in natural products, general protocols for their synthesis, and examples of their application in target oriented synthesis. Keywords: alkene thiofunctionalization

• , 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

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

• DFL-12 as well as PgaI2 from P. inhibens DSM 17395 were heterologously expressed in E. coli and the enzymes isolated for in vitro incubation experiments. The enzymes readily accepted shortened acyl coenzyme A analogs, N-pantothenoylcysteamine thioesters of fatty acids (PCEs). Fifteen PCEs were

• determined using GC/MS [9][10][32]. Coenzyme A or abbreviated ACP analogs, N-pantothenoylcysteamine thioesters of fatty acids (PCEs) were synthesized (Scheme 2) to serve as substrate substitutes for the native precursors. Calcium pantothenate (6) was protected with acetone forming acid 7 that was transformed

• . Biosynthesis of AHLs by ACP-dependent LuxI type enzymes. Synthesis of N-pantothenoylcysteamine thioesters (PCEs) for feeding experiments with AHL synthases. Presence of different AHLs in four strains of Roseobacter group bacteria.a Presence of bound or free fatty acids in four different Roseobacter group

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

• monothioester 1b is used. Importantly, representative compounds 6a,j and 8f readily reacted with benzylamine thus showing the possibility of esters 6 and thioesters 8 to be convenient amine acylating agents [32] and, hence, building blocks for direct preparation of the amide derivatives (see Supporting

• be increased by introduction of the ester functionality at position 5 as well as allyl, various benzyl or phenyl substituents at position 1 of the pyrimidine core. Notably, esters 6 and thioesters 8 are remarkable for their potential application as smooth amine acylating agents. It has been shown

Rh(II)-mediated domino [4 + 1]-annulation of α-cyanothioacetamides using diazoesters: A new entry for the synthesis of multisubstituted thiophenes

• Jury J. Medvedev,
• Ilya V. Efimov,
• Yuri M. Shafran,
• Vitaliy V. Suslonov,
• Vasiliy A. Bakulev and
• Valerij A. Nikolaev

Beilstein J. Org. Chem. 2017, 13, 2569–2576, doi:10.3762/bjoc.13.253

• 6e (Figure 4), and by analogy with literature data [54][55]. According to the literature findings, dirhodium(II) tetracarboxylates can form 1:2 adducts with such neutral ligands as thioamides [54][55] and thioesters [56][57][58]. The reactions give adducts with up to quantitative yields which is an

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• enzymatic reactions as a starting point to test the implementation of our design strategy. A more recent example of a chemical network capable of auto-amplification using thiols and thioesters (Figure 8) provides the ultimate proof that complex molecular systems can be designed “from scratch” [101]. Future

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research

• Ben Shirt-Ediss,
• Sara Murillo-Sánchez and
• Kepa Ruiz-Mirazo

Beilstein J. Org. Chem. 2017, 13, 1388–1395, doi:10.3762/bjoc.13.135

• membrane components. These protocells, hypothetically making use of the first ‘energy transduction mechanisms’ (leading to precursor ‘energy currencies’ – based on thioesters [62] and/or pH gradients [53], for instance) and a metabolism that incorporated oligonucleotides and oligopeptides (to become RNA

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

• , essential for compartmentalisation [29]), a variety of (iso)peptides as in the synthesis of fatty acids today, non-ribosomal peptides and polyketides [30]. The involvement of thioesters in a primitive metabolism, predating the systematic input of phosphate has been documented by Segré and co-workers in a

• precursors of nucleotides via phosphorolysis, allowing for both the synthesis of all nucleotides and the creation of a carbon metabolism derived from D-ribose-phosphate (Figure 3). This scenario is of course a bold conjecture but it illustrates how syntheses based on the activity of thioesters [36] and a

Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

• Ramana Sreenivasa Rao and
• Chinnasamy Ramaraj Ramanathan

Beilstein J. Org. Chem. 2017, 13, 428–440, doi:10.3762/bjoc.13.46

• preparation of piperazine-2,6-dione derivatives from N-benzenesulfonyliminodiacetic acid at room temperature. After careful reviewing of reagents for amide bond formation, the reagent CDI proved to be a very successful reagent for the preparation of imides, amides, esters and thioesters. Therefore, the

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

• ) (rhiPKS) and synthetic SNAC-thioesters revealed that the chain branch originates from a syn-selective Michael addition of an ACP-bound malonate unit 133 to a KS-bound α,β-unsaturated thioester 132 (Scheme 20b) [130]. This results in an intermediate 134 in which the ACP and the KS domain are covalently

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• carbonyl compounds such as β-diketones, β-keto thioesters, acetoacetamides and nitroacetone have been shown to participate in the classical Biginelli reaction [25], β-ketophosphonates 6 were found to be unreactive in similar conditions [26]. However, Yuan et al. developed a modified Biginelli condensation

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

• stabilized by an O–H/π interaction with the indole ring to explain the improvement in enantioselectivity of the protonation step when brine is used as an additive (Scheme 32). α,β-Unsaturated thioesters Lewis acids In one of the early examples of conjugate addition–enantioselective protonation, Shibasaki and

• -unsaturated thioesters followed by enantioselective protonation (Scheme 33) [61]. During their initial investigations Shibasaki and co-workers examined the (R)-La-142 catalyzed enantioselective addition of 4-tert-butyl(thiophenol) to ethyl methacrylate 145 (X = O) (Scheme 33a), while good enantioselectivity

