Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• rt as described previously [20]. CF-polymers were cleaved by treatment with 20% piperidine for 45 min. The successful coupling was verified by a Kaiser test [43]. To cleave the peptides from the resin, a mixture of triisopropylsilane (TIS), H2O and concentrated trifluoroacetic acid (TFA) (1:1:38 v/v

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• and A succeeded as previously described in the literature; unit A (15) and C–D (16) were connected by Yamaguchi esterification to give 17 (Scheme 2) [45]. Then, Fmoc was cleaved from the N-terminus of unit C–D–A (17) using piperidine and the resulting crude amine was coupled to the corresponding

• , 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 °C, 3 h; (b) 1) piperidine, DMF, rt, 2 h; 2) 13 or 14, HOAt, EDC·HCl, Et3N, CH2Cl2, 0 °C → rt, overnight; (c) 1) TFA/CH2Cl2/H2O, rt, 2 h; 2) HATU, HOAt, DIPEA, DMF, rt, slow addition + 2 h; (d) 1) (CH3O)3CH, PPTS, CH2Cl2, rt, 2 h; 2) AcBr, CH2Cl2, rt, 4 h; 3

Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations

• Koichi Mitsudo,
• Junya Yamamoto,
• Tomoya Akagi,
• Atsuhiro Yamashita,
• Masahiro Haisa,
• Kazuki Yoshioka,
• Hiroki Mandai,
• Koji Ueoka,
• Christian Hempel,
• Jun-ichi Yoshida and
• Seiji Suga

Beilstein J. Org. Chem. 2018, 14, 1192–1202, doi:10.3762/bjoc.14.100

• reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be

• consistent with the Steven’s hypothesis. Keywords: cation pool; conformation; electroorganic synthesis; N-acyliminium ion; NMR analysis; piperidine; Introduction Cyclic amines are significant key motifs in pharmaceutical and natural products because a variety of compounds bearing those moieties exhibit

• give the disubstituted piperidine derivatives in an excellent diastereoselective manner (Scheme 1). This result inspired us to investigate the stereochemistry of the N-acyliminium ions by means of NMR spectroscopy, which is challenging to achieve without using cation pool methods. The current report

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

• shown in Scheme 2. The C-terminal amino acid was immobilized onto the 2-Cl-Trt-Cl resin in the presence of 3.0 equiv of DIPEA in DCM/DMF (v:v 1:1). Subsequent peptide chain elongation was completed via Fmoc-SPPS protocol, which includes deprotection with 20% piperidine/DMF and peptide coupling with 3.0

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

• GmbH, Marktredwitz, Germany) were used for the synthesis except Fmoc-Lys(Mtt)-OH that was applied for the development of branching in the peptide. The protocol of the SPPS was similarly as described in [17] as follows: (i) DMF washing (4 × 0.5 min), (ii) Fmoc deprotection with 2% DBU, 2% piperidine

• (Biolegend, San Diego CA). Samples were detected and analyzed by using an Attitude® Acoustic Focusing Cytometer (ThermoFischer Scientific). Schematic synthesis of cyclic KNGRE (A) and XNGRE (B) drug conjugates. a) Mtt-cleavage: 2% TFA/DCM; b) Fmoc-Aaa(X)-OH coupling; c) Fmoc-cleavage 2% piperidine/2% DBU/DMF

Anodic oxidation of bisamides from diaminoalkanes by constant current electrolysis

• Tatiana Golub and
• James Y. Becker

Beilstein J. Org. Chem. 2018, 14, 861–868, doi:10.3762/bjoc.14.72

• group attached to the N atom in various piperidine derivatives (Scheme 6) on the anodic oxidation of 'cyclic amides' was explored in methanol under different experimental conditions [17]. The results indicate that this type of amides mostly undergo mono- and dimethoxylation at the α and α'-positions to

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• amines experience only a modest change [67]. Accordingly, general acid/base catalysis may be studied with amine buffers at much lower hydroxide ion concentrations than in water. This technique was first applied by the group of Yatsimirsky to cleavage of a HPNP [38]. In 0.1 mol L−1 piperidine buffer, for

