Chiral synthesis via organoboranes. 18. Selective reductions. 43. Diisopinocampheylchloroborane as an excellent chiral reducing reagent for the synthesis of halo alcohols of high enantiomeric purity. A highly enantioselective synthesis of both optical isomers of Tomoxetine, Fluoxetine, and Nisoxetine

Abstract

103ChemInform Abstract The halogenated alkyl phenyl ketones (I) are selectively reduced with the di(isopinocampheyl)chloroborane, derived from (+)-α-pinene, to produce the optically active phenyl carbinols (II). The chlorophenylpropanol (IIc) forms the phenol ethers (IV) which undergo substitution reaction with dimethylamine (V) to give (+)-tomoxetine hydrochloride (VIa), (-)-fluoxetine hydrochloride (VIb), or (+)-nisoxetine hydrochloride (VIc) after acidic work-up. The corresponding enantiomers are prepared in an analogous manner, using the chloroborane obtained from (-)-α-pinene for the reduction of (Ic).

Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat

“…Fluoxetine HC1 was synthesized using a published procedure (Srebnik et al, 1988) and the chemical structure was verified by 1H and 13C NMR spectroscopy. In the acute fluoxetine study, following the collection of baseline microdialysis samples, rats were given a control saline injection (0.1 m a g , i.p.)…”

Development of Atom-Economical Catalytic Asymmetric Reactions under Proton Transfer Conditions: Construction of Tetrasubstituted Stereogenic Centers and Their Application to Therapeutics

“…Installation of the requisite 4-trifluoromethylphenyl group under basic conditions gave aryl ether 35. 194,195) A palladiumcatalyzed deallylation protocol with a following carbamate formation afforded 36 in 71% yield in two steps. 196) Reduction of 37 with LiAlH 4 and subsequent treatment with …”

A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

“…3,4 Due to its pharmaceutical importance and to the different pharmacological profiles of the individual enantiomers, the development of new strategies for preparing optically pure fluoxetine (1) has received growing interest in recent years. 13 Several methods of enantioselective synthesis of both enantiomers of fluoxetine (1) have been reported and chirality has been introduced via enantioselective hydroxylation, 14 enantioselective epoxidation followed by selective epoxide opening, 15-17 chemical [18][19][20][21][22][23] and enzymatic [24][25][26][27][28] reduction of ketones and β-ketoesters, stereoselective coupling reaction using chiral auxiliary or chiral catalyst, 29,30 as well as enzymatic 31,32 or chemical 33,34 resolution of benzylic alcohols. Among the strategies developed for enantiomerically pure (R)-fluoxetine [(R)-1], Miles and co-workers described the Ti(O i Pr) 4 /(R)-BINOL asymmetric ene reaction of 3-methylene-2,3-dihydrofuran (prepared in 63% yield from 3-furaldehyde as a 3.5:1 mixture with 3-methylfuran) with benzaldehyde which afforded (R)-fluoxetine hydrochloride [(R)-1.HCl] in 6 steps, 56% overall yield and >97% ee from 3-furaldehyde.…”