ABSTRACT
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Subject(s)
Enzyme Inhibitors/pharmacology , Liver/drug effects , Pyrrolidines/pharmacology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hep G2 Cells , Humans , Liver/enzymology , Liver/metabolism , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Stearoyl-CoA Desaturase/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.
Subject(s)
Oxazolidinones/chemical synthesis , Ruthenium/chemistry , Catalysis , Molecular Structure , Oxazolidinones/chemistry , Solvents/chemistry , StereoisomerismABSTRACT
A novel two-step procedure for the synthesis of 3-amino-5-substituted-isoxazoles is described. In the presence of a base, readily available 3-bromoisoxazolines react with amines to afford 3-aminoisoxazolines. An oxidation protocol was developed for these heterocycles to provide 3-aminoisoxazoles in consistently high yield.
Subject(s)
Amines/chemistry , Amines/chemical synthesis , Hydrocarbons, Brominated/chemistry , Isoxazoles/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Isoxazoles/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
Within the realm of catalytic asymmetric hydrogenation, the focus continues to be on the use of chiral metal complexes in conjunction with a hydrogen source. Recently, the widespread development of organocatalysis, including the invention of iminium activation, has led to the discovery of many new enantioselective transformations. Based on this strategy, a number of bioinspired processes for the enantioselective organocatalytic transfer hydrogenation of alpha,beta-unsaturated carbonyl compounds and imines have been discovered. These topics will be the focus of this Account.
Subject(s)
Organic Chemicals/chemistry , Amination , Catalysis , Hydrogenation , Imines/chemistry , StereoisomerismABSTRACT
The first enantioselective organocatalytic transfer hydrogenation of cyclic enones has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated cycloalkenones, to generate beta-stereogenic cyclic ketones. The use of imidazolidinone 4 as the asymmetric catalyst has been found to mediate the hydrogenation of a large class of enone substrates with tert-butyl Hantzsch ester serving as an inexpensive source of hydrogen. The capacity of catalyst 4 to enable enantioselective transfer hydrogenation of cycloalkenones has been extended to five-, six-, and seven-membered ring systems. The sense of asymmetric induction is in complete accord with the stereochemical model first reported in conjunction with the use of catalyst 4 for enantioselective ketone Diels-Alder reactions.
Subject(s)
Cycloparaffins/chemistry , Hydrocarbons, Cyclic/chemistry , Hydrocarbons, Cyclic/chemical synthesis , Ketones/chemistry , Ketones/chemical synthesis , Catalysis , Hydrogen/chemistry , Models, Molecular , Molecular Conformation , Oxidation-Reduction , StereoisomerismABSTRACT
The first enantioselective organocatalytic hydride reduction has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated aldehydes to generate beta-stereogenic aldehydes. The use of imidazolidinone 2 as the asymmetric catalyst has been found to mediate the transfer of hydrogen to a large class of enal substrates from ethyl Hantzsch ester. The capacity of catalyst 2 to accelerate E-Z isomerization prior to selective E-olefin reduction allows the implementation of geometrically impure enals in this operationally simple protocol.
Subject(s)
Aldehydes/chemistry , Dihydropyridines/chemistry , Hydrogen/chemistry , Imidazolidines/chemistry , Imines/chemistry , Models, Molecular , Oxidation-Reduction , Proline/chemistry , StereoisomerismABSTRACT
[reaction: see text] 2-Vinyloxiranes have been found to be excellent surrogates to beta,gamma-unsaturated aldehydes. These valuable electrophiles, generated in situ by treatment of a 2-vinyloxirane with a catalytic amount of Sc(OTf)(3), are effectively trapped by the chiral allylating agents based on alpha-pinene, affording bishomoallylic alcohols in high yield and excellent selectivity.
