- Gold-Catalyzed Asymmetric Thioallylation of Propiolates via Charge-Induced Thio-Claisen Rearrangement
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A gold(I)-catalyzed enantioselective thioallylation of propiolates with allyl sulfides is described. The key mechanistic element is a sulfonium-induced Claisen rearrangement which helps minimize the allyl dissociation and render higher enantioselectivity. This protocol features remarkable scope of the allyl moiety, allowing enantiocontrolled synthesis of all-carbon quaternary centers, and exhibits exceptional functional group compatibility with many Lewis bases and π-bonds. This intermolecular variant of Claisen rearrangement forges both C-S and C-C bonds concomitantly, providing efficient access to interesting optically active organosulfur compounds which can be transformed further through the vinyl sulfide as a functional handle. The rate of the reaction was zeroth order with respect to allyl sulfides, which suggested a reversible inhibition, providing a resting state for the catalyst. The Hammett plot displayed a correlation with σp values, suggesting a turnover-limiting sigmatropic rearrangement where decreased electron-density on sulfur accelerated the rearrangement.
- Kim, Hanbyul,Jang, Jiwon,Shin, Seunghoon
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p. 20788 - 20795
(2020/11/27)
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- Process development and scale-up of the PPAR agonist NNC 61-4655
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A scalable synthetic route of the nonselective but PPARα-preferring potent PPAR agonist NNC 61-4655 aimed for treatment of type 2 diabetes was developed. The synthetic pathway comprises the convergent synthesis and coupling of the two key intermediates E-5-(chloropent-3-en-1-ynyl)benzene 8 (prepared in a five-step synthesis in 18% overall yield) and (S)-2-ethoxy-3-(4- hydroxyphenyl)propanoic acid isopropyl ester 9. The 2-aminoethanol salt of NNC 61-4655 was selected in a preclinical salt selection program as the appropriate salt form for further development. More than 900 g of NNC 61-4655, 2-aminoethanol was finally synthesized under GMP in 98.7% purity. In comparison to the original medicinal chemistry route, starting from phenylpropargyl aldehyde 1, the overall yield towards NNC 61-4655 could be enhanced from 24 to 37%. An improved scalable two-step synthesis for 8 was developed on a laboratory scale (≥33-35% overall yield) shortly after the GMP batch.
- Deussen, Heinz-Josef,Jeppesen, Lone,Schaerer, Norbert,Junager, Finn,Bentzen, Bjorn,Weber, Beat,Weil, Volker,Mozer, Sandor Josef,Sauerberg, Per
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p. 363 - 371
(2013/09/05)
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- Large Dimeric Ligands with Favorable Pharmacokinetic Properties and Peroxisome Proliferator-Activated Receptor Agonist Activity in Vitro and in Vivo
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Two potent nonselective, but PPARα-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.
- Sauerberg, Per,Bury, Paul S.,Mogensen, John P.,Deussen, Heinz-Josef,Pettersson, Ingrid,Fleckner, Jan,Nehlin, Jan,Frederiksen, Klaus S.,Albrektsen, Tatjana,Din, Nanni,Svensson, L. Anders,Ynddal, Lars,Wulff, Erik M.,Jeppesen, Lone
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p. 4883 - 4894
(2007/10/03)
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- A stereoselective synthesis of (E)-1-halo-6,6-dimethyl-2-hepten-4-yne: A key intermediate for terbinafine
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A study of the stereoselective halogenation of 6,6-dimethyl-1-hepten-4- yn-3-ol (1) using a series of halogenating agents is described. Of the many agents investigated, boron trichloride is the most successful reagent for stereoselective halogenation (E:Z=9:1(max)). The resulting (E)-1-halo-6,6- dimethyl-2-hepten-4-yne (2), a key intermediate for terbinafine, an antifungal agent, is obtained in good yield and stereoselectivity. Two structurally related enyne alcohols have been studied likewise and shown similar versatility. (C) 2000 Elsevier Science Ltd.
- Chou, Shan-Yen,Tseng, Chin-Lu,Chen, Shyh-Fong
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p. 3895 - 3898
(2007/10/03)
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