Synthesis of bi- and bis-1,2,3-triazoles by copper-catalyzed Huisgen cycloaddition: A family of valuable products by click chemistry

• Zhan-Jiang Zheng,
• Ding Wang,
• Zheng Xu and
• Li-Wen Xu

Beilstein J. Org. Chem. 2015, 11, 2557–2576, doi:10.3762/bjoc.11.276

• azide, leading to the corresponding bistriazoles. In 2006, Aucagne and Leigh reported the synthesis of the TMS-alkyne and terminal-alkyne bis-functionalized tripeptide [28]. Here they used the CuAAC reaction of the terminal-alkyne-containing tripeptide 25 with the azide-containing dipeptide 26 in t-BuOH

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• N-acyliminium species have been developed, resulting in the synthesis of a number of lactams and lactam-derived heterocycles [52]. One representative example is depicted in Scheme 10, where dipeptide 25 cyclizes via intramolecular nucleophilic attack of the hydroxy group on the anodically generated

• explored [52]. The cyclization of dipeptide 27 as a model reaction is shown exemplarily in Scheme 11. Since the tethered olefin group is easier to oxidize than the amide unit, a dimethylphenylsilyl group was introduced in α-position to the amide and served as electroauxiliary. The cyclization was then

• . Anodic cyclization of dipeptide 25. Anodic cyclization of a dipeptide using an electroauxiliary. Anodic cyclization of hydroxyamino compound 29. Cyclization of unsaturated thioacetals using the ArS(ArSSAr)+ mediator. Cyclization of biaryl 35 to carbazol 36 as key-step of the synthesis of glycozoline (37

(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

• (DCPM) ester of N-Fmoc-protected Ile 37, was condensed with N-Z-protected (βMe)Phe-OH 39. After removal of the Z group from the N-terminus of the resulting dipeptide 42 by catalytic hydrogenation, the product was coupled with N-Fmoc-protected (2R,1'R,2'R)-[3-(mono-, di- or tri-)fluoromethylcyclopropyl

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• above, was postulated. Attracted by the phosphine-catalyzed reactions described above, Lu and co-workers prepared versatile dipeptide-derived phosphines for asymmetric annulations [54]. Their multifunctional catalyst framework comprised a dipeptide moiety and a tertiary phosphine unit. In the presence

•  23). Shortly after, the Lu group further expanded the substrate scope of asymmetric [3 + 2] annulations with allenoates to a series of 3,5-dimethyl-1H-pyrazole-derived acrylamides (Scheme 24) [55]. The dipeptide-based phosphine H10 effectively promoted the reaction in good to excellent yields, albeit

• low to moderate enantioselectivities. In 2012, Lu, Shi, and co-workers found that the dipeptide-based phosphine H10 was also quite effective as a chiral catalyst for [3 + 2] annulations of various maleimides with allenoates (Scheme 25) [56]. They obtained a wide range of bicyclic cyclopentenes in good

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• cyclic dipeptide [5]. In these reactions, N-substituted imines react with HCN to yield (S)-α-aminonitriles with remarkably high enantiomeric excess (ee). One example is shown in Scheme 3. However, when benzaldehyde and NH3 instead of the N-substituted imine were employed as the substrates, the reaction

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• its epimer (Scheme 21) [87]. After completion of the synthesis of the urea dipeptide 53 bearing the cyclic moiety found in muraymycin D2, the four-component condensation was performed similarly as in [86] to yield the protected product 54 as a 1:1 diastereomeric mixture. Functional group manipulation

•  22) [89]. The urea dipeptide 55, 2,4-dimethoxybenzylamine, the protected (S)-2-(methylamino)propanal, and isonitrile 56 were simply combined in ethanol at ambient temperature for 48 h. The expected compound 57 and its epimer were obtained in reasonable yields, and were separated by column

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• incorporated antigen. Here we describe the design, automated synthesis and immunological evaluation of a set of four muramyl dipeptide–peptide antigen conjugates. Muramyl dipeptide (MDP) represents a well-known ligand for the intracellular NOD2 receptor and our study shows that covalently linking an MDP-moiety

