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Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols: Synthetic Applications and Mechanistic Studies
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
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 [en]
kinetic resolution, organocatalysis, secondary alcohols, reaction progress kinetic analysis
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-233734ISBN: 978-91-554-9075-1 (print)OAI: oai:DiVA.org:uu-233734DiVA: diva2:756041
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
List of papers
1. Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst
Open this publication in new window or tab >>Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst
2013 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 69, no 2, 753-757 p.Article in journal (Refereed) Published
Abstract [en]

Optically pure 1,2-azidoalcohols are widely used as precursors for other high value organic products. A non-enzymatic kinetic resolution procedure for the stereoselective synthesis of chiral 1,2-azidoalcohols from the readily available racemic counterparts has been developed, employing a planar-chiral DMAP derivative catalyst. Following this procedure, a range of aromatic 1,2-azidoalcohols was obtained in good selectivities (up to S=45) and high enantiomeric excess (up to 99% ee).

Keyword
Non-enzymatic kinetic resolution, 1, 2-Azidoalcohols, Planar-chiral DMAP derivative catalyst, Ferrocenyl catalyst
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-189450 (URN)10.1016/j.tet.2012.10.077 (DOI)000314371800045 ()
Available from: 2013-01-02 Created: 2013-01-02 Last updated: 2017-12-06Bibliographically approved
2. Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst
Open this publication in new window or tab >>Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst
2014 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 70, no 24, 3807-3811 p.Article in journal (Refereed) Published
Abstract [en]

Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be incorporated into a variety of synthetic strategies for the preparation of other high value organic products. A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up to S=68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess (>94% ee).

Keyword
Non-enzymatic kinetic resolution, 2-Hydroxy-2-arylethylphosphonates, Planar chiral DMAP derivative catalyst
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-227994 (URN)10.1016/j.tet.2014.03.102 (DOI)000336710200010 ()
Available from: 2014-07-04 Created: 2014-07-02 Last updated: 2017-12-05Bibliographically approved
3. Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst
Open this publication in new window or tab >>Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst
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.

Keyword
non-enzymatic kinetic resolution, β-hydroxy esters, planar-chiral DMAP catalyst, ferrocenyl catalyst
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-224444 (URN)10.3390/molecules190914273 (DOI)000343093100085 ()25215586 (PubMedID)
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
4. A Mechanistic Investigation of the Kinetic Resolution of Secondary Aromatic Alcohols Using a Ferrocene-Based Planar Chiral 4-(Dimethylamino)pyridine Catalyst
Open this publication in new window or tab >>A Mechanistic Investigation of the Kinetic Resolution of Secondary Aromatic Alcohols Using a Ferrocene-Based Planar Chiral 4-(Dimethylamino)pyridine Catalyst
2015 (English)In: CHEMISTRY-A EUROPEAN JOURNAL, ISSN 0947-6539, Vol. 21, no 14, 5623-5631 p.Article in journal (Refereed) Published
Abstract [en]

A detailed kinetic analysis for the acetylation of 1-phenylethanol with acetic anhydride catalyzed by the planar chiral DMAP catalyst (–)-1 is presented. The study include a computational investigation of the potential energy surface including the rate-limiting and stereoselective transitionstates at the DFT level of theory. The kinetic study suggests that the reaction proceeds with first order in catalyst and in 1-phenylethanol, while the acetic anhydride shows a fractional order. The fractional order is racionalized based on an equilibrium between the free and the acetylated catalyst.

Keyword
Reaction progress kinetic analysis, DFT calculation
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-233714 (URN)10.1002/chem.201405793 (DOI)000352504500041 ()25677932 (PubMedID)
Available from: 2014-10-09 Created: 2014-10-08 Last updated: 2015-05-12Bibliographically approved

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