ABSTRACT
Using cinchona alkaloid-derived primary amines as catalysts and aqueous hydrogen peroxide as the oxidant, we have developed highly enantioselective Weitz-Scheffer-type epoxidation and hydroperoxidation reactions of α,ß-unsaturated carbonyl compounds (up to 99.5:0.5 er). In this article, we present our full studies on this family of reactions, employing acyclic enones, 5-15-membered cyclic enones, and α-branched enals as substrates. In addition to an expanded scope, synthetic applications of the products are presented. We also report detailed mechanistic investigations of the catalytic intermediates, structure-activity relationships of the cinchona amine catalyst, and rationalization of the absolute stereoselectivity by NMR spectroscopic studies and DFT calculations.
Subject(s)
Cinchona Alkaloids/chemistry , Epoxy Compounds/chemistry , Hydrogen Peroxide/chemistry , Alkenes/chemistry , Amines/chemistry , Catalysis , Cyclization , Cyclohexanones/chemistry , Gas Chromatography-Mass Spectrometry , Hydrolysis , Imines/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Quaternary Ammonium Compounds/chemistry , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Structure-Activity Relationship , Trifluoroacetic Acid/chemistrySubject(s)
Ketones/chemistry , Carbon/chemistry , Catalysis , Molecular Structure , Oxygen/chemistryABSTRACT
An asymmetric catalytic epoxidation of alpha-branched, alpha,beta-unsaturated aldehydes is presented. A highly synergistic combination of a primary cinchona-based amine and a chiral phosphoric acid was found to promote the reaction with excellent enantiocontrol for alpha-monosubstituted and alpha,beta-disubstituted enals.
ABSTRACT
Nucleophilic ring opening of methyl 1-nitrocyclopropanecarboxylates by phenol derivatives in the presence of Cs2CO3 is described. The reaction tolerates a variety of substituents on both the aromatic alcohol and the cyclopropane and affords the products in good yields (53-84%) and with complete preservation of the enantiomeric excess at C-4. The methodology was applied in an enantioselective synthesis of the norepinephrine reuptake inhibitor atomoxetine (Strattera).
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Cyclopropanes/chemical synthesis , Nitro Compounds/chemical synthesis , Phenols/chemistry , Propylamines/chemical synthesis , Atomoxetine Hydrochloride , Carbonates/chemistry , Cesium/chemistry , Methylation , Models, Chemical , StereoisomerismABSTRACT
The Lewis acid-catalyzed ring-opening of methyl 1-nitrocyclopropanecarboxylates with amine nucleophiles is described. The reaction proceeds at room temperature and with complete preservation of the enantiomeric purity from the electrophilic center of the cyclopropane to the acyclic product. The methodology was applied in an enantioselective synthesis of the dual serotonin/norepinephrine reuptake inhibitor (3R)-3-(1 H-indol-1-yl)- N-methyl-3-phenylpropan-1-amine.