• attack of the 2´-OH. The situation seems, however, to be rather different with dinucleoside-3´,5´-monophosphates. The buffer-catalyzed reaction of UpU is not so much faster than the buffer-independent reaction, in 0.1 mol L−1 piperidine buffer only 4-fold faster [68]. No second-order dependence of rate

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• -hydroxybenzotriazole hydrate (HOBt), N,N’-diisopropylcarbodiimide (DIC), triisopropylsilane (TIS), piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), trifluoroacetic acid (TFA), diisopropylethylamine (DIPEA), acetic anhydride (Ac2O), methanol (MeOH), n-butyric anhydride and solvent for HPLC (acetonitrile (ACN

• )-OH, Fmoc-His(Trt)-OH and Fmoc-Ser(t-Bu)-OH. Pyroglutamic acid (Glp or piperidine, 2% DBU in DMF (4 times; 2 + 2 + 5 + 10 min

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• -aminopyrazole 16, arylaldehyde 47, and 2H-thiopyran-3,5(4H,6H)-dione (79) in glacial acetic acid in presence of ammonium acetate (Scheme 20). The multicomponent reaction of 5-amino-3-hydroxypyrazoles 82, substituted salicylic aldehydes 83 and acetylacetic ester 81 in acetic acid with few drops of piperidine was

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

• the Fmoc deprotection of the fluorinated amino acids, free N-termini were capped by adding a mixture of acetic anhydride (Ac2O, 10% (v/v)) and N,N-diisopropylethylamine (DIPEA, 10% (v/v)) in DMF (3 × 10 min). Fmoc deprotection was achieved by treatment with 20% (v/v) piperidine in DMF (3 × 10 min

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• allowing access to various β-trifluoromethyl ketones 24 featuring aryl, alkyl, functionalised alkyl, alkenyl, acetal, silylated alcohol, pyran, and piperidine functionalities (R group in 24). Mechanistic studies by 19F NMR allowed to identify CF3 complexes of copper(I) and copper(III) and the predominance

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• the nucleophilic agents used in these reactions were usually prepared by reaction of sodium hydride or sodium ethoxide with a proper nucleophile, such as diethylamine, piperidine, pyrrole, ethanol, p-toluenesulfonamide, thiophenol and others. Depending on the reactants used, Z- or E-stereoisomers of

One-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates using Togni’s reagent

• Azim Ziyaei Halimehjani,
• Martin Dračínský and
• Petr Beier

Beilstein J. Org. Chem. 2017, 13, 2502–2508, doi:10.3762/bjoc.13.247

• afforded the corresponding isothiocyanate in high yield. A variable temperature NMR study revealed a rotational barrier of 14.6, 18.8, and 15.9 kcal/mol for the C–N bond in the dithiocarbamate moiety of piperidine, pyrrolidine, and diethylamine adducts, respectively. In addition, the calculated barriers of

• Discussion We started our investigation with a one-pot, three-component reaction of piperidine, CS2, and a cyclic hypervalent iodane (Togni's reagent I) as a model reaction to find the optimal reaction conditions for the preparation of S-trifluoromethyl dithiocarbamates (Table 1). In the first run, we

• observed that the reaction of piperidine (1 equiv) with CS2 (2 equiv) in THF for 10 min followed by the addition of Togni's reagent I (1 equiv) and stirring for 2 hours at room temperature afforded the corresponding trifluoromethyl dithiocarbamate 4a in 25% isolated yield and the corresponding thiuram

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• . Consequently it was not removed prior to the rearrangement experiments. Treatment of 11i and 11k with the mild base piperidine led to the formation of α,β-unsaturated sulfinylimines 12i and 12k. The structures of the rearranged products were proven unequivocally by 1H and 13C NMR spectroscopy and X-ray crystal

• turned brightly yellow when treated with bases like piperidine. The X-ray crystal structures of 11i and 12i confirm unequivocally the structure of the products and thus the postulated two-step rearrangement. Both, the rearrangement of the alkyne to the allene and the subsequent tautomerism to the α,β

