Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• of an NRP despite the fact that this feature is known to be important for bioactivity [79][80]. Typically, the C-terminus of the NRP intermediate is covalently linked via a thioester bond to the phosphopantetheine prosthetic arm of the peptide carrier protein (also known as the thiolation (T) domain

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• stability of thioester groups in aqueous environments, we also decided to apply conditions conducive to hydrophobic amplification [37], which unfortunately also did not yield the intended effect. Another approach is to generate and stabilize the active nucleophile form as an anion thus increasing its

• the ideal tool in addition to reactions to cyclic enones and benzylidene acetones. However, our concern was whether the thioester group, whose activity towards nitrogen nucleophiles significantly exceeds that of analogous oxo-esters [26][27][40], would remain unaffected in the presence of a

• donors [29]. In the context of imine catalysis using acid, the catalyst AQ-1's ability to abstract protons from bisthiomalonate, thereby activating the nucleophile may be at least restricted. Consequently, we chose to investigate the impact of the thioester group on the outcome, including stereochemical

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• N,S-acetals; β-keto amide; β-keto thioester; dodecylbenzenesulfonic acid; hydrolysis; Introduction In the past decades, the application of easily available and stable α-oxo ketene N,S-acetals as significant synthons has received more and more attention in organic synthesis due to their unique

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• biosynthetic pathway as proposed by Cox, based on bioinformatic analyses of polyketide synthase (PKS) modules and in vitro studies. Initially, highly reducing iterative polyketide synthase (HR-iPKS) SorbA forms the thioester 30 on its acyl carrier protein (ACP) domain from acetate and two units of malonyl-CoA

• . Subsequently, the downstream HR-iPKS module, SorbB, catalyzes both the extension of polyketide chain from 30 using two additional malonyl-CoAs and C-methylations exploiting two units of SAM (S-adenosyl methionine) to generate thioester 31 on the ACP domain. Then, the reduction (Red) domain located at the C

• -terminus of SorbB catalyzes conversion of thioester 31 using NADPH to liberate aldehyde 32, and subsequent Knoevenagel condensation-type cyclization leads to sorbicillin (33). The FAD-dependent monooxygenase SorbC, utilized in the chemo-enzymatic total synthesis of 2, catalyzes the oxidative

Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• -handle solids that can be readily produced on a multigram scale from relatively inexpensive starting materials. During the optimisation studies for the latter process with carboxylic acid substrates, in addition to the desired (trifluoromethyl)thioester products, small amounts of the corresponding acyl

• equiv of NaH in DCM under conditions similar to our previous reports on the deoxygenative trifluoromethylthiolation of carboxylic acids [31]. 19F NMR analysis of the crude reaction mixture after 2 h at rt revealed no conversion towards the desired acyl fluoride product 2a, however, 30% of thioester 3a

• 2.0 equiv of diisopropylethylamine (DIPEA), 2a could be obtained in quantitative 19F NMR yield although a reduction to 1.5 equiv led to a significant drop in efficiency, delivering the acyl fluoride in only 30% 19F NMR yield together with 45% of thioester 3a (Table 1, entries 4 and 5). At this stage

Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• second ketosynthase of the polyketide synthase BaeJ involved in bacillaene biosynthesis (BaeJ-KS2). For this purpose, both enantiomers of a 13C-labelled N-acetylcysteamine thioester (SNAC ester) surrogate of the proposed natural intermediate of BaeJ-KS2 were synthesised, including an enzymatic step with

• performed to eliminate any unreacted free 11 in the reaction mixture. The resulting protein preparations were subsequently analysed by 13C NMR spectroscopy. While the signal for the thioester carbonyl group of free 11 dissolved in incubation buffer was observed at δ = 203.33 ppm (Figure 1A), for both

• sample was subsequently subjected to another round of centrifugation using an ultrafiltration centrifugal tube, resulting in the detection of a signal for a thioester carbonyl group in the filtrate for both samples derived from (S)- and (R)-11 at δ = 203.35 ppm (Figure 1E). This observation supports

