Synthesis of acylglycerol derivatives by mechanochemistry

• Karen J. Ardila-Fierro,
• Andrij Pich,
• Marc Spehr,
• José G. Hernández and
• Carsten Bolm

Beilstein J. Org. Chem. 2019, 15, 811–817, doi:10.3762/bjoc.15.78

• the mechanosynthesis of DAGs 5 was established, we turned our efforts towards the conjugation of DAG 5a with 7-hydroxycoumarin (9) (Scheme 5). Initially, removal of the TBDMS protecting group of 5a was attempted by milling. However, reacting DAG 5a with a mixture of BF3·CH3CN and silica gel followed

• through acyl migration of 6a under the basic milling conditions. Subsequently, the reaction mixture containing 8a and 8a’ was milled with 7-hydroxycoumarin (9) and triethylamine to achieve the conjugation of the DAGs 8 in 53% yield after two steps (Scheme 5c). A mixture of 10a and 10a’ (10a/10a’ 72:28

• ) was separated from the unreacted starting materials, and analyzed by UV–vis spectroscopy (Figure 3). Comparison of the UV–vis spectra of 6a and 10a/10a’ showed the successful conjugation of the DAG with the coumarin moiety [47]. Conclusion The implementation of ball milling techniques has provided the

Catalyst-free assembly of giant tris(heteroaryl)methanes: synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts

• Rodrigo Abonia,
• Luisa F. Gutiérrez,
• Braulio Insuasty,
• Jairo Quiroga,
• Kenneth K. Laali,
• Chunqing Zhao,
• Gabriela L. Borosky,
• Samantha M. Horwitz and
• Scott D. Bunge

Beilstein J. Org. Chem. 2019, 15, 642–654, doi:10.3762/bjoc.15.60

• despite significant steric crowding. Steric congestion restricts the conjugation of the carbocationic center with the aromatic/heteroaromatic substituents, as evidenced by the bond length shortenings from only 0.052 Å to 0.111 Å observed upon hydride abstraction. The optimized geometries confirm the

Design and synthesis of multivalent α-1,2-trimannose-linked bioerodible microparticles for applications in immune response studies of Leishmania major infection

• Chelsea L. Rintelmann,
• Tara Grinnage-Pulley,
• Kathleen Ross,
• Daniel E. K. Kabotso,
• Angela Toepp,
• Anne Cowell,
• Christine Petersen,
• Balaji Narasimhan and
• Nicola Pohl

Beilstein J. Org. Chem. 2019, 15, 623–632, doi:10.3762/bjoc.15.58

• recognition. To allow for both surface functionalization of this glycan to the bioerodible microparticles and conjugation of the fluorophore, two amine handles would be necessary (Figure 3). The design would also benefit from the development of a more efficient synthesis of the mannose oligomer sidechain

• used alkene fluorous tag [11][52][53]. The CbzF tag was also removed during global deprotection to readily provide an amine handle for conjugation to the dendrimeric core, avoiding further synthetic manipulations. Synthesis of glycodendrimer Attachment of the 5(6)-TAMRA fluorophore to the dendrimeric

• mechanisms of L. major immune suppression and evasion. The fluorescent-tagged pathogen-associated oligosaccharide probe was synthesized through orthogonal conjugation for ease of attachment to bioerodible microparticles. The PAMP carbohydrate 16 was further synthesized through iterative glycosylation and

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• access to a variety of structural types. On the contrary, when di(poly)functionalized substrates display conjugation between the reactive FGs, selectivity may arise. When the initial MCR adduct is less reactive than the starting material, a sequential procedure may lead to the following transformation

Convergent synthesis of the pentasaccharide repeating unit of the biofilms produced by Klebsiella pneumoniae

• Arin Gucchait,
• Angana Ghosh and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2019, 15, 431–436, doi:10.3762/bjoc.15.37