• /piperidine (3:1), rt, 2 h. (b) (COCl)2, DMSO, NEt3, −78 °C, DCM. (c) (R)-tert-Butyl sulfinamide ((R)-1), CuSO4, DCM, rt, 3 d (see GP-2). (d) iPrMgBr, THF, −38 °C, AlMe3 in n-hexane (4a, 13%, dr 99:1). (e) MeLi in Et2O, toluene, −30 °C, AlMe3 in n-hexane (4b, 4%, dr 52:48). (f) MeMgBr in Et2O, toluene, −35 °C

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

• piperidine-2,5-dione scaffold might prove more tractable in the future, but this has not yet been investigated in our laboratories. Since the first two approaches to target 6 (Scheme 1 and Scheme 2) were unsuccessful, we reasoned that a better-precedented synthetic method was needed. O’Hagan and co-workers

Curcuminoid–BF₂ complexes: Synthesis, fluorescence and optimization of BF₂ group cleavage

• Henning Weiss,
• Jeannine Reichel,
• Helmar Görls,
• Kilian Rolf Anton Schneider,
• Mathias Micheel,
• Michael Pröhl,
• Michael Gottschaldt,
• Benjamin Dietzek and
• Wolfgang Weigand

Beilstein J. Org. Chem. 2017, 13, 2264–2272, doi:10.3762/bjoc.13.223

• ]. Boric acid esters like tri-n-butyl borate are normally used to scavenge water being produced during the reaction, while piperidine [9] and n-butylamine [10][11] are typical bases used as catalysts for this type of reaction (Scheme 1). Although working well with vanillin and similar derivatives, the

Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly

• Weizhun Yang,
• Bo Yang,
• Sherif Ramadan and
• Xuefei Huang

Beilstein J. Org. Chem. 2017, 13, 2094–2114, doi:10.3762/bjoc.13.207

• /AgOTf [18], N-iodosuccinimide (NIS)/TMSOTf [18], dimethyl(methylthio)sulfonium triflate (DMTST) [18], 1-(benzenesulfinyl)piperidine (BSP)/Tf2O [18][19][49], S-(4-methoxyphenyl)benzene-thiosulfinate (MBPT)/Tf2O [50], Ph2SO/Tf2O [36][51], O,O-dimethylthiophosphonosulfenyl bromide (DMTPSB)/AgOTf [52], and

• , then Tf2O, 46, −60 °C to 0 °C. Effects of anomeric leaving groups on glycosylation outcomes. Reagents and conditions: (a) Ph2SO, Tf2O, TTBP, CH2Cl2, −40 °C; then acceptor, −40 °C to rt, (b) 1-(benzenesulfinyl)piperidine, Tf2O, CH2Cl2, −60 °C, then acceptor, (c) 10% trifluoroacetic acid in Ac2O, 0 °C to

• rt, then 6% piperidine in THF. Reactivity-based one-pot chemoselective glycosylation. Preactivation-based iterative glycosylation of thioglycosides. BSP/Tf2O promoted synthesis of 75. Proposed mechanism for preactivation-based glycosylation strategy. The more electron-rich glycosyl donor 91 gave a

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

• amounts of organic solvents (DMF, NMP, 1,4-dioxane, DCM), coupling agents (uroniums, phosphoniums, carbodiimides and auxiliary nucleophiles) and bases (Et3N, DIPEA, piperidine) are required for their synthesis and purification [4][7]. Unfortunately, these chemicals present highly undesirable safety

• of Fmoc-V-OH with H-IA-resin and for the deprotection of Fmoc-IA-resin that were performed during 90 min at room temperature, the coupling steps were performed at 70 °C for 7 min under microwave irradiation. The deprotection steps were carried out with piperidine/DMF 1:4 for 3 min at 70 °C. After the

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• -type amine–isothiocyanate coupling reaction (Scheme 4). In the case of secondary amines (piperidine, morpholine and thiomorpholine) and sterically hindered amines (2,4- and 2,6-dimethylanilines), ball milling again resulted in ≥99% yields in 10 minutes, except for the reactions involving 4

