Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety

• Iteng Ng-Choi,
• Àngel Oliveras,
• Lidia Feliu and
• Marta Planas

Beilstein J. Org. Chem. 2019, 15, 761–768, doi:10.3762/bjoc.15.72

• steps were performed on the solid support. In this context, herein our aim was to extend our expertise in the formation of biaryl linkages to the solid-phase synthesis of biaryl bicyclic peptides. To the best of our knowledge, there is only one example on the preparation of this type of compounds on

• solid support, even though the final cyclization was performed in solution [24][25]. In contrast, in the present study we envisaged a synthetic strategy for the preparation of biaryl bicyclic peptides in which all the steps would be carried out on solid phase. It would benefit from the advantages

• intrinsic to the solid-supported chemistry, such as the avoidance of tedious work-up procedures, and the facile elimination by filtration of reagents and byproducts generated during the reactions. Therefore, this work would constitute the first synthetic approach on solid support of biaryl bicyclic peptides

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• part in Supporting Information File 1). However, in the synthesis of ON1 and ON2 the yield dropped to approximately 40% after the incorporation of the modified unit. The analysis of the crude product by LC–MS after cleavage from the solid support and deprotection, revealed the presence of 5

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

• ineffective, ii) possess low resin loading, iii) incompatible in medium to strongly acidic [30] or basic conditions employed for deprotection of coupled amino acids and iv) undergo premature cleavage of polypeptide chain from solid support resulting in moderate yield during deprotection of acid sensitive side

Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• molecular electronic materials and optoelectronic devices. 4.3. TTF-Based rotaxanes on solid support If one aims at creating macroscopic effects, the concerted action of many molecular machines is needed. It is then useful to deposit switchable AMMs on interfaces such as a surface of a solid support [87][88

• written data could be read out even after waiting for 12 h. Besides data storage, a substantial challenge of AMMs is the transfer of molecular motion into a useful macroscopic output. An example of rotaxanes on a solid support which could achieve this is shown in Figure 19 [96]. The [3]rotaxane 21

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• through amide bond (this can be carried out on a solid support, prior to the cleavage of the peptide from the resin). In the conjugates used as reference compounds, Dox was coupled to the Lys in position 8 of GnRH-III through glutaric acid linked via an ester bond (O-glut) (1) (similarly to AN-152) or an

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• oligonucleotide analogues was performed on solid support using H-phosphonate chemistry (Scheme 1). Thus, solid phase-linked thymidine 12 was coupled with 5'-dimethoxytrityl-(DMTr)-protected thymidine 3'-H-phosphonate 13 to give dimeric H-phosphonate 14, which was then acidically DMTr-deprotected to furnish 15

• . After the desired number of such coupling-deprotection cycles, the phosphite-linked oligo-thymidine 16 was transformed in an oxidative amidation reaction [42] in the presence of iodine and N,N,N'-trimethylethylenediamine (17) to yield, after basic cleavage from the solid support, the envisioned

• , which was then acidically cleaved from the solid support and reductively Troc-deprotected to afford octameric thymidinyl DNG 29. Based on this method, the solid phase-supported synthesis operating in the 3'→5' direction was later developed. As described by Bruice and co-workers, it was compatible with

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

• test whether the FPID/(4-MeOC6H4)3P system can be used in SPPS. We selected the commercially available 2-chlorotrityl chloride resin (2-Cl-Trt-Cl resin) as the solid support and [(9-fluorenylmethyl)oxy]carbonyl (Fmoc) as the α-amino protecting group. The peptides were synthesized following the route as

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

• protecting group was achieved by using 2% TFA in DCM for 6 × 4 min. The coupling of the isopropylidene protected aminooxyacetic acid [17] to the N-terminus of the linker sequence was carried out by using standard protocol DIC/HOBt coupling. The cleavage from the solid support was performed at rt in a

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

• Katharina Hiebler,
• Georg J. Lichtenegger,
• Manuel C. Maier,
• Eun Sung Park,
• Renie Gonzales-Groom,
• Bernard P. Binks and
• Heidrun Gruber-Woelfler

Beilstein J. Org. Chem. 2018, 14, 648–658, doi:10.3762/bjoc.14.52

• economical aspects [13]. One possibility to prepare heterogeneous transition metal catalysts is to immobilise palladium directly on a solid support such as activated carbon [14], zeolites [15], modified silica [16][17][18] or molecular sieves [19] to name but a few. Another option is the complexation of

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• features. Copying on solid support As mentioned above, one option to avoid stalling of primer extension reactions is to perform them on solid support. For RNA, the immobilization of the primer–template duplex was achieved by employing a biotinylated capture strand that was bound to streptavidin-coated

• immobilized RNA duplex, as reported by Deck et al. [32]. Extension cycle of aminoterminal primer with N-protected nucleotides on solid support, as described by Kaiser et al. [47]. Formation of a highly reactive methylimidazolium bisphosphate from methylimidazolides of nucleotides. 31P NMR spectrum (161.9 MHz

