Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• . Perfluoroalkyl substituents are particularly interesting as they often lead to a significant increase in lipophilicity and thus bioavailability albeit with a modified stability. Therefore, it is of continual interest to develop new, environmentally benign methods for the introduction of these groups into target

• important role in pharmaceutical [124] and agrochemical research [16][125]. The trifluoromethylthio group belongs to the most lipophilic substituents as expressed by the Hansch lipophilicity parameter (π = 1.44) [126][127][128][129] and the high electronegativity of the SCF3 group improves significantly the

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide

• Yuzo Nakamura,
• Motohiro Fujiu,
• Tatsuya Murase,
• Yoshimitsu Itoh,
• Hiroki Serizawa,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2013, 9, 2404–2409, doi:10.3762/bjoc.9.277

• , biological, and physical properties [1][2][3][4][5][6]. Particularly, trifluoromethylated compounds can be widely employed as one of the most effective analogues of bioactive compounds, because the trifluoromethyl group enhances the metabolic stability, lipophilicity, and bioavailability of these compounds

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• TgCRDN8 mouse brain sections by in vitro autoradiography [22]. [18F]-Labeled stilbene derivatives have enhanced brain kinetics rendering them appropriate for clinical use [23][24][25]. In order to control the lipophilicity and keep the partition coefficient (log P) value between 1 and 3, which reduces

• uptake rates (1.07–2.06% ID/g at 2 min) and slower washout rates (3.29–2.01% ID/g at 60 min) than their 1,3,4 counterparts [48]. These findings, together with the close structural similarities between compounds 50a–f and 51a–e, highlight the importance of lipophilicity as a factor in controlling brain

• radiotracers in which the ionic charge was removed to increase lipophilicity and to enhance in vivo BBB permeability. Overall, this class of compounds shows high affinity for Aβ aggregates with promising in vivo pharmacokinetics. One of the earliest radiolabeled benzothiazoles, [11C]6-Me-BTA-1 ([11C]56a; note

Synthesis and evaluation of cell-permeable biotinylated PU-H71 derivatives as tumor Hsp90 probes

• Tony Taldone,
• Anna Rodina,
• Erica M. DaGama Gomes,
• Matthew Riolo,
• Hardik J. Patel,
• Raul Alonso-Sabadell,
• Danuta Zatorska,
• Maulik R. Patel,
• Sarah Kishinevsky and
• Gabriela Chiosis

Beilstein J. Org. Chem. 2013, 9, 544–556, doi:10.3762/bjoc.9.60

• biotin directly or via a linker through an amide bond. We chose to make analogues of both 1a and 1b because the isopropyl group in 1a may result in considerable effects on cell-permeability properties due to its increased lipophilicity, while having little effect on the affinity for Hsp90. While it is

Synthesis of SF₅-containing benzisoxazoles, quinolines, and quinazolines by the Davis reaction of nitro-(pentafluorosulfanyl)benzenes

• Petr Beier and
• Tereza Pastýříková

Beilstein J. Org. Chem. 2013, 9, 411–416, doi:10.3762/bjoc.9.43

• various applications due to an unusual combination of the properties of the SF5 group, such as high lipophilicity, with strong electron-acceptor character. One important property of the SF5 group is its high thermal and chemical stability [14][15][16][17]. The main reason that prevents further development

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• , N-alkylated ones (peptoid moieties) allow different low-energy conformations, and contrary to common belief they are more restricted in conformational space [32]. Moreover, they commonly possess a higher lipophilicity and protease stability, and this combination seems to improve their antibiotic

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• -1 and its MDR subclone KB-V1. This fact was quite surprising because the fluorinated cryptophycins were expected to display higher lipophilicity compared to the parent compound cryptophycin-52 and, therefore, exhibit equal or even higher activities. In contrast, more amphiphilic or polar compounds

Preparation of mixed trialkyl alkylcarbonate derivatives of etidronic acid via an unusual route

• Petri A. Turhanen,
• Janne Weisell and
• Jouko J. Vepsäläinen

Beilstein J. Org. Chem. 2012, 8, 2019–2024, doi:10.3762/bjoc.8.228

• biodegradable derivatives of BPs. One rather straightforward way to improve the lipophilicity of these compounds is to prepare alkyl carbonate derivatives of BPs. Alkyl carbonate derivatives of phenol and naphthols have been reported to undergo chemical and enzymatic hydrolysis [21][22] and so they have been

