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An enantioselective route to alpha-methyl carboxylic acids via metal and enzyme catalysis
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.
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.

Place, publisher, year, edition, pages
2007. Vol. 9, no 24, 5095-5098 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-11741DOI: 10.1021/ol702261tISI: 000250975000042OAI: oai:DiVA.org:su-11741DiVA: diva2:178260
Available from: 2008-01-14 Created: 2008-01-14 Last updated: 2017-10-16
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)
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
2. Synthetic Transformations via Metal- and Enzyme-Catalyzed Dynamic Kinetic Resolution
Open this publication in new window or tab >>Synthetic Transformations via Metal- and Enzyme-Catalyzed Dynamic Kinetic Resolution
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the preparation of a new half-sandwich type ruthenium(II)- catalyst for racemization of optically active secondary alcohols and the development of a highly efficient method in combination with lipases such as Candida antarctica lipase B and Pseudomonas cepacia lipase for dynamic kinetic resolution of various functionalized alcohols under mild reaction conditions.

It was shown that the RuCl(CO)25-C5Ph5) complex can racemize optically active aliphatic and aromatic secondary alcohols at room temperature in rather short times. Different parameters, such as the nature of the catalyst, catalyst loading and solvent effect were studied. After the optimization steps, the Ru-catalyzed racemization of (S)-1-phenylethanol in the presence of Candida antarctica lipase B was also investigated. The compatibility of the metal- and enzyme-catalyzed reactions led to a highly efficient coupled catalytic system for transformation of racemic alcohols to their enantiomerically pure acetates. This protocol was applied for a wide range of secondary alcohols. It was shown that in the case of allylic alcohols the obtained enantiopure allylic acetates are useful compounds for synthesis of α-methyl carboxylic acids such as (R)-Flurbiprofen and acyloin acetates. Highly selective dynamic kinetic asymmetric transformation of 3,5-piperidine diol to deliver various 3,5-dioxygenated piperidines is also described.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi, 2007. 66 p.
Keyword
ruthenium, racemization, lipase, dynamic kinetic resolution, secondary alcohol, Candida antarctica lipase B
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-6876 (URN)978-91-7155-463-5 (ISBN)
Public defence
2007-06-20, Magnélisalen, Arrheniuslaboratoriet, Svante Arrhenius väg 12, Stockholm, 10:00
Opponent
Supervisors
Available from: 2007-05-30 Created: 2007-05-23 Last updated: 2017-10-16Bibliographically approved
3. Asymmetric Synthesis and Mechanistic Studies on Copper(I)-Catalyzed Substitution of Allylic Substrates
Open this publication in new window or tab >>Asymmetric Synthesis and Mechanistic Studies on Copper(I)-Catalyzed Substitution of Allylic Substrates
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the copper-catalyzed substitution of allylic substrates.

In the first part of this thesis, the synthesis of a series of metallocenethiolates is described. The thiolates were examined as ligands in the enantioselective copper(I)-catalyzed γ-substitution of allylic acetates.

The second part describes a study on copper-catalyzed α-substitution of enantiomerically pure secondary allylic esters. It was observed that the degree of chirality transfer is strongly dependent on the reaction temperature. The loss of chiral information is consistent with an equilibration of the allylCu(III) intermediates prior to product formation, which is essential in order to realize a copper-catalyzed dynamic kinetic asymmetric transformation process.

The third part describes a study on copper-catalyzed stereoselective α-substitution of enantiopure acyclic allylic esters. This method, when combined, with ruthenium and enzyme catalyzed dynamic kinetic resolution of allylic alcohols, provides a straightforward route to pharmaceutically important α-methyl carboxylic acids.

The fourth part is a mechanistic study on the reaction of perfluoroallyl iodide with organocuprates. Experimental studies as well as theoretical calculations were used to explain the contrasting reactivity of perfluoroallyl iodide vs. allyl iodide in cuprate allylation reactions.

In the fifth part, the development of a practical and useful method for the preparation of pentasubstituted acylferrocenes is presented.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi, 2006. 53 p.
Keyword
copper, allylic substitution, ferrocene, DYKAT, cross-coupling, homo-coupling, DFT
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-1031 (URN)91-7155-280-4 (ISBN)
Public defence
2006-06-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Supervisors
Available from: 2006-05-08 Created: 2006-05-08 Last updated: 2017-12-01Bibliographically approved

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