• incorporated SIINFEKL epitope on MHC-I molecules. However, stimulation of the NOD2 receptor in DCs was not sufficient to provide a strong immunostimulatory signal. Keywords: automated synthesis; glycopeptide; innate immunity; muramyl dipeptide; NOD2 receptor; solid phase synthesis; Introduction In recent

• MurNAc 10 in 93% yield [39][40]. Fully protected MDP 14 was obtained by condensation of acid 10 and dipeptide 13. To this end, Fmoc-protected tert-butyl glutamic acid 11 was reacted with di-tert-butyl dicarbonate and transformed into 12 [41]. In a one-pot procedure compound 12 was deprotected with DBU

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• heterogeneous synthesis In the past, pioneering of Emil Fischer at the beginning of the 20th century [15] and du Vigneaud in 1953 [16] have made the synthesis of peptides possible, as at that time, they were relatively unknown biomolecules. Fischer synthesized the first dipeptide, called glycylglycin, and

• . Formation of a dipeptide 3. Reaction of the amino group of amino acid 2 with the carboxylic acid moiety of amino acid 1 leads to a mesomeric peptide bond (highlighted in red). Peptide assembly by SPPS, exemplarily shown for a tetrapeptide. First, the C-terminal amino acid is coupled to the linker. The

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• , acidic deprotection afforded the desired building blocks 13a,b suitable for N-derivatization, with the compounds not being fully purified. In order to demonstrate the synthetic versatility of these 3-hydroxyleucine derivatives, they were coupled with urea dipeptide 14 [36], thus providing protected

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• 9, followed by the generation of α-adduct 10 formed via an attack of the isocyanide to the imine and a subsequent attack of the carboxylate to the resulting nitrilium ion (Scheme 3). The final dipeptide-like product is formed via a subsequent Mumm rearrangement of the α-adduct 10. In addition, pre

• ]. Review Small ring constraints In the first part of this review four- to seven-membered cyclic peptidomimetics will be discussed. These small rings, particularly heterocycles, have received much attention as dipeptide mimics due to their capable interaction with defined protein motifs and due to their

• , oxazoles, thiazoles and triazoles incorporated into peptide structures will be described. Pyrrolidines 2-substituted pyrrolidine-based dipeptide mimics were obtained from an Ugi-4CR followed by a Pd-catalyzed Sn2 cyclization as described by Banfi et al. [51] . Herein, the Ugi reaction provided a small

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

• Werner Telle,
• Gerhard Kelter,
• Heinz-Herbert Fiebig,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2014, 10, 316–322, doi:10.3762/bjoc.10.29

• . There are also other, enantioselective syntheses of 7 [7] and Boc-protected versions of MMMAH [8][9], but we intended to also have the (3S)-epimer of 7 at our disposal. After hydrogenation of 7, the resulting secondary amine was coupled with Cbz-valine (8) affording dipeptide 9 (DEPCl, diethyl

• possible. The occurrence of conformers has been mentioned by Scheuer and co-workers and is also known for dolastatin 10 [12] and symplostatin 1 [13]. As an alternative route to the N-terminal tripeptide 11, we also investigated the coupling of the N-terminal dipeptide 15 with MMMAH tert-butyl ester (16

• , Scheme 2). However, after treatment of dipeptide 15 with secondary amine 16 (0.43 equiv) and DEPC (17, 2.5 equiv), the only isolable product was oxazolylphosphate 18 (35%) without any amide formation occurring. The structure elucidation of 18 required C–P coupling constant analysis, which showed doublet

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• most efficient reagents for peptide bond formation. Seeberger and co-workers demonstrated the use of a silicon-based microreactor for the effective synthesis of peptides (Scheme 8) [68]. The condensation reaction completed in only 3 min at 90 °C to afford the dipeptide in high yield. Under the

• conditions at higher temperatures and/or leaving in prolonged contact with the reagents, decreasing the chemical yield of the desired dipeptide and increasing the amount of the tripeptide were observed. Using a flow microreactor system, precise residence-time control avoided the formation of undesired