• further improvement in enantioselectivity was observed (Scheme 33b). For example, for R = Me an 86% yield and 96.5:3.5 er was obtained [61]. The Shibasaki group went on to apply their conjugate addition–enantioselective protonation of α,β-unsaturated thioesters to the total synthesis of epothilones A and

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• their pKa values (approximately 19 in DMSO) [19] are much higher, one exception being thioesters [20][21] and pyrazoleamides [22]. As an alternative, some specific heterocycles have been proposed as carboxylic acid surrogates. Examples of this type of heterocycles are oxazol-5-(4H)-ones (or azlactones

Biosynthesis of α-pyrones

• Till F. Schäberle

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

• investigated in detail. In vitro assays using NAC thioesters of the western and eastern chains in the biosynthesis of 36 [88], as well as simplified substrate mimics of both antibiotics [88][89] provided experimental evidence that the free-standing ketosynthases are responsible for the α-pyrone ring formation

• -oxohexanoyl thioester and different thioesters of straight-chain and iso-branched chain fatty acids [14]. The mechanism proposal also includes the catalytic cysteine. The first chain, i.e., thioester-activated 9-methyldecanoic acid, gets covalently tethered to that important residue within the active site

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

• introducing a methyl group in extended Michael acceptors through the addition of MeMgBr. A follow-up study then aimed to tackle this challenge and demonstrated that α,β,γ,δ-unsaturated thioesters 36 were the substrates of choice in order to conduct this valuable transformation (Scheme 9) [29]. A variety of α

• ,β,γ,δ-unsaturated thioesters produced from a Horner–Wadsworth–Emmons reagent were submitted to a 1,6-ACA catalyzed by the L8/CuBr·SMe2 system, followed by a reconjugation reaction in the presence of DBU to selectively afford 37 (ratio between 1,6 and 1,4-ACA products ranged from 85/15 to 99/1) in

• high yields (78–88%) and enantioselectivities (82–89%). The obtained α,β-unsaturated thioesters 37 were subsequently reacted in a 1,4 copper-catalyzed ACA, using this time L9 (Josiphos)/CuBr·SMe2. This approach enabled the synthesis of anti (38) or syn (39) 1,3-deoxypropionate units depending on the

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

• functional and complementary template in enzymatic DNA synthesis [6]. We have recently begun to explore synthesis methods to prepare α-fluorovinyl thioethers, to open up the possibility of exploring this motif as a mimetic for enols and enolates of biochemically relevant thioesters. Thioesters of low

• thioesters offer prospects as thioester enol/ate mimetics [7]. HF·Py mediated hydrofluorinations of 1a. BF3·Et2O/3HF·Et3N mediated hydrofluorination of 1a. Proposed Lewis acid-mediated hydroflurination of sulfides 1. Lewis acid screening. Optimisation of BF3·Et2O/3HF·Et3N mediated hydrofluorination

Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

• Jingjing Wang,
• Samuel Z. Y. Ting and
• Joanne E. Harvey

Beilstein J. Org. Chem. 2015, 11, 1815–1822, doi:10.3762/bjoc.11.197

• , if the α-phosphoranylidene ester or amide is formed in the presence of an aldehyde, ketone or ester, an additional in situ Wittig reaction can occur [12][13][14][15][16][17][18]. In this way, amides, esters and thioesters can be obtained through three-component couplings [14][16]. Intramolecular

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

• OleA, which is part of the olefin biosynthesis in Xanthomonas campestris by promoting a head-to-head condensation of two long-chain fatty acid thioesters to form a long-chain β-ketoacid that can be further processed to an olefin [14]. KS with acylating activity have been reported in the cervimycin [15

• either ACP (acyl carrier protein) or CoA (coenzyme A) bound thioesters depending whether they originate from fatty acid biosynthesis or degradation, respectively. Due to the variability of the first substrate regarding chain length and starting unit, the different photopyrones A–H (1–8) are produced. We

• condensation of two long-chain fatty acid thioesters, similar to the proposed mechanism of PpyS (Scheme 1). The dimeric structure of OleA revealed a unique feature that has not been described previously for other KS, in which one glutamic acid residue reaches inside the binding pocket of the adjacent monomer

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

• Mohammad Abbasi Reza Khalifeh Chemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran Department of Chemistry, Shiraz University of Technology, Shiraz, Iran 10.3762/bjoc.11.141 Abstract An efficient and odourless procedure for a one-pot synthesis of thioesters by

• 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

• many uses in organic synthesis as intermediates, mild acyl transfer agents and thiol sources [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Thioesters can be synthesized in the laboratory by means of different methods using diverse reagents and substrates [20][21][22][23][24][25

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• , or copper) were performed with cyclohexanone, 2-methylcyclohexanone, cyclohexene, 1-octene, cumene, xylene, dimethylaniline, and dioxane [201]. The enantioselective oxidative coupling of 2,6-dialkylphenyl-β-keto esters and thioesters 215 with tert-butyl hydroxycarbamate 216 was performed using the Cu

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

• Paweł Borowiecki,
• Daniel Paprocki and
• Maciej Dranka

Beilstein J. Org. Chem. 2014, 10, 3038–3055, doi:10.3762/bjoc.10.322

• very expensive, S-ethyl thioesters generate undesirable flavor of the formed thiols, employment of anhydrides yields free carboxylic acids causing enzyme deactivation, and finally application of conventional esters, despite their great availability and low price, could reverse acylation into