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Enantioselective synthesis of α-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Vise andre og tillknytning
2010 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, nr 20, s. 6842-6847Artikkel i tidsskrift (Fagfellevurdert) 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%.

sted, utgiver, år, opplag, sider
2010. Vol. 75, nr 20, s. 6842-6847
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-45772DOI: 10.1021/jo1011653ISI: 000282604900012OAI: oai:DiVA.org:su-45772DiVA, id: diva2:369622
Forskningsfinansiär
Knut and Alice Wallenberg FoundationTilgjengelig fra: 2010-11-11 Laget: 2010-11-11 Sist oppdatert: 2017-10-11bibliografisk kontrollert
Inngår i avhandling
1. Transition Metal- and Enzyme-Catalyzed Reactions of Primary Amines and Allylic Alcohols: Powerful Tools in the Preparation of Pharmaceutically Important Compounds
Åpne denne publikasjonen i ny fane eller vindu >>Transition Metal- and Enzyme-Catalyzed Reactions of Primary Amines and Allylic Alcohols: Powerful Tools in the Preparation of Pharmaceutically Important Compounds
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm, Sweden: Department of Organic Chemistry, Stockholm University, 2010. s. 68
Emneord
Dynamic kinetic resolution, racemization, catalysis, hydrogen transfer, kinetic resolution, norsertraline, alpha-methyl carboxylic acids, pipecoloxylidide
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-38839 (URN)978-91-7447-061-1 (ISBN)
Disputas
2010-06-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Kemiska Övningslaboratoriet, 10:00 (engelsk)
Opponent
Veileder
Merknad

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.

Tilgjengelig fra: 2010-05-11 Laget: 2010-04-29 Sist oppdatert: 2017-10-11bibliografisk kontrollert

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