• contrast to the natural version. The synthesized molecules can be linked with appropriate functionalities for their conjugation with a protein for the preparation of glycoconjugates. Recently, Cescutti et al. [11] reported the structure of a pentasaccharide composed of D-glucose, D-mannose and D-glucuronic

• pentasaccharide may provide ready availability of an amino functionality to expedite the conjugation of the pentasaccharide with an appropriate protein without affecting the sugar rings in the molecule [12][13]. Results and Discussion The target pentasaccharide as its 2-aminoethyl glycoside 1 was synthesized

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• substituent at C1. Whereas conjugation with the phenyl group (R = Ph) provides the driving force for the base-promoted isomerization of 1-benzyl-3,3-difluorocyclopropene (A’, R = Ph) into the corresponding benzylidene(gem-difluoro-cyclopropane) (B’) [18], methylene(gem-difluorocyclopropane) (B’’, R = H) is

• rearrangement of 10a occurred was attributed to the relief of ring strain but also to the favorable conjugation of the olefin with the two phenyl groups (R1 = R’1 = Ph). Alkylidenecyclopropane 11a could also be obtained in similar yields (92% or 87%, respectively) by heating acetate 10a in dichloromethane at

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• Pharmaceuticals GmbH, Leberstr. 20, A-1110 Vienna, Austria 10.3762/bjoc.15.11 Abstract Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY

• strongly hampered in its cytotoxic activity, and the peptide moiety ensures the target-specific toxin delivery toward the diseased cells, while omitting (most) healthy cells. To assess the impact of the chemical modifications due to the linker-assisted peptide–toxin conjugation and toxin liberation on the

• the target cells much lower toxicity than the cytotoxic compound tubugi-1 alone, thus opening a feasible therapeutic window for the class of tubugi toxins. In that context, a loss of tubugi-1 activity is expectable due to its chemical modification caused by the linker-based conjugation, and after

A simple and effective preparation of quercetin pentamethyl ether from quercetin

• Jin Tatsuzaki,
• Tomohiko Ohwada,
• Yuko Otani,
• Reiko Inagi and
• Tsutomu Ishikawa

Beilstein J. Org. Chem. 2018, 14, 3112–3121, doi:10.3762/bjoc.14.291

• by deprotonation of a single OH group of quercetin (2) were calculated. The deprotonation is an endothermic process in this calculation model. The most stable anion was derived from the OH group at 7 position (7-anion 2A), which is stabilized by the conjugation with the carbonyl group at 4 position

• reduced from that of the neural species (2B: −43.8°). In particular, 4'-anion 2B and 5-anion 2B are affected by conjugation between the chromenone moiety and the phenyl group (biaryl dihedral angle: −29.6° in 4'-anion 2B; −29.6° in 5-anion 2B). Change of proton affinity during the methylation reaction

1,8-Bis(dimethylamino)naphthyl-2-ketimines: Inside vs outside protonation

• A. S. Antonov,
• A. F. Pozharskii,
• P. M. Tolstoy,
• A. Filarowski and
• O. V. Khoroshilova

Beilstein J. Org. Chem. 2018, 14, 2940–2948, doi:10.3762/bjoc.14.273

• internitrogen space, even if other centres of basicity are present in the molecule. The only exceptions are compounds 2 and 3 which are protonated to aza- and carbonyl groups, respectively (Scheme 2) [6]. This unusual protonation site originates from the conjugation between the C=N (C=O) and the NMe2 groups

• substituent that is more basic than the peri-dimethylaminonaphthalene core. Such an imine basicity boost can originate from the fact that upon protonation, NMe2 groups lose conjugation with the ring whereas the C=N moiety does not. As a result, the imino nitrogen saves the electron density supply from both

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• investigated, including methylene (Ru-4), ethylene (Ru-5) to a propylene (Ru-6) spacers [56]. Thereby, it was aimed to locate the active center properly within the protein cavity. The challenge in the conjugation of the GH-type catalyst into narrow protein cavities is to overcome the space demand of the bulky

