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

• acid attached to chlorotrityl resin via dipeptide intermediate 6 to give the tripeptide intermediate 7. The tripeptide 7 was then attached to strategic lysine amino acid, Fmoc-Lys-(Pg)-OH, whose ε-amino group is protected as either an Mtt (4-methyltrityl) or an Mmt (4-methoxytrityl) protecting group

• methodology, Fmoc amino acids such as Fmoc-Asp(Ot-Bu)-OH, Boc-Dap(Fmoc)-OH were coupled in sequence to STrt protected cysteine amino acid attached to a chlorotrityl resin to give dipeptide 6 and tripeptide 7 intermediates. The tripeptide 7 was then attached to Fmoc-Lys-(Tfa)-OH to give tetrapeptide 8c. The

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• , is an imperative goal to stay ahead of the evolution of antibiotic resistance. Herein we report the synthesis of a 3-decyltetramic acid analogue of the ureido dipeptide natural antibiotic leopolic acid A. The key step in the synthetic strategy is an intramolecular Lacey–Dieckmann cyclization reaction

• -decyl-2,3-pyrrolidinedione ring linked to the ureido dipeptide L-Phe-L-Val. The 2,3-pyrrolidinedione ring is a quite unusual skeleton. A limited number of compounds containing this system have been synthesized so far [5][6][7] and, to the best of our knowledge, natural compounds with a 2,3

• appears well suited to a convergent synthetic approach based around two fragments, the ureido dipeptide L-Phe-L-Val and the 3-decyltetramic acid core (Figure 1). Initially, we focused on the synthesis of the 2,4-pyrrolidinedione core. A review of the existing literature on tetramic acids syntheses

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

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• conjugates highly depended on their structure, cellular uptake and propensity to deamidation. The most active conjugate with dual acting properties was Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 (K, control conjugate in this study). In this conjugate the cyclic NGR peptide was attached through a Gly-Gly dipeptide

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• with L-Leu-OMe to afford dipeptide 15. Acidic hydrolysis of 15 using TFA, and coupling with the third amino acid (Boc-L-Ser(Bzl)-OH, Boc-L-Thr(Bzl)-OH, (2S,3R)-Boc-CF3-Thr, (2S,3S)-Boc-CF3-Thr), using HBTU/HOBt in the presence of DIPEA in DMF, afforded tripeptides 16a–d in good yields (48–83%). The

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• by converting 2,4-disubstituted aniline 1 to the non-fluorescent dipeptide analogue H-Gly-Pro-1 for the use as a fluorogenic substrate for dipeptidyl peptidase-4 (DPP-4). The progress of the enzymatic hydrolysis of H-Gly-Pro-1 with DPP-4 was monitored by fluorometric determination of 1 released into

• -protected glycine was condensed with proline methyl ester under microwave irradiation. Subsequent hydrolysis of the ester gave N-protected Gly-Pro-OH (6). Condensation of dipeptide 6 with 1 was achieved using the corresponding acid chloride. Deprotection of the amino group was achieved by treatment with

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• incorporated into peptides, it is normally necessary to first synthesize a dipeptide where the amide bond has been replaced with a monofluoroalkene. In that context, this review will present the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres described since 2007. Some

• applications of those compounds will also be presented. Keywords: dipeptide isosteres; monofluoroalkene-based amide bonds; monofluoroalkenes; peptides; synthesis; Introduction Nowadays, the pharmaceutical industry is interested in the development of new categories of drugs. While small molecules were the

• ][22]. In order to be incorporated into peptides, it is normally necessary to first synthesize a dipeptide where the amide bond has been replaced with a monofluoroalkene. This review is the follow-up of the last one published by Taguchi and Yanai in 2009 which covered the literature until 2007 [5] and

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• progression in the study of fluorinated amino acids develops into the concept of α,β,γ-trifluoro-δ-amino acids (e.g., 6, Figure 1). δ-Amino acids such as 6 are of special interest because they have the same backbone length as a dipeptide of α-amino acids, and thus may potentially be substituted for a two

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

• only to symmetrical products and can be detrimental for more fragile molecules such as substituted enantiomerically pure compounds. As shown by a retrosynthetic analysis (Scheme 1), a classical milder approach would consist in preparing first the dipeptide, followed by an intramolecular ester

• ][24][25][27] to prepare the Pro–Pro dipeptide from the corresponding amino acid derivatives. We investigated the coupling of proline N-hydroxysuccinimide ester with proline methyl ester in a vibrating ball mill (vbm, Scheme 2) [23]. Surprisingly, while the coupling of various other amino acids

• (Table 1, entries 1–3). Gratifyingly, the initial results showed that this method was adequate to prepare the Pro–Pro dipeptide 7 albeit in fair yield (Table 1, entry 1). Adding more starting material 6 (Table 1, entry 2) and changing the base (Table 1, entry 3) did not provide much improvement. Finally

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

• Ophélie Maurin,
• Pascal Verdié,
• Gilles Subra,
• Frédéric Lamaty,
• Jean Martinez and
• Thomas-Xavier Métro

