57451-13-5Relevant academic research and scientific papers
A metathesis-based approach to the synthesis of 2-pyridones and pyridines
Donohoe, Timothy J.,Fishlock, Lisa P.,Procopiou, Panayiotis A.
, p. 285 - 288 (2008/09/19)
(Chemical Equation Presented) The ring-closing metathesis reaction has been successfully employed to form a range of dihydropyridone intermediates, which are in the correct oxidation state to undergo a base-induced elimination to reveal the aromatic 2-pyridone. This mild and novel approach to six-membered heteroaromatic compounds then provides access to a wide variety of substituted pyridines in excellent overall yield.
Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability
Staas, Donnette D.,Savage, Kelly L.,Sherman, Vanessa L.,Shimp, Heidi L.,Lyle, Terry A.,Tran, Lekhanh O.,Wiscount, Catherine M.,McMasters, Daniel R.,Sanderson, Philip E.J.,Williams, Peter D.,Lucas Jr., Bobby J.,Krueger, Julie A.,Dale Lewis,White, Rebecca B.,Yu, Sean,Wong, Bradley K.,Kochansky, Christopher J.,Reza Anari,Yan, Youwei,Vacca, Joseph P.
, p. 6900 - 6916 (2007/10/03)
Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2×APTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (Ki = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg).
Indium mediated allylation of glyoxylate oxime ethers, esters and cyanoformates
Ritson, Dougal J.,Cox, Russell J.,Berge, John
, p. 1921 - 1933 (2007/10/03)
An indium mediated procedure has been developed for the allylation of activated O-functionalised oximes and nitriles as exemplified by a variety of glyoxylate derivatives. This method gives the corresponding free (or protected) amine in a one pot-process. The method is regiospecific and is carried out under remarkably mild conditions so that even oxime esters can be subjected to the typical reaction conditions.
Reactions of alkyl radicals with oxime ether: One-pot synthesis of α- amino acids
Miyabe, Hideto,Ueda, Masafumi,Yoshioka, Naoko,Yamakawa, Kumiko,Naito, Takeaki
, p. 2413 - 2420 (2007/10/03)
The addition of water-resistant carbon radicals to glyoxylic oxime ether provided a new method for the one-pot synthesis of α-amino acids via a carbon-carbon bond formation. The reaction of 2-hydroxy-2-methoxyacetic acid methyl ester with benzyloxyamine a
Intermolecular alkyl radical addition to the carbon-nitrogen double bond of oxime ethers and hydrazones
Miyabe, Hideto,Shibata, Ryouhei,Sangawa, Masato,Ushiro, Chikage,Naito, Takeaki
, p. 11431 - 11444 (2007/10/03)
Intermolecular carbon radical addition to the carbon-nitrogen double bond of oxime ethers and hydrazones was studied. The reaction of unactivated aldoxime ethers proceeded smoothly in the presence of BF3·OEt2 to give the alkylated products in high yields via the free radical-mediated carbon- carbon bond-forming process.
Thermal Hetero [3 + 2] Cycloaddition of Dipolar Trimethylenemethane to O-Alkyloximes. Straightforward Synthetic Routes to Substituted Pyrrolidines and Prolines
Yamago, Shigeru,Nakamura, Masaharu,Wang, Xiao Qun,Yanagawa, Masao,Tokumitsu, Shuzo,Nakamura, Eiichi
, p. 1694 - 1703 (2007/10/03)
Thermal hetero [3 + 2] cycloaddition reaction of a dipolar trimethylenemethane 2 with an O-alkyloxime produces a substituted pyrrolidine. Thus, heating of a mixture of an alkylidenecyclopropane 1 an anti-O-alkyloxime 3 proceeds smoothly in good yield to give a substituted pyrrolidine 4 bearing a ketene acetal group in its 3-position, which upon hydrolysis under mild conditions gives a 3-alkoxycarbonylpyrrolidine 5 in quantitative yield. On the other hand, the cycloaddition to a syn-oxime is extremely slow. The cycloaddition reaction can be achieved by starting with nearly equimolar quantities of the two starting materials, and the reaction is quite insensitive to the choice of solvent and to the presence of oxygen and water. In the reaction of a substituted methylenecyclopropane 1 (R ≠ H), the reaction may take place with high regio- and stereoselectivity, which is in consonance with the concerted nature of the cycloaddition reaction. The present synthesis represents one of the rare examples of the imine-based route to pyrrolidines, which have been much less explored than the 1,3-dipolar cycloaddition route using olefin and azomethine ylide.
