Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• showed higher lipophilicity, which can improve its pharmacokinetic properties. Altman and co-workers also studied a fluorinated mutant of the Leu-enkephaline [41]. The isostere Boc-Tyr-ψ[(Z)-CF=CH]-Gly (see Scheme 12) was coupled to a tripeptide to afford Boc-Tyr-ψ[(Z)-CF=CH]-Gly-Gly-Phe-Leu. Then, the

Electrophilic trifluoromethylselenolation of terminal alkynes with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate

• Clément Ghiazza,
• Anis Tlili and
• Thierry Billard

Beilstein J. Org. Chem. 2017, 13, 2626–2630, doi:10.3762/bjoc.13.260

• ][8][9][10][11][12][13][14][15]. In the objective to design new molecules with specific properties, novel fluorinated substituents have been developed, such as diverse trifluoromethylchalcogeno groups, due to their particular electronic properties [16] and, more especially, to their high lipophilicity

• [25][26][27][28][29][30][31][32][33] and drug design [34][35][36][37]. Furthermore, very recently, the Hansch lipophilicity parameter of CF3Se has been determined (πR = 1.29) – a high value lying between that of CF3O and CF3S [38]. Consequently, trifluoromethylselenolated molecules could represent

¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• natural compounds is a widely used approach in medicinal chemistry [1]. The increased lipophilicity of adamantane-containing compounds compared with non-adamantylated derivatives [2] leads to considerably higher solubility of these compounds in blood plasma and their easier penetration through cell

Synthesis and supramolecular properties of regioisomers of mononaphthylallyl derivatives of γ-cyclodextrin

• Markéta Bláhová,
• Sergey K. Filippov,
• Lubomír Kováčik,
• Jiří Horský,
• Simona Hybelbauerová,
• Zdenka Syrová,
• Tomáš Křížek and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2017, 13, 2509–2520, doi:10.3762/bjoc.13.248

• CDs are attractive building blocks for various types of supramolecular structures [6][7]. Necessary non-covalent interactions depend on the type and derivatization of CD, on lipophilicity, shape, and size of the guest molecule, and on conditions such as temperature, pH, or solvent used [8]. In

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

• fields of pharmaceuticals, agrochemicals, and materials sciences. The key properties such as metabolic and chemical stability, polarity, bioavailability, viscosity and lipophilicity can be altered in molecules containing the CF3 group in comparison with the nonfluorinated analogues. Numerous methods have

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• used to model the effects of fluorination on the lipophilicity, hydrolytic stability and on conformational properties. The conformational impact of the 2,2-difluoromethyl ester on several neutral and charged oligopeptides was also investigated. Our results demonstrate that partially fluorinated esters

• -mimicking models [39] did not support this suggestion. Though, this was reported later in a context of a hydrophobic core of model protein structures [40]. Furthermore, the influence of the fluorinated groups on lipophilicity remains uncertain, especially in biochemical literature. The impact of partially

• fluorinated alkyl groups on the polarity of small molecules was recently investigated in a series of model studies by Huchet and others [41][42][43][44]. These investigations demonstrated the checkmark-shape of the lipophilicity (logP) changes upon increasing the number of fluorine atoms in the terminal

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• found that halogenated compounds have an important role in therapeutic application increasing their lipophilicity, metabolic stability and improving interactions of protein–ligand complexes [36]. Taking into consideration the aforementioned, we have designed and synthesized 6-phenylquinoline derivatives

Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines

• Satoru Mori and
• Norio Shibata

Beilstein J. Org. Chem. 2017, 13, 2273–2296, doi:10.3762/bjoc.13.224

• phthalocyanines and subphthalocyanines are easy to handle, it is possible to obtain diverse derivatives and to fully demonstrate their functions. They are also expected to be developed into new material fields due to their high stability, high solubility and high lipophilicity. By combining the characteristics of

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• widely recognized as a general strategy toward drug development in pharmaceutical research. This is connected to fluorine's electronegativity, size, and lipophilicity [15][16], which can strongly improve the biological properties of molecules through, for instance, increase of metabolic stability and

