Strategies towards modular syntheses of fluoroorganics
Item
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Title
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Strategies towards modular syntheses of fluoroorganics
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Identifier
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d_2009_2013:a1acd7b262f5:11555
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identifier
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12093
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Creator
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Kumar, Rakesh,
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Contributor
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Rakesh Kumar
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Date
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2012
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Language
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English
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Publisher
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City University of New York.
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Subject
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Organic chemistry | 5-fluorobenzo[c]phenanthrene | deoxyadenosine adduct | fluoroorganics | fluorovinyl triazoles | modular synthesis | polycyclic aromatic hydrocarbons
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Abstract
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Synthesis of TMS-protected fluoropropargyl benzothiazolyl sulfone, a bifunctional fluoro-Julia-Kocienski reagent, was achieved by metalation-electrophilic fluorination of benzothiazolyl propargyl sulfone. Reactions of the fluoro-Julia-Kocienski reagent with carbonyl compounds produced fluoroenynes in high yields and with high E-selectivity. Olefinations proceeded with LHMDS, or the milder base, DBU. A one-pot deprotection-copper-catalyzed azide alkyne cycloaddition (CuAAC) to the alkyne moiety in the Julia-Kocienski reagent provided a new class of triazole-derived fluorinated and unfluorinated Julia-Kocienski reagents. Competitive experiments showed higher reactivity of the fluorinated reagent in the CuAAC than the protio analog. Computational analysis of electron densities in fluoro and protio propargyl sulfones showed that fluorine lowers electron density at the terminal alkynyl carbon, which can contribute to its higher reactivity. These triazole-derived "second generation" Julia-Kocienski reagents reacted smoothly with aldehydes and ketones, and olefinations could be tuned towards E- or Z-stereoselectivity by change in reaction conditions. The CuAAC-Julia olefination sequence was also used for the synthesis of triazole-derived analogs of biologically relevant combretastatin A-4. Biological testing of these compounds against HeLa cancer cell lines showed that two analogs displayed modest activity.;Putative fjord region dihydrodiol and diol epoxide metabolites of 5-fluorobenzo[ c]phenanthrene (5-FBcPh), arising by the oxidation of the angular ring remote to the fluorinated ring, were synthesized. A key step in the chemistry was fluoro-Julia-Kocienski olefination, followed by photocyclization. Deoxyadenosine adducts of the (+/-)-series 2 diol epoxide of 5-FBcPh were synthesized. Trans opening of this epoxide by azide, followed by reduction, furnished (+/-)-aminotriol. SNAr reaction of the aminotriol with silyl protected 6-fluoro-9-(2'-deoxy-beta- D-ribofuranosyl)purine gave two diastereomeric deoxyadenosine adducts. Unequivocal stereochemical assignment to the individual adduct diastereomers came via conversion of the racemic trans dihydrodiol to the bis(--)-menthoxy acetate ester, and chromatographic separation of the diastereomers. Resolved enantiomers were converted to bis-p-( N,N)-dimethylaminobenzoates of a trans tetrahydrodiol. Absolute configuration was determined by CD spectroscopy. R,R-dihydrodiol enantiomer was converted to the R,S,S,R diol epoxide of 5-FB cPh, which was used for the synthesis of a single diastereomer of the 2'-deoxyadenosine adduct, whose CD spectrum and optical rotation were recorded. This allowed configurational assignment to the adenosine adducts, obtained from the racemic diol epoxides.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Chemistry