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• responsible for the structural diversity of natural products, both NRPS and PKS contain thioesterase (TE) domains in the final elongation module, which contribute to terminating biosynthesis [13][14]. Typically, TE domains cleave the thioester bond between the last PCP or ACP domain and the intermediate of

• chemically synthetic mimics before developing the enzymatic transformation. Due to N-acetylcysteamine (NAC) having a substructure to the phosphopantetheinyl arm of the carrier protein [24][25], the corresponding thioester can be recognized by TE domains and has become the most common substrate in enzymatic

• macrocyclizations (Scheme 1c). NAC thioester and other related mimics (such as coenzyme A (CoA), phosphopantetheine, and thiophenol) span the gap between the chemical synthesis and biosynthesis languages and expand the substrate promiscuity of TE domains. This bridge makes the in vitro TE-catalyzed macrocyclization

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• reductive elimination to yield ketone 78. In the acylthiolation cycle, the azaphilic ZnCl2 activated NTSE 1’’’ via N–Zn coordination to facilitate the leaving ability of succinimide. Then, nucleophilic substitution of arylmagnesium bromide 75 to intermediate IV provided thioester 79. In 2022, Gao and co

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• presence of dimethylaminopyridine (DMAP). Then, 27.2 reacted with potassium thioacetate to produce the thioester 27.3. Its reduction with lithium aluminium hydride produced the free thiol 27.4 that was used as nucleophile on octadecyl iodide to install the C18 lipid chain. The deprotection of the primary

• Markowska et al. in 1993 [134]. As detailed in Figure 28, the synthesis starts with a Mitsunobu esterification of 28.1 with thioacetic acid to produce the thioester 28.2. Then, the reduction with lithium aluminium hydride produced the thiol 28.3. Finally, the phosphocholine moiety was introduced by using

Retraction: 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. 2023, 19, 1170–1170, doi:10.3762/bjoc.19.85

• 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.19.85 Keywords: benzoic anhydride; Michael addition; nucleophilic displacement; thioester

Intermediates and shunt products of massiliachelin biosynthesis in Massilia sp. NR 4-1

• Till Steinmetz,
• Blaise Kimbadi Lombe and
• Markus Nett

Beilstein J. Org. Chem. 2023, 19, 909–917, doi:10.3762/bjoc.19.69

• ] and the photoxenobactins [32]. A unifying theme in the biosynthesis of these natural products is the use of a thiotemplate-based assembly strategy [33]. The molecular building blocks that are needed for the biosynthesis are covalently bound via thioester bonds to multi-domain enzymes. The domains

•  4), the biosynthesis starts from hexanoic acid which, upon its thioesterification, is elongated by three decarboxylative Claisen condensations with malonyl-CoA to a 6-pentylsalicyl thioester. A condensation with cysteine and a subsequent cyclization generate a 6-pentylsalicyl-thiazolinyl thioester

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• irradiation [49]. Secondly, the presence of a highly reactive thioester group C4=O [50] in FPDs 1 made us to expect the position C4 (Figure 2) to be the most reactive electrophilic center in these molecules, which would also contribute to the development of a new synthetic approach to PBTAs. We started our

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• eight-membered ring. Indeed, in the initial strategy, thioester 22 was the first substrate subjected to the cyclization. In the presence of G-I catalyst, the reaction delivered the dimeric compound 23 whereas [5-7] bicycle 24 was formed in the presence of the G-II catalyst (Scheme 3). The formation of

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• ) may superficially look like a sulfur-substituted acrolein derivative, with a reactive vinylogous thioester moiety, but in fact their reactivity is more akin to that of an arylaldehyde, as shown by the example of the synthesis of Hantzsch ester 20 from a condensation of ammonia with 18 and

