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Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols: Synthetic Applications and Mechanistic Studies
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2014. , s. 54
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1191
Emneord [en]
kinetic resolution, organocatalysis, secondary alcohols, reaction progress kinetic analysis
HSV kategori
Forskningsprogram
Kemi med inriktning mot organisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-233734ISBN: 978-91-554-9075-1 (tryckt)OAI: oai:DiVA.org:uu-233734DiVA, id: diva2:756041
Disputas
2014-11-28, A1:111a, BMC, Husargatan 3, Uppsala, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2014-11-07 Laget: 2014-10-09 Sist oppdatert: 2015-02-03
Delarbeid
1. Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst
Åpne denne publikasjonen i ny fane eller vindu >>Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst
2013 (engelsk)Inngår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 69, nr 2, s. 753-757Artikkel i tidsskrift (Fagfellevurdert) 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).

Emneord
Non-enzymatic kinetic resolution, 1, 2-Azidoalcohols, Planar-chiral DMAP derivative catalyst, Ferrocenyl catalyst
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-189450 (URN)10.1016/j.tet.2012.10.077 (DOI)000314371800045 ()
Tilgjengelig fra: 2013-01-02 Laget: 2013-01-02 Sist oppdatert: 2017-12-06bibliografisk kontrollert
2. Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst
Åpne denne publikasjonen i ny fane eller vindu >>Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst
2014 (engelsk)Inngår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 70, nr 24, s. 3807-3811Artikkel i tidsskrift (Fagfellevurdert) 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).

Emneord
Non-enzymatic kinetic resolution, 2-Hydroxy-2-arylethylphosphonates, Planar chiral DMAP derivative catalyst
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-227994 (URN)10.1016/j.tet.2014.03.102 (DOI)000336710200010 ()
Tilgjengelig fra: 2014-07-04 Laget: 2014-07-02 Sist oppdatert: 2017-12-05bibliografisk kontrollert
3. Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst
Åpne denne publikasjonen i ny fane eller vindu >>Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst
2014 (engelsk)Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, nr 9, s. 14273-14291Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
non-enzymatic kinetic resolution, β-hydroxy esters, planar-chiral DMAP catalyst, ferrocenyl catalyst
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-224444 (URN)10.3390/molecules190914273 (DOI)000343093100085 ()25215586 (PubMedID)
Merknad

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

Tilgjengelig fra: 2014-10-08 Laget: 2014-05-12 Sist oppdatert: 2017-12-05bibliografisk kontrollert
4. A Mechanistic Investigation of the Kinetic Resolution of Secondary Aromatic Alcohols Using a Ferrocene-Based Planar Chiral 4-(Dimethylamino)pyridine Catalyst
Åpne denne publikasjonen i ny fane eller vindu >>A Mechanistic Investigation of the Kinetic Resolution of Secondary Aromatic Alcohols Using a Ferrocene-Based Planar Chiral 4-(Dimethylamino)pyridine Catalyst
2015 (engelsk)Inngår i: CHEMISTRY-A EUROPEAN JOURNAL, ISSN 0947-6539, Vol. 21, nr 14, s. 5623-5631Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
Reaction progress kinetic analysis, DFT calculation
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-233714 (URN)10.1002/chem.201405793 (DOI)000352504500041 ()25677932 (PubMedID)
Tilgjengelig fra: 2014-10-09 Laget: 2014-10-08 Sist oppdatert: 2015-05-12bibliografisk kontrollert

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