Beilstein J. Org. Chem. 2017, 13, 2087–2093, doi:10.3762/bjoc.13.206

• obtained in solution (89% vs 88% for the dipeptide, 89% vs 77% for the tripeptide and 78% vs 64% for the tetrapeptide) (Table 1, entries 1, 3 and 5). Besides, the deprotection steps always furnished the amino ester salts in excellent yields, either by using TFA/CH2Cl2 (solvent strategy) or gaseous HCl

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• -free conditions were performed using a combination of (S)-binam-L-Pro (A, 5 mol %) and benzoic acid (10 mol %) as organocatalyst [49]. Juaristi and co-workers investigated the mechanistic aspects of α,α-dipeptide derivatives of a (S)-proline- (A′)-catalyzed asymmetric aldol reaction (Scheme 2b) under

• -(S)-proline derived catalyst [49]. b) Report using α,α-dipeptide-based catalyst [50]. Mechanochemical Michael reaction [51]. Mechanochemical organocatalytic asymmetric Michael reaction [52]. Mechanochemical Morita–Baylis–Hillman (MBH) reaction [53]. Mechanochemical Wittig reactions [55

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• large and the vesicle boundary permeability is known to be high. However, an internal chemical production can achieve similar results [86][100]. The formation of a hydrophobic dipeptide [86] for example led to growth of functional protocells at the expense of non-functional ones. The division of

Versatile synthesis of the signaling peptide glorin

• Robert Barnett,
• Daniel Raszkowski,
• Thomas Winckler and
• Pierre Stallforth

Beilstein J. Org. Chem. 2017, 13, 247–250, doi:10.3762/bjoc.13.27

• intraspecies interactions will give insight into the fundamentals of cell signaling and access to a rich source of novel natural products. We describe a practical synthesis of the modified dipeptide glorin (1, Figure 1), the assumed acrasin for many of the early-diverged species of social amoebae. While

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• enables them to bind to the dipeptide terminus of the peptidoglycan precursor lipid II [1][2]. This three-dimensional structure is generated by the high degree of crosslinking exhibited by the glycopeptide antibiotics: in the case of the two most widely known natural examples (vancomycin and teicoplanin

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• gene clusters complete the total set involved in the biosynthesis of natural products. Contrasting the high number of biosyntheses deduced from genomic data, knowledge on the actual natural products is limited. Recently, the dipeptide auriculamide (1, Figure 1), and the diterpene O-methylkolavelool

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• spectra were recorded in a 1 cm path length cuvette using a Cary 50 UV–vis spectrophotometer (Varian, Palo Alto, CA, USA) and the absorbance maximum at 312 nm was compared to a standard curve of the dipeptide H2N-Abz-Gly-OH·HCl to calculate the concentration of the peptide stock solution. The stock

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

• ). 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

• NH of 68 was protected using Cbz-Cl before acid 111 was afforded after a two-step, deprotection-reprotection sequence. Fully protected enduracididine 111 was then coupled with L-isoleucine methyl ester 112 to give dipeptide 113. Cleavage of the N-Boc group and coupling with dipeptide 114 afforded

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• /bjoc.12.222 Abstract A dipeptide-based urea-amide tertiary amine (DP-UAA) was shown to be an effective Brønsted base catalyst for the first asymmetric annulation reaction between 5H-thiazol-4-ones and N-itaconimides. High levels of enantioselectivity (up to 99% ee) and diastereoselectivity (>19:1 dr

• ) were obtained for a series of spirocyclic 1,4-sulfur-bridged piperidinone-based succinimides. Keywords: [4 + 2] annulation; asymmetric organocatalysis; dipeptide-based Brønsted bases; 5H-thiazol-4-ones; N-itaconimides; Introduction Sulfur-containing tetrasubstituted carbon stereocenters are widely

• chemoselectivity and thus the moderate yield. When the H-bond donor was changed from thiourea to urea (catalyst II), it did not provide better results (Table 1, entry 2) [17][19]. In the [4 + 2] annulation of 5H-thiazol-4-ones with nitroalkenes, dipeptide-based thiourea−amide−tertiary amine III (DP-TAA) was

Synthesis and NMR studies of malonyl-linked glycoconjugates of N-(2-aminoethyl)glycine. Building blocks for the construction of combinatorial glycopeptide libraries

• Markus Nörrlinger,
• Sven Hafner and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 1939–1948, doi:10.3762/bjoc.12.183

• removed and the intermediate amine 9 was condensed with 2a to afford the corresponding glycosylated AEG dipeptide 4 in 58% yield. All glycoconjugate building blocks showed the presence of cis and trans rotamers. Compounds 1a, 1b and 4 were subjected to temperature dependent 1H NMR spectroscopy in order to

• DMF at room temperature for 3.5 h gave partially protected compound 8 which was used for the next step without further purification. Coupling of 2a with crude 8 using HBTU, 1-hydroxytriazole (HOBt) and diisopropylethylamine (DIPEA) in DMF gave dipeptide 4 in 58% yield (Scheme 3). 1D-NMR investigation

