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

• under mild and operationally simple conditions while peptide coupling between two amino acids could be efficiently conducted using the longer-chain perfluoroalkyl reagent BT-SC5F11. Mechanistic studies revealed that each equivalent of the benzothiazolium reagent can feasibly generate two equivalents of

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• dipeptide with the aim to overcome issues found in batch in relation to product stability and scale-up concerns. The peptide coupling reaction was performed continuously aided by a MSMPR crystallizer system. This system ultimately shortened the holding time for the quenched solution, leading to a robust

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• isolated. Moreover, the coupling of benzothiazines with amino acids was realized. In doing so, an enantioselective synthesis of the nonproteinogenic amino acid 2-amino-3-propylhexanoic acid was accomplished. Keywords: amino acid; benzothiazine; oxidative dimerization; peptide coupling; stereoselective

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• lithium hydroxide monohydrate [29] to give the desired indole-2-acetic acid (14) in 95% yield. The peptide coupling reaction [30] of indole-2-acetic acid (14) and 2-iodoaniline afforded 15 in 23% yield (Scheme 3). Subsequent protection of both the indole and the amide nitrogen with tert-butyloxycarbonyl

• batch of 1a was reduced. It is likely that 2a can be cyclized by base catalysis, or by using common peptide coupling reagents (e.g., EDCI, HATU) upon saponification of the ester group. However, we opted for a trimethylaluminum-mediated amidation reaction [4][39] to give rise to 8-benzyl-7-hydroindolo

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• hoshinoamide A. Hindered peptide coupling: conditions and yields. Supporting Information Supporting Information File 278: NMR (1H NMR and 13C NMR) spectra of compounds 2−8, and comparison of the spectral data of natural and synthetic hoshinoamide A. Acknowledgements The authors also sincerely thank Mr

Synthesis of new asparagine-based glycopeptides for future scanning tunneling microscopy investigations

• Laura Sršan and
• Thomas Ziegler

Beilstein J. Org. Chem. 2020, 16, 888–894, doi:10.3762/bjoc.16.80

• containing glycopeptides were prepared in solution. The applicability of two common peptide coupling reagents, using an orthogonal Fmoc/t-Bu strategy along with acetyl protecting groups for the carbohydrate moiety, was studied. Thus, the prepared libraries of glycopeptides were designed as model systems of

• we previously obtained with the onium salt-mediated peptide coupling protocol with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, Scheme 2 and Table 1) [6][32]. Here, we compared

• significantly higher yield than HBTU. The Fmoc cleavage of the compounds 3–5 was performed with piperidine in DMF (20 vol %) [36]. The reaction products were not isolated and purified but instead immediately used for the succeeding peptide coupling step to give the dipeptides 4 and 5 from the glycosylated

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

• performed following solution phase Boc-protected peptide coupling and functional group interconversion (Scheme 1). The central alanine carrying nonnatural derivatives were sequentially synthesized from C- to N-terminus, using ester protected glycine or sarcosine and coupling to Boc-protected ᴅ- or ʟ-alanine

Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

• Miriam Schehr,
• Daniel Hugenbusch,
• Tobias Moje,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2018, 14, 2799–2804, doi:10.3762/bjoc.14.257

• functionalization such as cross coupling, peptide coupling or further functionalization. The photoswitchable properties of the S-diazocines 1–5 were investigated using UV–vis and NMR spectroscopic methods. The photostationary states (PSS), half-lives (t1/2) and absorption maxima (λmax) were recorded in acetone and

• precursors for the incorporation in photopharmacophores using cross-coupling, peptide coupling or further functionalization methods such as nucleophilic substitution reaction of the benzyl alcohol 5. The yield determining steps prior to the Baeyer–Mills reaction are the formation of the hydroxylamine with

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

• resin. The protecting groups of other amino acids present in 11 remain intact during this process. After the successful cleavage of the Tfa protecting group to give 11, the free ε-amino group was covalently bonded to a fluorescent tag such as rhodamine B using standard peptide coupling chemistry to

• peptide coupling procedures. 1H and 13C NMR data were recorded using a Bruker AV 400 MHz NMR spectrometer with TMS (tetramethylsilane) as internal reference. Mass spectra were recorded on a Brukermicro TOF-Q II spectrometer in positive mode and negative mode electrospray ionization methods. Reactions were

• bed and washed with DCM (3 × 5 mL). The solvent was evaporated under reduced pressure and the crude product was purified through column chromatography (hexane/ethyl acetate = 50:50) to afford the tris(tert-butoxy)-protected DUPA precursor 4 which was further used for peptide coupling reaction in the