• NHC ligand. The conjugation was performed via maleimide-thiol “click” reaction under slightly basic (pH 7.5) conditions. Within the small cavity of NB4, only the GH-type catalyst Ru-6 with the longest spacer was able to undergo conjugation; however, the conjugational yield was very low (25%). Within

• the bigger cavity of NB11, all three catalysts Ru-4/5/6 were able to undergo conjugation, and gradually increasing conjugation yields by elongation of the spacer was observed (from 29% for Ru-4 up to 89% for Ru-6; Scheme 5) [56]. These artificial metalloproteins were purified and characterized by

Oxidative and reductive cyclization in stiff dithienylethenes

• Michael Kleinwächter,
• Ellen Teichmann,
• Lutz Grubert,
• Martin Herder and
• Stefan Hecht

Beilstein J. Org. Chem. 2018, 14, 2812–2821, doi:10.3762/bjoc.14.259

• approximation reflecting the HOMO–LUMO gap. The sole exception to this trend is the only derivative with an H-substituted double bond ethene-Me, which exhibit the expected behavior of a less facile oxidation of the Z-isomer due to its somewhat twisted π-system leading to less pronounced π-conjugation and

• -conjugation between both hemispheres. Similar to the model compound sDTE66-Me, all available sDTE66 derivatives as well as both Z-configured sDTE77 derivatives undergo electrocyclization upon oxidation. This also holds true for all cyclopentene-bridged DTE derivatives. However, in butene-Me the formation of

• the Z-isomers of sDTEs are able to undergo oxidative cyclization. In contrast, in the dianionic state formal cross-conjugation between the thiophene moieties and the central double bond persists and no rotation takes place. Thus, only the dianion of the Z-isomer undergoes cyclization while the

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• allyl-substituted substrates 13ab and 13bb underwent an isomerisation under the reaction conditions, with the double bond moving into conjugation with the amine to give inseparable mixtures of enamine-type products 14ab and 14bb. Given the likely hydrolytic instability of synthetic precursors possessing

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• may be an interesting candidate for siderophore conjugation. Results and Discussion Typically siderophore–antibiotic conjugates consist of a linker joining the siderophore and antibiotic components. As the target is membrane-associated NDH-2 we decided to functionalise our conjugate with a non

• due course. NDH-2 is a validated target for 1 with an MIC of 1.1 µg/mL against M. tuberculosis. Synthesis of phenothiazine-PEG-amine component. Synthesis of the azotochelin siderophore component. Final conjugation and deprotection to yield a phenothiazine siderophore conjugate. Supporting Information

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• facilitated the discovery of novel PqsD-targeting compounds through CuAAC-mediated conjugation of a fluorescent dye (Figure 9) [62]. Finally, Sangshetti et al. reported the discovery of linezolid-like Schiff bases, which showed promising anti-biofilm activity in the double-digit micromolar range [63]. Notably

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• targeted chemotherapy favor conjugation methods resulting in a better stability of a conjugate in systemic circulation as well as GnRH derivatives with high affinity for tumor’s GnRH-R and negligible endocrine activity [13][14]. The GnRH-III (Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2), a native variant

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• nucleobases are located outside of the macrocycle. The intensity of NOE’s for the CH2 groups decreased with increasing distance (Supporting Information File 1, Figures S21 and S35). As the triple bonds of the macrocycles 4 and 8 are in conjugation to the nucleobases they influence the UV spectra and affect

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• aromatic ring must lie in conjugation with the iminium double bond, making the orbitals of the ring orthogonal to the orbital in which the unpaired electron resides. The Xiao group have also published a method for making oxazoles using conditions that are very similar to those described above (Scheme 16

Functionalization of graphene: does the organic chemistry matter?