Selective enzymatic esterification of lignin model compounds in the ball mill

• Ulla Weißbach,
• Saumya Dabral,
• Laure Konnert,
• Carsten Bolm and
• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1788–1795, doi:10.3762/bjoc.13.173

• lipophilicity, for instance through sulfation [18], silylation or esterification [19] of the aliphatic hydroxy and phenolic groups found in lignin. Chemical esterification of lignin [19][20][21] or its model compounds [22], using acetic anhydride in organic solvents such as DCM or pyridine have previously been

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• peptoids the side chain of the Cα is bound to the nitrogen atom. Due to the consequent lack of the polar N–H bonds, their lipophilicity is increased, which may result in improved membrane permeability [16][17]. Furthermore, peptoids have also found utility in supra- and macromolecular engineering [18] and

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• calculated (total polar surface area; TPSA) and measured (pKa, log P/D and Pe) parameters are shown in Table 1. The lipophilicity of neutral species of naringenin and dracocephins A and B are 3.39, 2.52 and 2.39, respectively. Similarly to this lipophilicity trend, the TPSA value of (±)-naringenin is lower

• -permeable compounds, respectively. These results are in good correlation with a lower lipophilicity (log P/D7.4) and higher TPSA of dracocephins A and B compared to that of naringenin. Pharmacological studies In connection with the BBB penetration studies, 2a–d and 3a–d were tested for their potential

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• Novel, functionalized piperazine derivatives were successfully synthesized and fully characterized by 1H/13C/19F NMR, MS, elemental analysis and lipophilicity. All piperazine compounds occur as conformers resulting from the partial amide double bond. Furthermore, a second conformational shape was

• development of new building blocks for specific and bioorthogonal labeling of biologically active compounds is of high importance. Depending on their size and composition, building blocks can influence (bio-)chemical parameters such as the lipophilicity (log P) affecting the solubility and the biological

• ], FBAM (log P = 2.7) [41], 4-fluorobenzaldehyde (log P = 1.9) [42] or the click labeling building block p-[18F]F-SA (log P = 1.7) [43], the lipophilicity of our 18F-building blocks is reduced. The hydrophilic character of the building blocks enables a radiolabeling in aqueous solutions and the influence

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• solution phase synthesis of heptakis(6-deoxy-6-S-alkyl)-β-CDs is typical for the syntheses of intermediates of such compounds, however, their high lipophilicity means that isolation is not a technically trivial task. Scale up of the 1-dodecanethiol mechanochemical reaction (synthesis of compound 6, entry

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• desired intermediates were to be highly lipophilic, derivatisable and easy to synthesise on both small and multigram scales. A scaffold of general type 1 (Figure 1) was chosen as a synthetic target that could be N-alkylated with bulky alkyl groups for increased lipophilicity. An iodo substituent in the

• to increase lipophilicity. However, because the methyl group appeared likely to be the cause for the lack of reactivity of 13 and 14 towards alkylation, a synthesis of the corresponding quinolin-2-one derived from 4-iodoaniline (17) was pursued in order to increase the ease of alkylation. The initial

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• therapeutical candidates because of their high lipophilicity and membrane permeability [44][51]. A major catalytic entry to α,α-disubstituted (quaternary) amino acids is the α-functionalization of an appropriate template as, for instance, an α-imino ester or lactone, followed by hydrolysis [49][52][53]; but

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• lipophilicity of the substituent. Yamashita et al. studied truncated muraymycin analogues lacking the lipophilic side chain as described in the section on synthetic access (compounds of type 7, 8 and 10) [76]. The activities measured in a soluble peptidoglycan assay indicated a stereochemical preference for the

• postulated that this lipophilic side chain may not be necessary for target inhibition, but for cellular uptake through the lipid bilayer of the cytoplasmic membrane, as an increased lipophilicity is advantageous for this [77][114]. Consequently, several lipophilic derivatives 91a–d were prepared (Figure 9

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

• Štěpán Horník,
• Lucie Červenková Šťastná,
• Petra Cuřínová,
• Jan Sýkora,
• Kateřina Káňová,
• Roman Hrstka,
• Ivana Císařová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2016, 12, 750–759, doi:10.3762/bjoc.12.75

