A new member of the fusaricidin family – structure elucidation and synthesis of fusaricidin E

• Marcel Reimann,
• Louis P. Sandjo,
• Luis Antelo,
• Eckhard Thines,
• Isabella Siepe and
• Till Opatz

Beilstein J. Org. Chem. 2017, 13, 1430–1438, doi:10.3762/bjoc.13.140

• of the GHPD side chain building block. Thus, Cudic’s SPPS approach should be combined with the advantages of the late stage coupling employed by Jolliffe. Synthesis The C13-fragment was prepared starting from erucamide (6) in three simple operations. Reduction of the amide with lithium aluminium

• alcohol 12 was subjected to ozonolysis and Pinnick oxidation to furnish the protected GHPD acid 3 in an overall yield of 14.3%. The peptide core was synthesized manually according to a standard SPPS Fmoc protocol using HATU and NMM in NMP [16]. For protection of the threonine unit, it was converted into a

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

• et al. [47]. These syntheses substituted the enduracididine residue for the more readily available L-arginine. The total synthesis of the full teixobactin structure was completed in 2016 by Payne et al. [72] using Fmoc solid-phase peptide synthesis (SPPS). The key to the synthesis was access to the

• Fmoc-D-Thr(TES)-OH on HMPB-NovaPEG resin. Successive couplings afforded peptide 104 (Scheme 23). Esterification with Alloc-Ile-OH and extension of the linear chain using conventional Fmoc SPPS afforded ester-peptide 105. Deprotection of the N-alloc group and coupling of the key L-allo-enduracididine

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

• serves as a β-turn mimic in peptides and proteins [24][25][26]. Alternatively, Fmoc-Hot=Tap-OH (8, Figure 5) is available for oligomerization on SPPS to templates of adjustable length with a systematic increase of the number of cis-diol functions assembled on a rigid peptide backbone. In solution

Synthesis and evaluation of the biostability and cell compatibility of novel conjugates of nucleobase, peptidic epitope, and saccharide

• Dan Yuan,
• Xuewen Du,
• Junfeng Shi,
• Ning Zhou,
• Abdulgader Ahmed Baoum,
• Khalid Omar Al Footy,
• Khadija Omar Badahdah and
• Bing Xu

Beilstein J. Org. Chem. 2015, 11, 1352–1359, doi:10.3762/bjoc.11.145

• designed the nucleopeptides 5 and 6. In addition, we substituted thymine with adenine to generate nucleopeptides 7 and 8 that contain adenine, the nucleobase is complementary of thymine. Synthesis The NA conjugates 5–8 were obtained according to a facile method of solid-phase peptide synthesis (SPPS) [17

• ]. The conjugates NAS were produced by a combination of SPPS and liquid phase synthesis. Scheme 2 shows a representative synthesis route of a NAS conjugate (1). We loaded the first amino acid, Fmoc-Val-OH, on 2-chlorotrityl chloride resin, then removed the Fmoc group with 20% piperidine in

• repeating the removal of the Fmoc group and sequential addition of Fmoc-Thr(t-Bu)-OH, Fmoc-Thr(t-Bu)-OH and thymine-1-acetic acid. For the final step of the SPPS, we used 2,2,2-trifluoroethanol/dichloromethane (TFE/DCM 2:8) to cleave the fully protected NA from the resin. For conjugates 5–8, we cleaved the

Synthesis and biological evaluation of a novel MUC1 glycopeptide conjugate vaccine candidate comprising a 4’-deoxy-4’-fluoro-Thomsen–Friedenreich epitope

• Manuel Johannes,
• Maximilian Reindl,
• Bastian Gerlitzki,
• Edgar Schmitt and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2015, 11, 155–161, doi:10.3762/bjoc.11.15

• ’-fluoro-TF SPPS building block 11 started by conversion of peracetylated D-glucose 1 into β-thio-glycoside 2 [45][46] under Lewis acid catalysis in 81% yield (Scheme 1). Subsequent Zemplén deacetylation [47], followed by 4,6-benzylidene acetal formation and acetylation provided fully protected precursor 3

• -threonine building block 7a [49] affording the desired ß-configured 4’-deoxy-4’-fluorodisaccharide 8 in 80% yield. Subsequent two-step protecting group manipulation and acidolysis of the tert-butyl ester finally provided the orthogonally protected 4’-fluoro-TF-SPPS-building block 11 in 85% yield over three

• enzymatic stability upon fluorination, glycosyl amino acid 11 was incorporated at position 6 of a full 20mer MUC1 tandem repeat domain by SPPS following a previously published procedure [44] (Scheme 2 and Supporting Information File 1). Thus, by using HBTU/HOBt/DIPEA in DMF for the coupling of the standard

Synthesis of novel conjugates of a saccharide, amino acids, nucleobase and the evaluation of their cell compatibility