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• ). These results suggest that 2’-O-MDTM siRNAs fulfill some features of typical prodrug-type siRNAs. Similarly, our group has developed a post-synthetic method on a solid support to introduce various disulfide bond-containing groups at the 2’-OH of RNAs [15]. Using this versatile method, one precursor, 2

• is incompatible with the standard deprotection treatment under basic conditions (generally aqueous ammonia) used to cleave other common base-labile acyl protection groups from nucleobases and release ON from the solid support. Furthermore, as the aqueous solubility of fully modified SATE

• partially 2’-O-masked with PivOM groups were synthesized via a solid-phase method involving silyl-based protections on amino functions of the nucleobases combined to CNE on phosphates and Q-linker between pro-RNA and the solid support [48]. One of them with five PivOM groups at the 5’-end was active in a

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• account that the 3'-start nucleoside is required to be linked to the solid phase in a way that allows the cleavage of the trimer from the solid support, but leaves all other protecting groups intact. Therefore, the routinely used succinate linkage for immobilization of the start nucleotide cannot be used

• this strategy the large scale synthesis (5 g) of 3'-unprotected trinucleotides proceeded with a total 75–90% yield [20]. Other strategies with potential for the solid-phase synthesis of protected trinucleotides might rely on a universal solid support, from which oligomers with free 3'-OH function are

• dimers and extension to the trimer in either 5'- or 3'-direction. Removal of the 3'-O-protecting group under conditions that leave all other protecting groups at 5'-OH, nucleobases and internucleotide phosphates intact. Release of trinucleotide blocks from the solid support by cleavage of an oxalyl

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• following standard surface-hybridization protocols. The use of the solid support assay format also allows detection of DNA directly from the fluorescence signal of the CPP bound to the solid support without requiring labeling on the PNA probe [126]. Polystyrene microbeads self-assembled on patterned silicon

• chips have been used as the solid support for the PNA–CPP based DNA assay. Using this assay format, a combination of long-wavelength emissive CPP and PNA allowed detection of as low as 150 attomol of unlabeled DNA, or 300 copies (0.5 zeptomol) of Cy5-labeled DNA targets by confocal microscopy [127]. A

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• available purity and used as such. A detailed synthetic strategy for Fmoc-TfIle-OH is described in literature [44]. For the synthesis of Fmoc-HfLeu-OH see Supporting Information File 1. Peptide synthesis, purification and characterization Peptides were synthesized manually in a 0.05 mmol scale on a solid

• support by means of an Fmoc/tert-butyl protecting group strategy on a preloaded Fmoc-Lys(Boc)Wang resin (0.57 mmol/g loading) using 10 mL polypropylene reactors. HfLeu containing peptides were synthesized with an Activo-P11 automated peptide synthesizer (Activotec, Cambridge, United Kingdom). Couplings of

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• hydrolytically less stable than other purine nucleosides. Under basic conditions which are commonly used for RNA deprotection and cleavage from the solid support, opening of the imidazole ring of the 7-methylguanine would occur [111]. Thus, for synthesis of the cap structure on the solid support, standard

• ′-phosphorylated trimer synthesized by standard phosphoramidite chemistry. To address the problem of m7G instability under basic conditions, the TMG-capping reaction was carried out upon deprotection of all base-labile groups. Utilization of a novel, acid labile linker to the solid support allowed for subsequent

• multistep preparation of the triphosphate bridge, the Sekine group presented a synthetic route to RNA bearing a 5′-terminal TMG-capped pyrophosphate linkage on solid support. Since pyrophosphate formation is easier than triphosphate formation, this route resulted in higher coupling yields. Whether this RNA

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

• Abstract While presenting particularly interesting advantages, peptide synthesis by ball-milling was never compared to the two traditional strategies, namely peptide syntheses in solution and on solid support (solid-phase peptide synthesis, SPPS). In this study, the challenging VVIA tetrapeptide was

• synthesized by ball-milling, in solution, and on solid support. The three strategies were then compared in terms of yield, purity, reaction time and environmental impact. The results obtained enabled to draw some strengths and weaknesses of each strategy, and to foresee what will have to be implemented to

• research laboratories and for industrial production: synthesis in solution and synthesis on a solid support (also known as solid-phase peptide synthesis, SPPS). Indeed, liquid reaction mixtures enable efficient agitation when using a conventional batch reactor equipped with either magnetic stirring bar or

1,3-Dibromo-5,5-dimethylhydantoin as promoter for glycosylations using thioglycosides

• Fei-Fei Xu,
• Claney L. Pereira and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2017, 13, 1994–1998, doi:10.3762/bjoc.13.195