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

• Jiayang Li,
• Yi Kuang,
• Junfeng Shi,
• Yuan Gao,
• Jie Zhou and
• Bing Xu

Beilstein J. Org. Chem. 2013, 9, 908–917, doi:10.3762/bjoc.9.104

• and Ala–Ala, a nonaromatic dipeptide. The conjugates of NSAIDs and Ala–Ala, 1g, 3g, 4g, and 5g, behave differently from those conjugates that contain Phe–Phe. At a concentration of 0.8 wt %, while 1g and 3g afford white, opaque hydrogels at pH 4.0 and 1.0, respectively, compounds 4g and 5g fail to

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• levels at submicromolar concentration as determined in a NF-κB-linked reporter assay. Both probes selectively (>40-fold for 13, >8-fold for 17) inhibited NOD1-dependent activation of the NF-κB pathway without inhibiting MDP-stimulated (muramyl dipeptide and a NOD2-dependent signaling ligand) signal

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• -milling over traditional stirring in terms of reaction rate, product yield, and stereoselectivity was observed. In 2011, Hernández and Juaristi utilized the catalytic potential of α,α-dipeptide, i.e., methyl ester of (S)-proline-(S)-phenylalanine (III) for organocatalytic asymmetric aldol reaction of

• and 69% ee. In the previous studies by Szöllösi’s group on the dipeptide III catalysed asymmetric aldol reactions between acetone and 2-ethylbutanal in the presence of an excess of acetone (68:1) under traditional stirring affords (R)-β-hydroxyketone in moderate yield and 86% ee after 24 hours [36

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• a bidirectional sequence from the least- to the most-reactive amine (NMe-Val < H-Ant-OBn < H-Gly) to yield the protected tetrapeptide 2 (Scheme 1a). Alternatively, a multicomponent (MCR) approach based on a Ugi four-component reaction (Ugi-4CR) of dipeptide 3, isobutyraldehyde, methylamine and

• at least stability. Results and Discussion The 2-CR approach based on the peptide coupling of Boc-Gly and NMe-Val-OMe in the presence of EDCl and HOAt gave the central dipeptide 5 in 73% yield (Scheme 2) [15].The use of even more activating coupling reagents, such as HATU and BOP, was also

• investigated and resulted in increased formation of side products [11]. After saponification of intermediate 5 to dipeptide 6, the latter was coupled with benzyl anthranilate. This reaction was particularly challenging due to the very poor reactivity of this combination [10]. All attempts to perform this

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• activation reagent and 2-chlorotritylchloride resin to allow cleavage of the peptide from the solid support with side-chain protecting groups intact. In the case of 6, the ΨMe,Me'Pro was introduced by coupling the known dipeptide Fmoc-Val-D-a-Thr(ΨMe,Me'Pro)-OH [18] into the growing peptide chain. While

Partial thioamide scan on the lipopeptaibiotic trichogin GA IV. Effects on folding and bioactivity

• Marta De Zotti,
• Barbara Biondi,
• Cristina Peggion,
• Matteo De Poli,
• Haleh Fathi,
• Simona Oancea,
• Claudio Toniolo and
• Fernando Formaggio

Beilstein J. Org. Chem. 2012, 8, 1161–1171, doi:10.3762/bjoc.8.129

• ), and Boc-Gly9ψ[CS-NH]Ile-Leu11-OMe (for the preparation of ψ[CS-NH]9). Thionation of a peptide as short as a dipeptide is not recommended because a further synthetic step at the C-terminus of this compound would not take place satisfactorily, owing to the easy formation of a poorly reactive 1,3

Enantioselective supramolecular devices in the gas phase. Resorcin[4]arene as a model system

• Caterina Fraschetti,
• Matthias C. Letzel,
• Antonello Filippi,
• Maurizio Speranza and
• Jochen Mattay

Beilstein J. Org. Chem. 2012, 8, 539–550, doi:10.3762/bjoc.8.62

• were functionalized with leucyl-valine and valyl-leucine (I and III; Scheme 1a) methyl esters, and the enantioselectivity toward the same dipeptide esters used in their synthesis, namely, leucyl-valine-OMe and valyl-leucine-OMe (1 and 3; Scheme 1b) was investigated [43]. A configurational preference

• amine does not need to enter the cavity to interact with the chiral lower portion of the host before displacing the dipeptide G from the complex. This hypothesis agrees well with the external location of G in the [M∙H∙G]+ complex that was observed in independent solution experiments [44]. The