An efficient access to the synthesis of novel 12-phenylbenzo[6,7]oxepino[3,4-b]quinolin-13(6H)-one derivatives

• Wentao Gao,
• Guihai Lin,
• Yang Li,
• Xiyue Tao,
• Rui Liu and
• Lianjie Sun

Beilstein J. Org. Chem. 2012, 8, 1849–1857, doi:10.3762/bjoc.8.213

• . Compounds 4i–l containing tert-butyl groups are interesting candidates for medicinal applications since it was reported that the introduction of tert-butyl groups into organic molecules could increase the lipophilicity of the molecule, which is very important for allowing passage through the extraordinarily

Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry

• Teruo Umemoto,
• Lloyd M. Garrick and
• Norimichi Saito

Beilstein J. Org. Chem. 2012, 8, 461–471, doi:10.3762/bjoc.8.53

• attracted considerable interest in many areas such as medicines, agrochemicals, and other new materials, since the highly stable SF5 group is considered a “super-trifluoromethyl group” due to its significantly higher electronegativity and lipophilicity. This article describes the first practical method for

• for SF5; 1.09 for CF3) [4]. The high electronegativity results in high polarity in molecules. Thus, it is of significant note that there is no functional group other than SF5 that has both high electronegativity and high lipophilicity, because the two natures are generally in conflict. In addition

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

• Elizabeth P. Jones,
• Peter Jones,
• Andrew J. P. White and
• Anthony G. M. Barrett

Beilstein J. Org. Chem. 2011, 7, 1570–1576, doi:10.3762/bjoc.7.185

• . Incorporation of such units into peptidomimetics, not only affects lipophilicity, but also the secondary structure and hence the conformational rigidity, which can increase the resistance to enzymatic degradation [15][16][17][18][19]. Such units are also found in biologically interesting natural products, such

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• suffer from poor absorption and low bioavailability. At this stage a classical bioisostere exchange, i.e., replacing a carboxylic acid group with a tetrazole ring, was performed which resulted in increased lipophilicity [48] and the development of the orally active losartan. In the absence of a crystal

Synthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan

• Benjamin Cao,
• Jonathan M. White and
• Spencer J. Williams

Beilstein J. Org. Chem. 2011, 7, 369–377, doi:10.3762/bjoc.7.47

• ) lipophilicity allowing biphasic partitioning between butanol/water or purification by reversed-phase extraction, (ii) ability to be reduced to an aminooctyl chain for use in squarate conjugation chemistry, and (iii) capacity to be conjugated with fluorescent terminal alkynes using the Cu(I)-catalyzed azide

Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects

• Janja Makarević,
• Milan Jokić,
• Leo Frkanec,
• Vesna Čaplar,
• Nataša Šijaković Vujičić and
• Mladen Žinić

Beilstein J. Org. Chem. 2010, 6, 945–959, doi:10.3762/bjoc.6.106

• explained by the increased lipophilicity of the diester derivatives and, consequently increased solubility in more lipophilic solvents compared to the diacid gelators. It should be noted that the diester racemates (S,R)-1b/(R,S)-1b and (S,S)-1b/(R,R)-1b showed significantly increased effectiveness in

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• , chemical and biological properties [3]. The specific physical and chemical properties of fluorine in fluorine containing compounds, especially its strong electronegativity, lipophilicity and reaction ability, differ dramatically from those of other halogens and thus lead to changes in the interaction

Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

• Bruno Linclau,
• Leo Leung,
• Jean Nonnenmacher and
• Graham Tizzard

Beilstein J. Org. Chem. 2010, 6, No. 62, doi:10.3762/bjoc.6.62

• well as the lipophilicity, chemical and metabolic stability of the compound. Recent exciting reports describe weak but stabilising interactions between a C–F moiety and protein residues, which is certain to have implications in drug design [2][3]. Further important applications include molecular

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors

• Georg Schitter,
• Elisabeth Scheucher,
• Andreas J. Steiner,
• Arnold E. Stütz,
• Martin Thonhofer,
• Chris A. Tarling,
• Stephen G. Withers,
• Jacqueline Wicki,
• Katrin Fantur,
• Eduard Paschke,
• Don J. Mahuran,
• Brigitte A. Rigat,
• Michael Tropak and
• Tanja M. Wrodnigg