• -HexNAc [19], and 4,6-difluoro-D-GalNAc [19] were reported to exhibit antiproliferative properties against L1210 leukemia cells in micromolar concentrations (IC50 24–43 μM). It was found that O-deacetylated amino sugars were often inactive due to low lipophilicity and poor cellular uptake [19]. Compound 5

A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids

• Oksana S. Mikhalchenko,
• Dina V. Korchagina,
• Konstantin P. Volcho and
• Nariman F. Salakhutdinov

Beilstein J. Org. Chem. 2016, 12, 648–653, doi:10.3762/bjoc.12.64

• (corresponding thiols or acetonitrile) were elaborated. Of particular interest is the introduction of a fluorine atom into the molecule of the biologically active compound. The introduction of a highly electronegative centre can lead to an increase in stability and changes in lipophilicity. Furthermore, it

Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues

• Charlotte Collet,
• Françoise Chrétien,
• Yves Chapleur and
• Sandrine Lamandé-Langle

Beilstein J. Org. Chem. 2016, 12, 353–361, doi:10.3762/bjoc.12.39

• (Figure 1). These new inositol members could represent attractive tools for the development of further inositol analogues. Indeed, this arm could improve some properties as the lipophilicity for example and should allow the easy anchoring of various groups or molecules, such as carbohydrates for example

• . Two arm lengths of two or three carbons were envisioned, on the C2 for the myo-series and on the C1 for the scyllo-series, ending with a hydroxy group or a fluorine atom. Indeed the addition of fluorine could improve chemical properties including lipophilicity, brain penetration, enhanced binding

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

• Javier Ajenjo,
• Martin Greenhall,
• Camillo Zarantonello and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 192–197, doi:10.3762/bjoc.12.21

• pentafluorosulfanyl (SF5) group are promising candidates in the development of new agrochemicals, pharmaceuticals and advanced materials [1][2][3]. This is due to an unusual combination of properties such as high stability [4], lipophilicity [5] and strong electron-withdrawing character [6] similar but more extreme

Synthesis and reactivity of aliphatic sulfur pentafluorides from substituted (pentafluorosulfanyl)benzenes

• Norbert Vida,
• Jiří Václavík and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 110–116, doi:10.3762/bjoc.12.12

• applications ranging from advanced materials to bioactive compounds [1][2][3]. One such fluorinated functional group which has become the focus of systematic investigation only recently is the pentafluorosulfanyl (SF5) group [4][5]. The combination of high stability [6], lipophilicity [7] and strong electron

Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

• Tsuyuka Sugiishi,
• Hideki Amii,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286

• ][2][3][4][5][6][7]. The characteristic size, strong electron-withdrawing ability, and the high lipophilicity of the trifluoromethyl group are key properties of biologically active CF3-containing molecules [8]. Perfluoroalkylcopper compounds (CnF2n+1Cu), which are soft and relatively stable

Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

• Hang Ren,
• Haoyun An,
• Paul J. Hatala,
• William C. Stevens Jr,
• Jingchao Tao and
• Baicheng He

Beilstein J. Org. Chem. 2015, 11, 2509–2520, doi:10.3762/bjoc.11.272

• for specific reasons. The fluorine atom possesses unique characteristics; it enhances the lipophilicity of organic compounds and C–F bonds have low chemical reactivity imparting high enzymatic stability and resistance to metabolic processes. The high electronegativity of fluorine and the lipophilicity

Efficient synthesis of π-conjugated molecules incorporating fluorinated phenylene units through palladium-catalyzed iterative C(sp²)–H bond arylations

• Fatiha Abdelmalek,
• Fazia Derridj,
• Safia Djebbar,
• Jean-François Soulé and
• Henri Doucet

Beilstein J. Org. Chem. 2015, 11, 2012–2020, doi:10.3762/bjoc.11.218

• dramatically influence both chemical properties and reactivities owing to its electronegativity, size, lipophilicity, and electrostatic interactions. For example, introduction of fluorine into natural products can result in beneficial biological properties [6]. On the other hand, fluorinated π-conjugated