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Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. KTH-Royal Institute of Technology.
2014 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, 14273-14291 p.Article in journal (Refereed) Published
Abstract [en]

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 = 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.

Place, publisher, year, edition, pages
2014. Vol. 19, no 9, 14273-14291 p.
Keyword [en]
non-enzymatic kinetic resolution, β-hydroxy esters, planar-chiral DMAP catalyst, ferrocenyl catalyst
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-224444DOI: 10.3390/molecules190914273ISI: 000343093100085PubMedID: 25215586OAI: oai:DiVA.org:uu-224444DiVA: diva2:753756
Note

Alba E. DiazIvarez and Laura Mesas-Sanchez contributed equally to this work.

Available from: 2014-10-08 Created: 2014-05-12 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols: Synthetic Applications and Mechanistic Studies
Open this publication in new window or tab >>Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols: Synthetic Applications and Mechanistic Studies
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research described in this thesis focuses on the catalytic acylative kinetic resolution (KR) of aromatic secondary alcohols, using a planar-chiral 4-(dimethylamino)pyridine (DMAP) organocatalyst.

In the first part of this thesis, the substrate scope of the above mentioned process was expanded to aromatic secondary alcohols that contain an extra functional group in the alkyl moiety, such as 1,2-azido alcohols, 2-hydroxy-2-aryl-ethylphosphonates and 2-hydroxy-2-aryl esters. Thus, the preparation of highly functionalized compounds in their enantiomerically pure form with excellent enantiomeric excess (up to 99% ee) was achieved. Furthermore, the synthetic applicability of this methodology was illustrated through the synthesis of two high value compounds, (R)-Pronethalol and (S)-3-hydroxy-N-methyl-3-phenylpropanamide, which is an immediate precursor of bioactive molecules such as (S)-Fluoxetine.

The second part of this thesis deals with the mechanistic study of the acylative KR catalyzed by the planar-chiral DMAP derivative. Reaction Progress Kinetic Analysis methodology was used in the investigation of the reaction mechanism, probing that no notable product inhibition or decomposition of the catalyst occurs in the studied system. The reaction rate showed fractional order dependence on the concentration of both reactants. Furthermore, NMR spectroscopy was utilized to study the equilibrium between the different catalyst states, which explains the measured kinetics of the reaction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1191
Keyword
kinetic resolution, organocatalysis, secondary alcohols, reaction progress kinetic analysis
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-233734 (URN)978-91-554-9075-1 (ISBN)
Public defence
2014-11-28, A1:111a, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-11-07 Created: 2014-10-09 Last updated: 2015-02-03

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