• Dan Yuan,
• Xuewen Du,
• Junfeng Shi,
• Ning Zhou,
• Abdulgader Ahmed Baoum and
• Bing Xu

Beilstein J. Org. Chem. 2014, 10, 2406–2413, doi:10.3762/bjoc.10.250

• synthesis of a novel type of conjugate of three fundamental biological build blocks (i.e., saccharide, amino acids, and nucleobase) and their cell compatibility. The facile synthesis starts with the synthesis of nucleobase and saccharide derivatives, then uses solid-phase peptide synthesis (SPPS) to build

• . Synthesis Schemes 1–4 show the syntheses of the SAN conjugates formed by the reaction of the amino acid segment with the nucleobase and the saccharide derivative. The key steps include N-alkylation, acetylation, solid-phase peptide synthesis (SPPS) and N-hydroxysuccinimide (NHS)/N,N-diisopropylcarbodiimide

• (DIC)-catalyzed amidation reaction. As demonstrated by the example of the synthesis of 3, the use of reported methods [31][32][33][34][35] (Scheme 1) affords the nucleobase and saccharide derivatives 12, 16, and 19. We used SPPS [36] (Scheme 2) to synthesize the fully protected naphthAla-Phe-Arg-Gly

Convergent synthetic methodology for the construction of self-adjuvanting lipopeptide vaccines using a novel carbohydrate scaffold

• Vincent Fagan,
• Istvan Toth and
• Pavla Simerska

Beilstein J. Org. Chem. 2014, 10, 1741–1748, doi:10.3762/bjoc.10.181

• previously reported carbohydrate-based vaccine constructs [11] were prepared by a divergent approach, where the carbohydrate core was coupled to the resin-bound LCP adjuvanting moiety, followed by stepwise synthesis of the B cell epitopes using solid-phase peptide synthesis (SPPS). Using this divergent

• Discussion As part of the new convergent approach, here, we report an efficient and convenient synthesis of a versatile alkyne-functionalized carbohydrate building block 1, which can be conveniently incorporated into peptide sequences using SPPS (Scheme 1). The copper-catalyzed alkyne–azide cycloaddition

• , which were capable of opsonizing the GAS pathogen and inducing protective immunity against GAS [19]. In the current study, the J8 epitope was synthesized using standard Fmoc SPPS. Azidoacetic acid was synthesized according to Brabez et al. [34] and was coupled to the N-terminus of the J8 epitope. The

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

• . We here describe the assembly of MDP building blocks, suitable for automated solid phase peptide synthesis (SPPS), their use in the assembly of the four MDP-antigen conjugates 2–5 and the immunological evaluation of the constructs. Results and Discussion Synthesis of the conjugates The MDP-antigen

• conjugates 2–5 were prepared using an automated solid-phase peptide synthesis (SPPS) protocol. In all these syntheses commercially available Tentagel S RAM resin and amino acids were applied. The synthesis of the required MDP building blocks 10 and 16 is depicted in Scheme 1. The 3-azidopropanol spacer was

• with the reduction of the azide in compound 14 with PMe3 and subsequently the primary amine and Fmoc protected glutamic acid allyl ester were condensed under influence of HATU and DiPEA to give the orthogonally protected compound 15 in 57% yield. To make 15 suitable for SPPS, the allyl protective group

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

• their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS) offers a

• suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to

• application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies. Keywords

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

• Tatyana V. Abramova,
• Sergey S. Belov,
• Yulia V. Tarasenko and
• Vladimir N. Silnikov

Beilstein J. Org. Chem. 2014, 10, 1151–1158, doi:10.3762/bjoc.10.115

• efficient solid-phase-supported peptide synthesis (SPPS) of morpholinoglycine oligonucleotide (MorGly) mimics has been developed. The proposed strategy includes a novel specially designed labile linker group containing the oxalyl residue and the 2-aminomethylmorpholino nucleoside analogues as first subunits

• . Keywords: labile linker; morpholino oligomers; oligonucleotide mimics; solid-phase-supported peptide synthesis (SPPS); Introduction The phosphorodiamidate morpholino oligomers (PMO) and peptide conjugated PMO (PPMO) are currently promising candidates for antisense therapy of a number of infectious and

• motivated us to develop the SPPS method for the synthesis of these oligonucleotide mimics. We focused our efforts on the development of a new linker group to produce oligomers without dangling residues (Figure 2C), the synthesis of the corresponding Thy-containing monomers and the improvement of the SPPS

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

• -Fmoc-protected building blocks potentially suitable for solid-phase peptide synthesis (SPPS). It is well established that O-acylated β-hydroxy-α-amino acids can be used in Fmoc-strategy peptide syntheses without migration of the acyl unit [37][38][39]. Based on these findings, we have desired to

• oxidant to provide (2S,3S)-3-hydroxyleucine derivative 38, a potential building block for SPPS and post-synthetic modification of the peptide, in 85% yield. In order to demonstrate the feasibility of the olefin cross metathesis approach for the late-stage diversification of the acyl side chain, acid 38

