Abstract
The development of new approaches to obtain optically pure β-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic β-hydroxy esters was obtained in excellent selectivities (up to s = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form.
Highlights
In the recent decades, the development of methods for asymmetric synthesis of organic molecules has gained increasing importance [1]
In accordance with previous studies [51,56,57], the kinetic resolution of secondary alcohols catalyzed by the planar-chiral DMAP catalyst (−)-1 proceeds in an efficient and selective way in tert-amyl alcohol and in the presence of acetic anhydride (0.75 equiv.) as acylation agent
The influence of the temperature and addition of triethylamine was investigated in the kinetic resolution of rac-(2a), which was used as a model substrate in order to find the best conditions for the selectivity of the reaction
Summary
The development of methods for asymmetric synthesis of organic molecules has gained increasing importance [1]. There are four different kinetic resolution approaches to prepare β-hydroxy esters including: hydrolytic KR [37,38,39,40], oxidative KR [41,42], acylation reactions [43,44,45], and dehydrative KR [46] (Scheme 2a–d). Fu and co-workers developed the synthesis of planar-chiral ferrocenyl DMAP analogues, e.g., (−)-1, which catalyzed the kinetic resolution of secondary aryl [50,51], allylic [52] and propargylic [53] alkyl alcohols with good selectivity factors. We wish to present the non-enzymatic kinetic resolution of a variety of β-hydroxy esters with good to excellent selectivities, using the planar-chiral ferrocenyl DMAP catalyst (−)-1. The utility of the present method could be demonstrated in the synthesis of the (S)-3-hydroxy-N-methyl-3-phenylpropanamide, which is a key intermediate for highly selective norepinephrine or serotonin reuptake inhibitor aryloxyphenylpropylamine derivatives, such as fluoxetine, tomoxetine or nisoxetine, in their enantiomerically pure forms
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