Selective monofluorination : mechanistic studies and synthetic applilcations

646-673<span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">The<span style="font-size:12.0pt;line-height:115%; font-family:HiddenHorzOCR;mso-hansi-font-family:" times="" new="" roman";mso-bidi-font-family:="" hiddenhorzocr;color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;="" mso-bidi-language:hi"="" lang="EN-IN"> <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#7e7e7e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">i<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">ntroduction <span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">of <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">fluorine into organic molecules is an important tool in modifying their physical<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">, <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">chemical and <span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">biological properties<span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">. <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">This <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">review briefly presents the different approaches which can be used for selective monofluorination. The strategies that we have developed for fluorination vicinal to unsaturated <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">sy<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">s<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">tems<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#666666;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">, <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">p<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">a<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">ying attention <span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">to<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN"> <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">the regio-and <span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">stereo-control <span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">during the fluorination <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">step are <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">then discussed in detai<span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">l. <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">From <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">these <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">s<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">tudie<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">s, <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">two promising<span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN"> <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">a<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">pproaches emerge: the <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">first employs transition metal <span style="font-size: 12.0pt;line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:="" en-in;mso-bidi-language:hi"="" lang="EN-IN">complexes<span style="font-size: 12.0pt;line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:="" "times="" roman";color:#666666;mso-ansi-language:en-in;mso-fareast-language:="" en-in;mso-bidi-language:hi"="" lang="EN-IN">; <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">the <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">second <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">use<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">s <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">tailor made fluorinated ke<span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#666666;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">y <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">buildin<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">g<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN"> block<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#494949;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">s<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">. <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">Some applications <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">to the preparation <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">of <span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">natural product <span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#2e2e2e;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">analogues are also <span style="font-size:12.0pt; line-height:115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#171717;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">mentioned<span style="font-size:12.0pt;line-height:115%; font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:#929292;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">.</span

Soluble polymer supported asymmetric synthesis (SPSAS)^§

2116-2128Role of asymmetric catalysis in solid phase organic synthesis is described especially on the soluble polymer supports, namely, poly (ethylene glycol). The review focus only on the recent progress in this area. Some of advantage, as well as limitations posed by this soluble polymer system is also described. The popular reactions covered in this review include asymmetric dihydroxylation, epoxidation, reductions and C-C bond formations

A New Approach for the Synthesis of Sotolon in Racemic and Enantioenriched Forms

International audienceSotolon (3-hydroxy-4,5-dimethyl-2(5H)-furanone) has been synthezised both in racemic and enantioenriched forms by a short sequence involving intramolecular tandem isomerization-aldolisation and tandem izomerization/Mannich reactions as key steps. Optically active Sotolon has been obtained by using (S)-N-tert-butane sulfinimine as a chiral starting material

Sc(OTf)<SUB>3</SUB>-catalyzed intramolecular aza-Prins cyclization for the synthesis of heterobicycles

The coupling of (E)- and (Z)-hex-3-ene-1,6-ditosylamide with various aldehydes in the presence of 10 mol % Sc(OTf)<SUB>3</SUB> gave the corresponding trans- and cis-fused 1,5-ditosyl-octahydro-1H-pyrrolo[3,2-c]pyridines, respectively, in good yields via intramolecular aza-Prins cyclization, whereas the coupling of (E)- and (Z)-N-(6-hydroxyhex-3-enyl)-4-methylbenzenesulfonamide afforded the corresponding trans- and cis-fused octahydro-1-tosylpyrano[4,3-b]pyrroles derivatives, respectively, via intramolecular Prins-cyclization

Metal-free propargylation/aza-annulation approach to substituted beta-carbolines and evaluation of their photophysical properties

International audienceAn efficient acid-catalyzed propargylation/aza-annulation sequence was developed under metal-free reaction conditions, thus leading to a one-pot synthesis of a variety of substituted beta-carbolines starting from propargylic alcohols and indole 2-carbonyls. This versatile strategy was further extended to the synthesis of 5-azaindoles and 5-azabenzothiazoles. Optical properties suggested that manipulation of electron donor and acceptor moieties on beta-carbolines has an impact on their ground and excited state electronic behavior. This leads to blue or green emission and should facilitate the development of organic light emitting diodes (OLEDs). Electrochemical and stability studies revealed that 4a-6 shows ease of redox activity and photostability during illumination

gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect

International audienceIntroduction New fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflammatory effects in primary macrophages. Methods The synthesis of the designed molecules started from easily accessible and versatile gem-difluoro propargylic derivatives. The desired aromatic systems were obtained using Diels-Alder/aromatization sequences and this was followed by Pd-catalyzed coupling reactions and, when required, final functionalization steps. Both direct inhibitory effects on cyclooxygenase-1 or -2 activities, protein expression of cyclooxygenase-2 and nitric oxide synthase-II and the production of prostaglandin E-2, the pro-inflammatory nitric oxide and interleukin-6 were evaluated in primary murine bone marrow-derived macrophages in response to lipopolysaccharide. Docking of the designed molecules in cyclooxygenase-1 or -2 was performed. Results Only fluorinated compounds exerted anti-inflammatory activities by lowering the secretion of interleukin-6, nitric oxide, and prostaglandin E-2, and decreasing the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in mouse primary macrophages exposed to lipopolysaccharide, as well as cyclooxygenase activity for some inhibitors with different efficiencies depending on the R-groups. Docking observation suggested an inhibitory role of cyclooxygenase-1 or -2 for compounds A3, A4 and A5 in addition to their capacity to inhibit nitrite, interleukin-6, and nitric oxide synthase-II and cyclooxygenase-2 expression. Conclusion The new fluorinated diaryl ethers and bisarylic ketones have anti-inflammatory effects in macrophages. These fluorinated compounds have improved potential anti-inflammatory properties due to the fluorine residues in the bioactive molecules

Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues

International audienceIn the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-x(L)/Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-x(L)