• then debenzylated under standard hydrogenation conditions with concomitant reduction of the double bond, thus leading to lipidated amino acid building block 41 suitable for SPPS in 75% yield for the final step. Conclusion In summary, we have developed a divergent approach for the synthesis of several

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• for carbohydrate and peptide chemistry. Therefore, sugar units are introduced by side-chain ligation and labeling strategies on the peptide scaffold or were established by incorporation of sugar-β-amino acids by solid-phase peptide synthesis (SPPS) [36][37]. Sugar amino acid building blocks have

• -Amino acids were used in SPPS in order to get a conformationally stable and well-defined β-peptide 14-helix. The helix propensity is further improved by incorporation of the constrained cyclic amino acid trans-(1R,2R)-2-aminocyclohexanecarboxylic acid (ACHC) [53]. β-Homolysine was used to assure the

• literature protocol [49]. Synthesis of β-glycopeptides 1–8 Fmoc-protected sugar β-amino acids 12a–d were found to be compatible with SPPS conditions. Therefore, the sugar units were introduced in the β-peptide like regular amino acids using a modified Fmoc SPPS protocol on mild acid sensitive Sieber amide

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• ]. This is an attractive concept, because it can be combined with solid-phase peptide synthesis (SPPS) [4][5], as well as with native chemical ligation (NCL) utilizing an S→N acyl shift [3][6][7][8][9][10]. In addition, glycocysteine derivatives can be easily converted into the corresponding dimers by

• oxidation of the intermediate free thiol in good yield. As O-acetylated building blocks are often advantageous over the OH-free analogues for SPPS [2][3][4], our next step was to apply the synthesis outlined in Scheme 1 to the O-acetylated glycoamino acid derivative 4 (Scheme 2). The O-acetylated

• primary Nα amino group, the in situ generated fulvene is quenched by the cysteine thiolate, leading to S-Fm-protected 8. Next, we have investigated different reaction conditions for the conversions of 7 and 9 with piperidine, which is the common base used in SPPS. Deprotection of the S-Fm-protected

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• . Peptide synthesis The peptides used were synthesized as described previously [30] by automated solid-phase peptide synthesis (SPPS) on a multiple Syro II peptide synthesizer (MultiSynTech, Witten, Germany) following Fmoc/t-Bu-strategy utilizing a double-coupling procedure and in situ activation with Oxyma

• with a 3% solution of hydrazine in DMF for 12 × 10 min. Subsequently, the peptide was elongated to its final length by automated SPPS. N-terminal coupling of Cym2 or 5(6)-carboxyfluorescein was carried out by using 2 equiv of the substance to be coupled and activation with 2 equiv of HATU/DIPEA in DMF

• -2,6-dioxocyclohex-1-ylidene)ethyl; SPPS: solid-phase peptide synthesis; TFA: trifluoroacetic acid; TIS: triisopropylsilane; HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DIPEA: diisopropylethylamine; TA: thioanisole; TC: p-thiocresol. Peptide sequences.a Analytical

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• , peptides containing monosaccharide-substituted allo-L- and D-threonine building blocks were assembled by solid-phase peptide synthesis (SPPS). The retro-inverso AFGP analogue contained all amino acids in D-configuration, while the allo-L-diastereomer was composed of L-amino acids, like native AFGPs, with

• the peptide by using the stepwise, microwave-enhanced SPPS. Additionally, the corresponding aglycons lacking the carbohydrate moiety were synthesized. The conformation of these synthetic peptides was examined by CD spectroscopic experiments and the antifreeze effect of the glycopeptides was tested in

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• functionalization by amide bond formation. To protect the lysine side chain for selective and orthogonal amide-bond formation following the solid-phase peptide synthesis (SPPS), the protection groups fluorenylmethoxycarbonyl (Fmoc) and carbobenzyloxy (Cbz) were applied. Alteration of the amine in the third β

• protection of the primary α-amino group. Therefore, tert-butyloxycarbonyl (Boc) protection was used to mask all α-amino groups during solid-phase synthesis of the tripeptide. Synthesis of the cyclo-β-peptide scaffold The Boc protected β-amino acid building blocks for SPPS of the cyclic β-tripeptide were

• -phase chemistry [8][9]. Purification by chromatography is required after each coupling step, and the final cyclization reaction often results in poor yields. Herein, an alternative approach is described based on SPPS followed by on-resin cyclization. Recently, Waldmann et al. discovered an on-resin head

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• Fmoc-SPPS followed by sequential NCL [51]. The N-glycopeptide fragment RNase 26–39 (17) was prepared with a thioester in the C-terminal and a thiazolidine protected cysteine at the N-terminus. The chemical ligation was performed by coupling of the N-glycopeptide thioester RNase 26–39 (17) and the