- Synthesis of 15R-PGD2: A potential DP2 receptor agonist
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The first total synthesis of 15R-PGD2 3 was accomplished. The approach used in this report is also an efficient method to produce 15R-PGE 2. 15R-PGD2, a potential DP2 receptor agonist, could be an important novel tool for defining the role of this receptor in inflammatory diseases.
- Kim, Seongjin,Bellone, Sophie,Maxey, Kirk M.,Powell, William S.,Lee, Gue-Jae,Rokach, Joshua
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p. 1873 - 1876
(2007/10/03)
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- 15-Fluoro prostaglandin FP agonists: A new class of topical ocular hypotensives
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A novel series of 15-fluoro prostaglandins with phenoxy termination of the ω-chain was synthesized and evaluated for binding and functional activation of the prostaglandin FP receptor in vitro and for side effect potential and topical ocular hypotensive e
- Klimko, Peter,Hellberg, Mark,McLaughlin, Marsha,Sharif, Najam,Severns, Bryon,Williams, Gary,Haggard, Karen,Liao, John
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p. 3451 - 3469
(2007/10/03)
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- A novel tandem Michael addition/Meerwein-Ponndorf-Verley reduction: Asymmetric reduction of acyclic α,β-unsaturated ketones using a chiral mercapto alcohol
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The introduction of a thiol group into a chiral alcohol reagent for asymmetric Meerwein-Ponndorf-Verley (MPV) reductions allows asymmetric reduction of α,β-unsaturated ketones to secondary alcohols and allylic alcohols via a novel tandem Michael addition/MPV reduction. The reaction of acyclic α,β-unsaturated ketones 1 and an optically active 1,3-mercapto alcohol (-)-2 using dimethylaluminum chloride afforded the MPV reduction products 3 diastereoselectively in very high yields (up to 96%). Mechanistic studies elucidated (1) the structure of the chelation complex D with (-)-2 and Me2AlCl, (2) an asymmetric 1,7-hydride shift (intramolecular MPV reduction), and (3) dynamic kinetic resolution via reversible Michael addition. Subsequent reductive desulfurization of the MPV products 3 with a modified Raney nickel system led to the highly enantioselective reduction of α,β-unsaturated ketones to saturated secondary alcohols in 96-98% ee. β-Elimination of the corresponding sulfoxides gave the allylic alcohols in 86-98% ee. Applications to the asymmetric reduction of a synthetic intermediate 1m of prostaglandins and to a new asymmetric synthesis of the (+)-Rove beetle pheromone 11 are described.
- Node, Manabu,Nishide, Kiyoharu,Shigeta, Yukihiro,Shiraki, Hiroaki,Obata, Kenichi
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p. 1927 - 1936
(2007/10/03)
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- Stereocontrol in organic synthesis using silicon-containing compounds. A formal synthesis of prostaglandins controlling the stereochemistry at C-15 using a silyl-to-hydroxy conversion following a stereochemically convergent synthesis of an allylsilane
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Hydrosilylation of isoprene with chloro(diphenyl)silane gave (Z)-chloro(2-methylbut-2-enyl)-diphenylsilane 7. The cuprate reagent derived from this chloride underwent conjugate addition to methyl cinnamate 11, 1,2-silylcupration with hex-1-yne 16 and allene 18, and allylic displacement reactions with 1-vinylcyclohexyl acetate 20 and (Z)-1-cyclopentyloct-2-en-1-yl acetate 22. The silyl group in each of the products was converted into a hydroxy, with the removal of the 2-methylbut-2-enyl group taking place under much milder acidic conditions than those needed to remove the phenyl group from the dimethyl(phenyl)silyl group, and making this group suitable for the conversion of an allylsilane into an allyl alcohol. A stereospecifically anti conjugate displacement of the allylic benzoate group in (Z)-(1S,5R,6R,7R,1′S)-7-benzoyloxy-6-(1′-benzoyloxyoct-2′- enyl)-2-oxabicyclo[3.3.0]octan-3-one 52, and a stereospecifically syn conjugate displacement of the carbamate group in (Z)-(1S,5R,6R,7R,1′R)-7-benzoyloxy-6-(1′-N-phenylcarbamoyloxyoct- 2′-enyl)-2-oxabicyclo[3.3.0]octan-3-one 51, gave stereo-convergently the same allylsilane (1′ E,2″Z)-(1S,5S,6R,7R,3′S)-7-benzoyloxy-6-[3′-(2″- methylbut-2″-enyl)-diphenylsilyloct-1′-enyl]-2-oxabicyclo[3.3.0] octan-3-one 53. Silyl-to-hydroxy conversion gave the allyl alcohol (E)-(1S,5S,6R,7R,3′S)-7-benzoyloxy-6-(3′-hydroxyoct-1′-enyl)- 2-oxabicyclo[3.3.0]octan-3-one 54, having the relative and absolute stereochemistry at C-15 of the prostaglandins.
- Fleming, Ian,Winter, Stephen B. D.
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p. 2687 - 2700
(2007/10/03)
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