• Artur Kasprzak,
• Agnieszka Zuchowska and
• Magdalena Poplawska

Beilstein J. Org. Chem. 2018, 14, 2018–2026, doi:10.3762/bjoc.14.177

• carbodiimide-promoted reactions [13][14]. As presented in Figure 2, step a, the first step of a carbodiimide-type conjugation involves the generation of an O-acylisourea intermediate, which is highly electrophilic and which bears the urea-based good leaving group. Such activation of carboxyl groups onto a

• conjugation protocols do not uphold with the basic organic chemistry principles discussed above. Despite the interesting applications presented in these studies, important questions remain regarding the structure of the obtained materials. One common inaccuracy is a lack of the additives in the conjugation

• conjugation reaction, a tertiary amine (e.g., triethylamine) should be also included in the process. The tertiary amine’s role is to transform the amine hydrohalide into a free amine via the acid–base reaction. The free amine can then act as a strong nucleophile in the desired amidation process or can attack

Synthesis and characterization of π–extended “earring” subporphyrins

• Haiyan Guan,
• Mingbo Zhou,
• Bangshao Yin,
• Ling Xu and
• Jianxin Song

Beilstein J. Org. Chem. 2018, 14, 1956–1960, doi:10.3762/bjoc.14.170

• 1400 nm with several observable peaks. This remarkable absorption in the NIR region is comparable with that of the analogue “earring” porphyrins and reveals the π-conjugation between the subporphyrin and tripyrrin moiety. Conclusion In summary, we synthesized a π-extended “earring” subporphyrin from β

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• –Alder reaction [41][42][43][44], and hydrazone/oxime formation [45][46][47][48], have developed selective conjugation reactions under mild conditions. Although these bond-forming reactions have proven to be truly powerful approaches and will remain as first options to create novel bioconjugates

• the pure form, which could to be used for further reactions without column purification. With the optimized 5’-phosphitylation conditions in hand, we then investigated conjugation using the 5’-activated supported trinucleotide 2 as a model. As expected, unactivated nucleosides could be coupled to the

• activated 5’-terminus without difficulty (Scheme S2, Supporting Information File 1). Furthermore, to our delight, the conjugation was compatible with carboxylic acids that are potential nucleophiles for the activated 5’-terminus and can also induce side reactions of the phosphoramidite (Scheme 1). This

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• of nitriles, the strategy was also probed with aromatic nitriles 9 that were reacted with 8 under the same reaction conditions. The nucleophilicity of the N atom in aromatic nitriles should be lower than that of aliphatic ones owing to the conjugation of the triple bond with the benzene ring. To our

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• of the complex [38]. It should be noted that modifications of ligands to make the resulting complexes more lipophilic or the conjugation of a complex to a CPP do not provide any control on the way these complexes will be internalized by cells and prevent thus any targeting of malignant cells over

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• the shifts of the methylene protons α-situated vs the piperazine P-1 Nsp2 nitrogen involved in p→π LP(N)→π(C=N, s-triazine; C=O, amide) conjugation (3.78–3.91 ppm). To conclude, except the well-documented deshielding promoted by the magnetic anisotropy of π-delocalised systems, such as s-triazines and

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

• ]. These side effects can limit the applicability of these chemotherapeutic drugs. The conjugation of doxorubicin and daunorubicin to a GnRH-III-based targeting peptide could lead to decreased cardiotoxic effect through the more specific drug targeting. Drug delivery systems containing doxorubicin

• drug conjugates. Dox has three potential conjugation sites; i) a primary OH group at C-14 on the aglycone part, which is suitable for ester bond formation, ii) an oxo group at C-13 is available for the generation of an oxime linkage and iii) the amino group on the daunosamine sugar moiety, which can be

• showed no significant differences in the biological activity of Mtx isomers in conjugated form [24]. Fmoc-protected Dox was reacted with glutaric anhydride in DMF. The prepared Fmoc-Dox-14-O-hemiglutarate was used for conjugation using PyBOP in the presence of NMM, followed by the removal of Fmoc group