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• irritations and are implicated in the so-called “swimmers itch”. The compounds are also potent tumor promoters, which operate by competitively binding to protein kinase C (PKC). The characteristic indolactam ring of the toxin is synthesized by the bimodular NRPS LtxA [48]. The resulting dipeptide is tethered

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

• Elizabeth P. Jones,
• Peter Jones,
• Andrew J. P. White and
• Anthony G. M. Barrett

Beilstein J. Org. Chem. 2011, 7, 1570–1576, doi:10.3762/bjoc.7.185

• aromatic ring, to the same conditions yielded the dipeptide 9 and the desired methyl ester 10 in a 1:1 ratio (Scheme 7). Screening of various acidic hydrolysis reaction conditions in these systems led to the observation that when either 6a or 7c was stirred in neat 6 M sulfuric acid for three days, the

• dipeptide as the major product for all analogues with two methoxy groups (6a–6i). The only example where the use of low concentrations of acid coupled with a dimethoxy aryl group resulted in the principal formation of the desired ester was in the case of alcohol 6j. Mild acidic hydrolysis with 0.5 M HCl

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• , Schwarz and Wandrey developed a cascade of two membrane reactors for the production of dipeptides [35]. In the first reactor carboxypeptidase Y (CPD-Y) catalyzes the condensation between the ester 36 and the amide 37 of two amino acids (Scheme 12). Deamidation of the resulting dipeptide-amide 38 proceeds

• in the second reactor loaded with a selective peptide-amidase that does not react on dipeptide bonds. In a slow side reaction, however, CPD-Y hydrolyzes the final deamidated dipeptide 39, whereas it does not act on the intermediate 38. Separation of the two reactions was thus preferred in order to

• decarboxylase; E2: RecLb-alcohol dehydrogenase; E3: Formate dehydrogenase [2]. Production of a dipeptide 39 in a cascade of two continuously operated membrane reactors. E1: Carboxypeptidase Y; E2: Peptide amidase [35]. Continuous production of GDP-mannose (43) from mannose 1-phosphate (40) in a cascade of two

Synthesis of enantiomerically enriched (R)-¹³C-labelled 2-aminoisobutyric acid (Aib) by conformational memory in the alkylation of a derivative of L-alanine

• Stephen P. Fletcher,
• Jordi Solà,
• Dean Holt,
• Robert A. Brown and
• Jonathan Clayden

Beilstein J. Org. Chem. 2011, 7, 1304–1309, doi:10.3762/bjoc.7.152

• confirm that the alkylation of (S)-Ala by this method is mechanistically retentive, producing (R)-6* as the major enantiomer. Dipeptide 7 was made, as a ca. 2.5:1 mixture of diastereoisomeric isotopomers, on a preparative scale from enantiomerically enriched 6*. The dipeptide was deprotected by

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• chemistry were all well-tolerated. The method was also successfully applied to the synthesis of a dipeptide conjugate, indicating that the methodology is applicable to the synthesis of chromogenic substrates containing short peptides. The method has general applicability to the synthesis of chromogenic and

• that Boc-Arg-OH∙HCl could be activated with isopropyl chloroformate and the activated form was converted smoothly to the corresponding selenocarboxylate followed by the reaction with p-nitrophenyl azide to give the p-nitroanilide 16 in 81% yield (Table 2, entry 2). A dipeptide-pNA, Boc-Ser-Phe-pNA (18

• -aminoacyl-pNAs/AMCs, providing easy access to these important synthons for the construction of chromogenic/fluorogenic protease substrates through fragment condensation or stepwise elongation. The 3-step one pot procedure was also successfully applied to the synthesis of a dipeptide conjugate indicating

Amphiphilic dendritic peptides: Synthesis and behavior as an organogelator and liquid crystal

• Baoxiang Gao,
• Hongxia Li,
• Defang Xia,
• Sufang Sun and
• Xinwu Ba

Beilstein J. Org. Chem. 2011, 7, 198–203, doi:10.3762/bjoc.7.26

• based dendrimers, and especially to their gelation and liquid crystal properties [12][13]. Recently, a type of amphiphilic dendritic dipeptide was described by Percec et al. as self-assembling in helical pores [14]. In addition, Takashi Kato and co-workers have recently reported that dendritic