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A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution: application to the synthesis of norsertraline
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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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. Vol. 15, no 14, 3403-3410 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-30227DOI: 10.1002/chem.200802303ISI: 000264774400014OAI: oai:DiVA.org:su-30227DiVA: diva2:242204
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Transition Metal- and Enzyme-Catalyzed Reactions of Primary Amines and Allylic Alcohols: Powerful Tools in the Preparation of Pharmaceutically Important Compounds
Open this publication in new window or tab >>Transition Metal- and Enzyme-Catalyzed Reactions of Primary Amines and Allylic Alcohols: Powerful Tools in the Preparation of Pharmaceutically Important Compounds
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
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:nbn:se:su:diva-38839 (URN)978-91-7447-061-1 (ISBN)
Public defence
2010-06-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Kemiska Övningslaboratoriet, 10:00 (English)
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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

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