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• from p-nitrophenyl α-D-mannopyranoside (1), which was first reduced to the corresponding amine 6 [26][27] by catalytic hydrogenation (Scheme 1). HATU-mediated peptide coupling with Boc-protected glycine under basic conditions led to 7. After removal of the Boc protecting group using trifluoroacetic

• acid in water, the resulting crude product was subjected to a subsequent peptide-coupling reaction employing the carboxy-functionalized diazirine 8. Diazirine 8 was prepared in a nine-step synthesis according to the literature [28]. For the synthesis of ligand 4, mannoside 6 was first converted into

• the squaric acid monoester 10 employing squaric acid diester 9. The monoester 10 was reacted with N-Boc-ethylendiamine to obtain the squaric acid diamide 11. Then removal of the Boc protecting group with trifluoroacetic acid followed by peptide coupling with the diazirine 8 led to target molecule 4

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

• worth noting that FPID can be readily regenerated after the peptide coupling reaction. Keywords: cyclic peptide; FPID; hypervalent iodine(III) reagent; recyclable; solid-phase peptide synthesis (SPPS); Introduction The amide bond is one of the most fundamental functional groups in organic chemistry

• mediated by hypervalent iodine(III) reagents in recent years. In 2012, for the first time, we reported that the hypervalent iodine(III) reagent iodosodilactone (Figure 1) can serve as a condensing reagent to promote esterification, macrolactonization, amidation and peptide coupling reactions in the

• presence of PPh3 [28]. In addition, the peptide coupling reaction proceeds without racemization in the absence of a racemization suppressant and iodosodilactone can be readily regenerated after the reaction. In order to further enhance the reactivity of iodosodilactone, we designed and synthesized a new

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

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

• synthesized in two steps (Scheme 5). Herein, the treatment of methyl-terminated triethylene glycol monolayer-protected AuNPs (Me-EG3-AuNPs) with ω-carboxy tetraethylene glycol thiols (HOOC-EG4-SH) gave carboxy-functionalized AuNPs (HOOC-EG4-AuNPs). Peptide coupling of these HOOC-EG4-AuNPs with a DBCO-amine

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• . This was in agreement with the experimental formation of only 15a. As mentioned above, another possibility to exploit meso pyrrolidine cis-11 would be to desymmetrize [43] the ester functions by selective hydrolysis. The corresponding carboxylic acid could then be engaged in a peptide coupling. Pig

• substituted diketopiperazines based on the proline–proline framework. The synthetic schemes included two key reactions, which were performed under mechanochemical conditions, including a peptide coupling leading to the formation of Pro–Pro dipeptides, and a nucleophilic substitution furnishing substituted

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• synthesis and purification by using well developed peptide coupling reactions with or without the use of solid phase methods. To execute this concept, Fairbanks et al. investigated a number of peptide chains with various amino acids as templates (Scheme 9) [76][77]. Using DCC-mediated coupling reactions

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• free acid moiety available for peptide coupling over nine steps in 32% overall yield. Synthesis of a β-hydroxyenduracididine derivative by Cheng et al.: In 2016, Cheng et al. reported work towards the N-mannosyl-D-β-hydroxyenduracididine (69) residue of the mannopeptimycins (Scheme 13) [68]. Their

• ). Saponification of the ester of 88 and coupling with H-Ser(Bn)-O-Allyl and treatment with HCl afforded dipeptide 89. A second peptide coupling with acid 90 then gave tripeptide 78. With tripeptide 78 in hand, ligation with the remaining tripeptide 71 followed by cyclisation and global deprotection afforded the

• final stages of the synthesis (Scheme 21), benzyl protected mannosyl D-β-hydroxyenduracididine 97 was coupled with H-Ser(Bn)-OAllyl to afford dipeptide 100. Unmasking of the amino and alcohol functionalities and peptide coupling with L-β-hydroxyenduracididine 98 afforded tripeptide 101 with no loss of

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

• moiety. This led to many truncated muraymycin analogues based on the structures 7 and 8 [76]. Cbz deprotection and subsequent peptide coupling with the L-arginine-L-valine-derived urea dipeptide 9 gave various full-length muraymycin analogues 10 and 11 [76]. Some of the truncated and the full-length

• followed by an azide reduction, Boc protection, saponification of the ester, peptide coupling with the amino acid 17, oxidative cleavage of the double bond to give 18 and an intramolecular reductive amination in order to construct the seven-membered ring. Methylation with subsequent acidic global

• give 61. A sequence of desilylation and oxidation furnished the acid 62. Peptide coupling with amine 63 and acidic deprotection then afforded the desired aldehyde 64, which already contained the muraymycin linker unit (Scheme 8) [107]. Together with the uridine core structure 50 and the urea dipeptide

Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

• Jyotiprasad Mukherjee,
• Suman Sil and
• Shital Kumar Chattopadhyay

Beilstein J. Org. Chem. 2015, 11, 2487–2492, doi:10.3762/bjoc.11.270

• solution phase peptide coupling between L-Phe-D-Pro-OMe (6) (prepared by hydrogenolysis of the corresponding carbamate 5) and L-Cbz-Phe-OH (7) followed by elaboration of the resulting tripeptide 8 via N-terminus deprotection leading to 9 followed by a second peptide coupling of the latter with the known

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• (10–14mer PNA typically provides sufficient duplex stability) [35]. From a chemistry standpoint, the fact that PNA synthesis involves peptide coupling reactions with a broad arsenal of protecting group combinations facilitates the introduction of functionalities for the conjugation of glycans [36

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• ligands for a target protein. The hyperbranched polyglycerol amine (hPG-NH2) with different degrees of amine functionalization can easily be prepared from hPG-OH with high yields in three steps, as reported in the literature [15]. It can be used for peptide coupling, while it is still maintaining the

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

• Boris Schmidtgall,
• Claudia Höbartner and
• Christian Ducho

Beilstein J. Org. Chem. 2015, 11, 50–60, doi:10.3762/bjoc.11.8

• , the dimeric target structures could be constructed (Scheme 4). Using a standard procedure for peptide coupling, suitably protected nucleosyl amino acids (S)-9 and (R)-9 were activated and reacted with amine 8 to give bis-O-silylated NAA-linked A–T dimers (S)-26 and (R)-26 in yields of 71% and 68

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• complicated problem. "State of the art" peptide coupling methodology [59][60] allows one to prepare almost any peptides, that do not contain extremely sterically congested fragments such as α,α-dialkyl-substituted amino acids, N-alkyl amino acids or even the more challenging N-aryl amino acids. With a proper

A green approach to the synthesis of novel phytosphingolipidyl β-cyclodextrin designed to interact with membranes

• Yong Miao,
• Florence Djedaïni-Pilard and
• Véronique Bonnet

Beilstein J. Org. Chem. 2014, 10, 2654–2657, doi:10.3762/bjoc.10.278

• with a promising yield. Keywords: fatty ester; green chemistry; lipase; mono-substituted amphiphilic cyclodextrins; peptide Coupling; solvent-free medium; transesterification; Introduction Cyclodextrins (CDs) are sustainable compounds which are particularly interesting in the frame of pharmaceutical

• time in cyclodextrin chemistry via solvent-free substitution of aminocyclodextrin followed by the use of a new, more environmentally friendly peptide coupling agent known as COMU (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate). Finally, by optimized

• succinic anhydride can be recovered easily by filtration at low temperature but part of the compound underwent methanolysis, preventing its reuse for another reaction. Insertion of phytosphingolipidyl arm In this step, the peptide coupling reagent plays an important role. Different peptide coupling

Synthesis of aromatic glycoconjugates. Building blocks for the construction of combinatorial glycopeptide libraries

• Markus Nörrlinger and
• Thomas Ziegler

Beilstein J. Org. Chem. 2014, 10, 2453–2460, doi:10.3762/bjoc.10.256

• linked to the backbone by a malonyl moiety were prepared via peptide coupling. The orthogonally protected glycoconjugates, bearing an acetyl-protected glycoside, were converted into their corresponding acids which are suitable building blocks for combinatorial glycopeptide synthesis. Keywords: amino

• monosaccharides 11 in 53–76% yield. The medium yields in case of 11b–d (Table 1, entries 2–4) were due to some decomposition during chromatographic purification. Nevertheless, in our hands, HBTU was superior to other peptide coupling reagents because it resulted in the highest yields of compounds 11. HBTU was

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

• Mahesh K. Lakshman,
• Manish K. Singh,
• Mukesh Kumar,
• Raghu Ram Chamala,
• Vijayender R. Yedulla,
• Domenick Wagner,
• Evan Leung,
• Lijia Yang,
• Asha Matin and
• Sadia Ahmad

Beilstein J. Org. Chem. 2014, 10, 1919–1932, doi:10.3762/bjoc.10.200

• , primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From 31P{1H}, [18O]-labeling

• ][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis. Keywords: alkoxy; azabenzotriazole; benzotriazole; peptide-coupling; phosphonium; Introduction Benzotriazole derivatives are of importance in diverse contexts. As examples, in medicinal chemistry substituted benzotriazoles

• -azabenzotriazoles (At-OR) by a previously unstudied reaction of benzotriazole-based peptide-coupling reagents with alcohols [21]. We also describe studies on the underlying mechanism and a preliminary disclosure of the potential synthetic applications of these products. Figure 1 shows examples of commercially