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

• Atul A. Dhavan,
• Rahul D. Kaduskar,
• Loana Musso,
• Leonardo Scaglioni,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2016, 12, 1624–1628, doi:10.3762/bjoc.12.159

• Veterinary Medicine - Microbiology and Immunology, Università degli Studi di Milano, via Celoria 10, I-20133 Milano, Italy 10.3762/bjoc.12.159 Abstract The first total synthesis of leopolic acid A, a fungal metabolite with a rare 2,3-pyrrolidinedione nucleus linked to an ureido dipeptide, was designed and

• residue, which in turn, is connected to the ureido dipeptide L-Phe-L-Val. The compound showed antifungal and antibacterial activity against Mucor hiemalis and Staphylococcus aureus with a MIC of 32 and 16 μg/mL, respectively [2]. Compounds containing the isomeric 2,4-pyrrolidinedione ring system (tetramic

• be used in the preparation of various analogues. A retrosynthetic disconnection of 1 at the amide bond gave two fragments, the ureido dipeptide L-Phe-L-Val and 4-decyl-3-hydroxy-1,5-dihydropyrrol-2-one, which appeared well suited for a convergent synthetic approach (Figure 1). Results and Discussion

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

• deprotection led to the target compound (+)-caprazol (19) [90][92]. For the synthesis of muraymycins, Ichikawa, Matsuda et al. furthermore developed a new route towards the epicapreomycidine-containing urea dipeptide unit via C–H activation (Scheme 3) [96][97]. For this purpose, the commercially available δ-N

• urea dipeptide 27 [96][97]. Starting from the uridine derivative 28 used in the synthesis of (+)-caprazol, Ichikawa and Matsuda built up muraymycin D2 and its epimer (Scheme 4). They used an Ugi four-component reaction with an isonitrile derivative 29 obtained from the uridine-derived core structure 28

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• . Results and Discussion We started our investigation by attempting the alkynylation of valine-tryptophan dipeptide 4a as model substrate (Table 1). An often used carboxybenzyl (Cbz, Z) protecting group was chosen. Examining this substrate will tell if C2-alkynylation is possible in the presence of an ester

• reaction time. With the optimized conditions in hand, we investigated the scope of the reaction with different amino acids in the dipeptide (Scheme 2). With glycine as second amino acid, the desired product 5b could be obtained in 66% yield. The reaction was selective for tryptophan in the presence of

• , only traces of alkynylated dipeptide 5g with a tryptophan at the N-terminus could be obtained under these reaction conditions. A first example of valine–tryptophan–valine tripeptide was also examined, and product 5h was isolated in 50% yield, demonstrating that alkynylation of tryptophan inside a

Enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines catalyzed by a bifunctional dipeptide phosphine

• Huanzhen Ni,
• Weijun Yao and
• Yixin Lu

Beilstein J. Org. Chem. 2016, 12, 343–348, doi:10.3762/bjoc.12.37

• of a dipeptide phosphine catalyst, a wide range of highly functionalized cyclopentenes bearing an all-carbon quaternary center were obtained in moderate to good yields and with good to excellent enantioselectivities. Keywords: [3 + 2] annulation; α-substituted allenoate; dipeptide phosphine

• reaction was improved to 68%. To further improve the reaction results, we next utilized dipeptide phosphine catalysts, which are more structurally diverse and tunable. The L-thr-L-thr-derived catalyst 4a was a poor catalyst, on the other hand, L-val-L-thr-derived catalyst 4b led to adequately improved

• . The [3 + 2] annulation of α-substituted allenoates reported by He. Possible reaction mechanism. Screening of different amino acid-based bifunctional phosphine catalysts. Enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines catalyzed by dipeptide

My maize and blue brick road to physical organic chemistry in materials

• Anne J. McNeil

Beilstein J. Org. Chem. 2016, 12, 229–238, doi:10.3762/bjoc.12.24

• system, similar trends were observed. To determine whether these results were general, postdoctoral researcher Maria Muro-Small synthesized and measured dissolution enthalpies for 11 dipeptide-based compounds (6 gelators, 5 nongelators) [33]. Peptides were chosen because they represent the largest and

Assembly of synthetic Aβ miniamyloids on polyol templates

• Sebastian Nils Fischer and
• Armin Geyer

Beilstein J. Org. Chem. 2015, 11, 2646–2653, doi:10.3762/bjoc.11.284

• , Aβ peptide pentapeptide boronic acids 1 and 2 were synthesized by solid-phase peptide synthesis and studied in esterification experiments with polyhydroxylated templates. The bis-hydroxylated dipeptide Hot=Tap serves as a template of adjustable degree of oligomerization which spontaneously forms

• strands, which are expected to push the esterification towards quantitative conversion. Compound 5 combines side-chain cis-diol functionality for boronic ester formation and the potential of controlled oligomerization by peptide chemistry. Azido ester 5 is a precursor of the dipeptide Hot=Tap, which

• the supramolecular chemistry of Aβ with the concepts of reversible covalent chemistry. The present study shows how oligomers of the Hot=Tap dipeptide serve as templates for the reversible covalent esterification of boronic acids which mediate the assembly of monodisperse Aβ miniamyloids. The modular