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Transition Metal- and Enzyme-Catalyzed Reactions of Primary Amines and Allylic Alcohols: Powerful Tools in the Preparation of Pharmaceutically Important Compounds
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dynamic kinetic resolution (DKR) has been applied to primary amines utilizing a ruthenium catalyst and an (R)-selective lipase to provide the corresponding amides in up to 95% isolated yield and up to >99% ee. Further investigations of the chemoenzymatic DKR of amines show that it is general and can be applied to a wide range of amines. The protocol was found to be applicable with both isopropyl acetate and dibenzyl carbonate as acyl donors. In the latter case, release of the free amine from the carbamate products was carried out under very mild conditions. A new route to prepare norsertraline, an antidepressant, utilizing DKR as one of the key steps has also been developed.

Further investigations of the DKR of 1-phenylethylamine led to the development of a protocol that could be used on gram scale. Several parameters were studied including catalyst loading, acyl donor used, and concentration of the reaction. The Ru-catalyst loading was decreased from 4 mol% to 1.25 mol% and the enzyme catalyst loading was decreased from 40 mg/mmol substrate to 10 mg/mmol substrate.

The racemization of pipecoloxylidide, an intermediate in the synthesis of commonly used anesthetics, was carried out. This racemization method was developed for its potential use in an integrated process that combines enantiomer separation techniques and racemization of the undesired enantiomer. The integration of racemization of the undesired enantiomer would increase the overall yield of the desired enantiomer and thus make the procedure highly efficient.

DKR has also been applied to allylic alcohols utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important a-methyl substituted carboxylic acids in high ee.

Place, publisher, year, edition, pages
Stockholm, Sweden: Department of Organic Chemistry, Stockholm University , 2010. , 68 p.
Keyword [en]
Dynamic kinetic resolution, racemization, catalysis, hydrogen transfer, kinetic resolution, norsertraline, alpha-methyl carboxylic acids, pipecoloxylidide
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-38839ISBN: 978-91-7447-061-1 (print)OAI: oai:DiVA.org:su-38839DiVA: diva2:316087
Public defence
2010-06-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Kemiska Övningslaboratoriet, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished  and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 7: Manuscript.

Available from: 2010-05-11 Created: 2010-04-29 Last updated: 2017-10-11Bibliographically approved
List of papers
1. A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution: application to the synthesis of norsertraline
Open this publication in new window or tab >>A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution: application to the synthesis of norsertraline
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2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 14, 3403-3410 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-30227 (URN)10.1002/chem.200802303 (DOI)000264774400014 ()
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
2. Practical chemoenzymatic dynamic kinetic resolution of primary amines via transfer of a readily removable benzyloxycarbonyl group
Open this publication in new window or tab >>Practical chemoenzymatic dynamic kinetic resolution of primary amines via transfer of a readily removable benzyloxycarbonyl group
2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 6, 977-979 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-13672 (URN)10.1016/j.tetlet.2007.12.017 (DOI)000253280500011 ()
Available from: 2008-12-03 Created: 2008-12-03 Last updated: 2017-12-13Bibliographically approved
3. Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine
Open this publication in new window or tab >>Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine
2010 (English)In: Beilstein Journal of Organic Chemistry, ISSN 1860-5397, Vol. 6, 823-829 p.Article in journal (Refereed) Published
Abstract [en]

Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1-phenylethylamine (1). Several reaction parameters have been investigated to modify the method for application on multigram scale. A comparison of isopropyl acetate and alkyl methoxyacetates as acyl donors was carried out. It was found that lower catalyst loadings could be used to obtain (R)-2-methoxy-N-(1-phenylethyl)acetamide (3) in good yield and high ee when alkyl methoxyacetates were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl donor.

Keyword
dynamic kinetic resolution, kinetic resolution, racemization, Shvo, Candida antartica lipase B
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-45770 (URN)10.3762/bjoc.6.97 (DOI)
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2015-12-04Bibliographically approved
4. Synthesis of (R)-2-methoxy-N-(1-phenylethyl)acetamide via Dynamic Kinetic Resolution
Open this publication in new window or tab >>Synthesis of (R)-2-methoxy-N-(1-phenylethyl)acetamide via Dynamic Kinetic Resolution
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:su:diva-38836 (URN)
Available from: 2010-04-29 Created: 2010-04-29 Last updated: 2010-04-30
5. Recycling of pipecoloxylidide via racemization
Open this publication in new window or tab >>Recycling of pipecoloxylidide via racemization
2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 52, 6802-6805 p.Article in journal (Refereed) Published
Abstract [en]

A method for the racemization of pipecoloxylidide with a ruthenium catalyst has been developed. This racemization method can be implemented in an integrated process that combines the separation of two enantiomers with racemization of the undesired enantiomer.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-51426 (URN)10.1016/j.tetlet.2010.07.051 (DOI)
Available from: 2011-01-10 Created: 2011-01-10 Last updated: 2017-12-11Bibliographically approved
6. An enantioselective route to alpha-methyl carboxylic acids via metal and enzyme catalysis
Open this publication in new window or tab >>An enantioselective route to alpha-methyl carboxylic acids via metal and enzyme catalysis
2007 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 9, no 24, 5095-5098 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic kinetic resolution of allylic alcohols to allylic acetates followed by copper-catalyzed allylic substitution gave alkenes in high yields and high optical purity. Subsequent oxidative C-C double bond cleavage afforded pharmaceutically important alpha-methyl substituted carboxylic acids in high ee.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-11741 (URN)10.1021/ol702261t (DOI)000250975000042 ()
Available from: 2008-01-14 Created: 2008-01-14 Last updated: 2017-10-16
7. Enantioselective synthesis of α-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution
Open this publication in new window or tab >>Enantioselective synthesis of α-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution
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2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 20, 6842-6847 p.Article in journal (Refereed) Published
Abstract [en]

An enantioselective method for the synthesis of α-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C−C double bond cleavage afforded pharmaceutically important α-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-45772 (URN)10.1021/jo1011653 (DOI)000282604900012 ()
Funder
Knut and Alice Wallenberg Foundation
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2017-10-11Bibliographically approved

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