Beilstein J. Org. Chem. 2010, 6, No. 21, doi:10.3762/bjoc.6.21

• losses during column chromatography. For increased lipophilicity as well as for analytical purposes, compound 15 was also coupled to 1-pyrenebutyric acid with TBTU in DMF in the presence of triethylamine to give compound 19 in 56% yield. The pyrenyl substituent was chosen because of its potential to

Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me₃SiCF₂SO₂Ph and PhSO₂CF₂H reagents catalyzed by chiral quaternary ammonium salts

• Chuanfa Ni,
• Fang Wang and
• Jinbo Hu

Beilstein J. Org. Chem. 2008, 4, No. 21, doi:10.3762/bjoc.4.21

• this field. Background Because of the unique properties of fluorine, selective introduction of fluorine atom(s) or fluorine-containing moieties into organic molecules often dramatically alter their stability, lipophilicity, bioavailability, and biopotency. It is estimated that as many as 30–40% of

Understanding the mechanism of Pd-catalyzed allylic substitution of the cyclic difluorinated carbonates

• Jun Xu,
• Xiao-Long Qiu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2008, 4, No. 18, doi:10.3762/bjoc.4.18

• phosphorylases and higher lipophilicity, two properties that are potentially beneficial in terms of increased in vivo half life, oral efficiency and cell wall penetration [1][2]. Based on CNA skeletons, 1,2-disubstituted carbocyclic nucleosides (OTCs) recently attracted more and more attention [3][4][5][6][7][8

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

• Frédéric R. Leroux,
• Baptiste Manteau,
• Jean-Pierre Vors and
• Sergiy Pazenok

Beilstein J. Org. Chem. 2008, 4, No. 13, doi:10.3762/bjoc.4.13

• latter are unfavorable all alternative mechanisms avoiding attack at fluorine always apply in biological systems [4]. Moreover, the presence of fluorine atoms in biologically active molecules can enhance their lipophilicity and thus their in vivo uptake and transport. In particular, the trifluoromethyl

• group (−CF3) confers increased stability and lipophilicity in addition to its high electronegativity [5][6][7][8][9]. However, another fluorinated substituent, the trifluoromethoxy group, is becoming more and more important in both agrochemical research and pharmaceutical chemistry [10][11]. The

• : 36°) [51]. Lipophilicity On the basis of its electronic properties, which are close to those of a chlorine or a fluorine atom [52], the trifluoromethoxy group has been referred to as a super- [53] or a pseudo-halogen [54]. The advantage of incorporating a trifluoromethoxy group into a molecule can be

Cimicifoetisides A and B, two cytotoxic cycloartane triterpenoid glycosides from the rhizomes of Cimicifuga foetida, inhibit proliferation of cancer cells

• Li-Rong Sun,
• Chen Qing,
• Yan-Li Zhang,
• Shu-Yu Jia,
• Zhong-Rong Li,
• Shen-Ji Pei,
• Ming-Hua Qiu,
• Michael L. Gross and
• Samuel X. Qiu

Beilstein J. Org. Chem. 2007, 3, No. 3, doi:10.1186/1860-5397-3-3

• higher lipophilic nature of triterpene glycosides could be critical to the cytotoxicity as observed for 1 and 2 whose cytotoxicity are proportional to their lipophilicity (vs. cimigenol 3-O-β-D-xylopyranoside, which is devoid of appreciable activity) with the introduction of acetyl groups. Interestingly

Study of thioglycosylation in ionic liquids

• Jianguo Zhang and
• Arthur Ragauskas

Beilstein J. Org. Chem. 2006, 2, No. 12, doi:10.1186/1860-5397-2-12

• species, as shown in Figure 1. A broader spectrum of anionic counter ions have been reported, including: halides, carbonates, sulfonates, tetrafluorborates, nitrates and chloroaluminates. Changes in the physical properties of ionic liquids, including their melting point, hydrophilicity, lipophilicity and

Synthesis of novel (1-alkanoyloxy- 4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives

• Petri A. Turhanen and
• Jouko J. Vepsäläinen

Beilstein J. Org. Chem. 2006, 2, No. 2, doi:10.1186/1860-5397-2-2

• hydrophilic, highly anionic and their bioavailabilities are very poor. [12][13][14] It would be a clear advance to prepare more lipophilic and biodegradable derivatives of BPs. A rather straightforward method to improve the lipophilicity of amino BPs is to convert hydroxyl or/and amino group or the phosphonic