Synthesis and metal binding properties of N-alkylcarboxyspiropyrans

• Alexis Perry and
• Christina J. Kousseff

Beilstein J. Org. Chem. 2017, 13, 1542–1550, doi:10.3762/bjoc.13.154

• transformation proved relatively ineffective for alkylcarboxyindolium salts 3 and consequently, we applied alternative conditions using MEK and piperidine [27]. This two-step approach was used to synthesise a range of N-alkylcarboxyspiropyrans derived from bromoalkanoic acids of varying chain length in two-step

1-Imidoalkylphosphonium salts with modulated C_α–P⁺ bond strength: synthesis and application as new active α-imidoalkylating agents

• Jakub Adamek,
• Roman Mazurkiewicz,
• Anna Węgrzyk and
• Karol Erfurt

Beilstein J. Org. Chem. 2017, 13, 1446–1455, doi:10.3762/bjoc.13.142

• 6 (3.0 mmol) and silica gel-supported piperidine (SiO2-Pip; 200 mg, 0.22 mmol) were added. The electrolysis was carried out under stirring at a current density of 0.3 A/dm2 at 0 °C until a 2.7–3.75 F/mol charge had passed. Solid SiO2-Pip was filtered off, methanol was evaporated under reduced

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

• , 12 h, quant.; b) Fmoc-OSu, NaHCO3, 1,4-dioxane, H2O, 0 °C to rt, 87%; c) 1: O3, DCM, –78 °C, 2: Zn, HOAc, –78 °C to 10 °C, 66%; d) allylmagnesium chloride, 15, Et2O, –78 °C, 84%, 94% ee; e) MOMCl, DIPEA, DCM 0 °C to rt; f) piperidine, DCM, rt; g) 14, NEt3, DCM, 49% (over 3 steps); h) 1: O3, DCM, –78

Effect of the ortho-hydroxy group of salicylaldehyde in the A³ coupling reaction: A metal-catalyst-free synthesis of propargylamine

• Sujit Ghosh,
• Kinkar Biswas,
• Suchandra Bhattacharya,
• Pranab Ghosh and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 552–557, doi:10.3762/bjoc.13.53

• component (Figure 1). Changing the phenylacetylene to other substituted arylacetylenes like p-tolylacetylene, o-bromophenylacetylene, p-bromophenylacetylene or switching from morpholine to other amines like piperidine, 4-benzylpiperidine and pyrrolidine also react smoothly to afford the corresponding

• 80–90 °C (Figure 1, 3k–p). Varying the secondary amine component with 4-benzylpiperidine, piperidine also worked efficiently to produce the corresponding propargylamine derivatives (3q–t). All products were characterized by FTIR, 1H and 13C NMR spectral data. Scaling up the reaction to gram-scale

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• Knoevenagel olefinations, followed by a Nazarov cyclization using FeCl3 or AlCl3. The 2-phosphorylated chalcones (Z)-145 and non-phosphorylated ones (E)-146 could be obtained from the same substrates, β-ketophosphonates 143 and aromatic aldehydes 144 depending on the reaction conditions used (piperidine

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• ). For this reaction, self-optimisation is important as multiple products were identified that could form in parallel; from 1 the possible products we expected to see were a mixture of piperidine (2a), N-methylpiperidine (2b), N- and O-methylated 1, as well as oligomers. We chose to target 2b only for

• several different alcohols by flowing a starting mixture of 1 with the alcohol as the solvent (Table 2, entries 2–4). As might be expected, the cyclisation to N-alkylated piperidines was observed for the primary alcohols. The yield of the corresponding N-alkylated piperidine falls as the longer chain

• alcohols are reacted. When the secondary alcohol isopropanol was used as the solvent, no N-alkylation was observed and piperidine 2a was found as the major product. As this catalyst system has been used previously for the etherification of alcohols [31][32][33][34][35][36][37][38], it is possible that