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• aldehyde 2 followed by substrate attachment through Cys268 to form thiohemiacetal 3. A second oxidation reveals thioester 4 which, following hydrolysis, releases the product 5. As GMD does not exist in humans, strategies that could prevent its mechanism of action could open a pathway for new and selective

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• the thioester, which is more basic than the MAHT-enolate and can thus be protonated by the ammonium fragment in the macrocycle. This leads to the neutral product, which can easily escape from the macrocyclic cavity, releasing the macrocycle catalyst to enter the next catalytic cycle. As suggested by

Amamistatins isolated from Nocardia altamirensis

• Till Steinmetz,
• Wolf Hiller and
• Markus Nett

Beilstein J. Org. Chem. 2022, 18, 360–367, doi:10.3762/bjoc.18.40

• form a salimethyloxazolinyl-thioester intermediate, which then undergoes a C–N bond opening resulting in an ester formation. Eventually, the thioester undergoes a hydrolysis reaction leading to compound 6. The compounds, which were discovered in this study, are members of the large family of nocobactin

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• naturally occurring HDAC inhibitors contain sulfur moieties like, e.g., disulfides or thioesters. They seem to lack a zinc-chelating group at first sight, but the disulfide or thioester acts as a prodrug and are reduced/cleaved in vivo to liberate the free thiol, a strong Zn-binding group [24][25]. Results

• reactions. The chain length in 14 should generally be suitable for effective HDAC inhibition and the thioester moiety might act as a prodrug as described for the natural HDAC inhibitor largazole. Further investigations are currently in progress. Naturally occurring HDAC inhibitors. Naturally occurring HDAC

Chemoselective N-acylation of indoles using thioesters as acyl source

• Tianri Du,
• Xiangmu Wei,
• Honghong Xu,
• Xin Zhang,
• Ruiru Fang,
• Zheng Yuan,
• Zhi Liang and
• Yahui Li

Beilstein J. Org. Chem. 2022, 18, 89–94, doi:10.3762/bjoc.18.9

• be obtained efficiently. Beside indole, carbazole can also take part in this reaction. Representative pharmaceuticals containing N-acylindole moieties. A) Strategies for the synthesis of N-acylindoles; B) thioester as dicarbonylation reagent; C) recent work of our group; D) this work. Reactions of

Isolation and characterization of new phenolic siderophores with antimicrobial properties from Pseudomonas sp. UIAU-6B

• Emmanuel T. Oluwabusola,
• Olusoji O. Adebisi,
• Fernando Reyes,
• Kojo S. Acquah,
• Mercedes De La Cruz,
• Larry L. Mweetwa,
• Joy E. Rajakulendran,
• Digby F. Warner,
• Deng Hai,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2021, 17, 2390–2398, doi:10.3762/bjoc.17.156

• (see Supporting Information File 1). The biosynthesis hypotheses of compounds 1–5 were proposed to have originated as an extension of the reported pseudomonine (6) biosynthesis [37][38][39][40] via the salimethyloxazolinyl-thioester intermediate 8 (Figure 3). We speculated that compounds 1–3 occur

• through deviation of the salimethyloxazolinyl-thioester intermediate 8 from the assembly line via an unusually facile C–N-bond opening of the ring to generate an ester bond, and followed directly by amination (+ NH3), the addition of histamine and phenethylamine units to form compounds 1, 2, and 3

• -thioester intermediate followed by dehydration [44]. The incorporation of the decarboxylated phenylalanine by a nucleophilic unit to the intermediate salimethyloxazolinyl-thioester resulted in the formation of compound 5 without a rearrangement to isooxazolidinone owing to lack of N–OH in the phenylalanine

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• has improved further the C–H acylation procedures by working under mild reaction conditions. Thus, Doyle and Joe reported a mild C–H acylation protocol for the direct functionalization of α-amino C(sp3)–H bonds of N-arylamines 1 with acyl electrophiles such as anhydrides 72 and 2-pyridyl thioester 73

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