• oligosaccharides [20][47]. Ideally, stable and non-toxic reagents should be used on such instruments. The automated synthesis of disaccharide 16 served to assess the suitability of the DBDMH/TMSOTf activation system using functionalized resin 15 [48] as solid support (Scheme 1). After two coupling cycles with

Encaging palladium(0) in layered double hydroxide: A sustainable catalyst for solvent-free and ligand-free Heck reaction in a ball mill

• Wei Shi,
• Jingbo Yu,
• Zhijiang Jiang,
• Qiaoling Shao and
• Weike Su

Beilstein J. Org. Chem. 2017, 13, 1661–1668, doi:10.3762/bjoc.13.160

• . Thus, Pd catalysts anchored on heterogeneous solid support materials such as MCM-41 [29], alumina [30], silica [31], carbon nanotubes [32], microporous polymers [33], SBA-15 [34], or some dendrimers [35] were preferred to develop a ligandless and recyclable catalyst system. However, to the best of our

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

• fragment to give the desired product 1 (Scheme 1). For the synthesis of the cyclodepsipeptide portion, a convergent route was envisaged in which the complete GHPD side chain should be attached in solution after assembly of the cyclodepsipeptide on solid support. The hitherto only published synthesis of a

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• Harri Lonnberg Department of Chemistry, University of Turku, FIN-20014 Turku, Finland 10.3762/bjoc.13.134 Abstract Oligonucleotides are usually prepared in lab scale on a solid support with the aid of a fully automated synthesizer. Scaling up of the equipment has allowed industrial synthesis up

• . While P(III)-based phosphoramidite and H-phosphonate chemistries are almost exclusively used on a solid support, the “outdated” P(V)-based phosphotriester chemistry still offers one major advantage for the synthesis on a soluble support; the omission of the oxidation step simplifies the coupling cycle

• blocks, (ii) the scale up procedure would be more straightforward and (iii) expensive solid support material is not needed. In addition, the possibility to characterize the growing chain by mass or NMR spectroscopy after each coupling is an attractive feature, although not possible with all soluble

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

Towards open-ended evolution in self-replicating molecular systems

• Herman Duim and
• Sijbren Otto

Beilstein J. Org. Chem. 2017, 13, 1189–1203, doi:10.3762/bjoc.13.118

• instead of parabolic growth of the replicators. A successful approach to overcoming product inhibition involves the immobilization of the template molecules by fixing them onto a solid support. This approach was partially inspired by the notion that surfaces of minerals might have played a major role in

• , depicted in Figure 5, an oligonucleotide template strand is immobilized via an irreversible interaction with a solid support. A complementary strand is then produced via the template-directed binding of free nucleotides from the solution. The copied strand is released from the template and is in turn

• itself immobilized on a solid support, thereby preventing product inhibition via the formation of stable template dimers. As von Kiedrowski and coworkers rightfully notice, this system allows for evolutionary processes to take place. Moreover, such immobilized systems are proposed to be even capable of

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• the saccharide. Finally, these results represent a solid support for the design of new and more effective nanoparticles based systems. A different approach towards the development of a synthetic HIV vaccine candidate based on GAuNPs, exploit the glyco-nanosystem as a tool which modulate and control

DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support

• Johnny N. Naoum,
• Koushik Chandra,
• Dorit Shemesh,
• R. Benny Gerber,
• Chaim Gilon and
• Mattan Hurevich

Beilstein J. Org. Chem. 2017, 13, 806–816, doi:10.3762/bjoc.13.81

• 10.3762/bjoc.13.81 Abstract Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of

• Scanlan adjusted the o-NBS strategy to solid-phase synthesis and introduced a general three-step procedure for Nα-mono-methylation of amino acids on solid support that was based on the work of Fukuyama [17][22][23]. Kessler and co-workers presented a time saving and cost effective three-step N-methylation

• procedure on solid support [3][24][25]. These improvements enabled, for the first time, the synthesis of a combinatorial library of all possible N-methylated analogues of a given sequence [26]. These strategies have been used over two decades as standard procedures for N-methylations of linear and cyclic

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• acylnitroso moieties. The reactivity of dienes has also been studied for the reaction with acyl- [78] and arylnitroso dienophiles [42] that are bound to a solid support. In general, cyclic dienes were more reactive than their acyclic counterparts, and dienes with electron-donating substituents, such as α

• regioselectivity of carbamoylbenzyl 1,2-oxazines prepared from diene 89 and benzyl nitrosoformate (96) in solution (derivative 97) [100] and 4-substituted benzyl nitrosoformates on a solid support (derivatives 91–95) [78]. It is obvious that although the substitution on benzyl nitrosoformate is quite distant from

• the site of the 1,2-oxazine formation, it influences the regioselectivity of the reaction. Therefore, the comparison of reactions performed in solution and on a solid support is impossible. It is important to note that in the solid as well as in the solution-phase reactions, the solvent was