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New Methods for the Synthesis of Vicinal Stereocenters: Palladium-Catalyzed Domino Reactions and Asymmetric Transfer Hydrogenation
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. (Peter Somfai)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the synthesis of vicinal stereocenters is investigated in two distinct contexts, namely the construction of 3,3-disubstituted oxindoles and the synthesis of b-hydroxy-a-amino acids. Both scaffolds are prevalent in a range of natural products and biologically relevant compounds and, therefore, methods for their synthesis are of great import.

First, the construction of 3,3-disubstituted oxindoles using palladium-catalyzed domino reactions is described.  This covers two stereospecific methods for the construction of the desired oxindoles based on domino carbopalladation sequences.  The termination events for these domino reactions are carbonylation or cross-coupling.  In the carbopalladation-carbonylation reaction, we studied the possibilty of suppressing b-hydride elimination for substrates possessing pendant b-hydrogens.  In the carbopalladation-cross-coupling sequence, we examined the role of the boron source and substrate scaffold in the outcome of the reaction.  In both of these methods, an intricate balance of rates needs to be attained in order to achieve the desired domino sequences.  Thus, these investigations offer insight into the rates of the competing reactions, and the factors that influence these processes.

Secondly, the stereoselective synthesis of b-hydroxy-a-amino acids is explored.  This has lead to two separate methods for the construction of this scaffold.  We first examined a 1,3-dipolar cycloaddition of azomethine ylides to aldehydes for the construction of syn-b-hydroxy-a-amino esters.  It was found that one set of azomethine ylides reacted through a 1,3-dipolar cycloaddition, while the other set reacted via a direct aldol reaction.  Finally, we studied an asymmetric transfer hydrogenation reaction to provide anti-b-hydroxy-a-amido esters from the corresponding a-amido-b-ketoesters.  Two protocols were developed for the reduction of these substrates, one using triethylammonium formate and the other using sodium formate in an emulsion.  The latter method gives high yields, diastereoselectivities and enantioselectivities for a broad range of substrates.

 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. , 75 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2012:27
Keyword [en]
asymmetric synthesis, domino reactions, palladium-catalyzed reactions, oxindoles, amino alcohols
National Category
Natural Sciences Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-95327ISBN: 978-91-7501-374-9 (print)OAI: oai:DiVA.org:kth-95327DiVA: diva2:527801
Public defence
2012-08-17, F3, Linstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20120605Available from: 2012-06-05 Created: 2012-05-22 Last updated: 2012-06-05Bibliographically approved
List of papers
1. Addition of Azomethine Ylides to Aldehydes: Mechanistic Dichotomy of Differentially Substituted alpha-Imino Esters
Open this publication in new window or tab >>Addition of Azomethine Ylides to Aldehydes: Mechanistic Dichotomy of Differentially Substituted alpha-Imino Esters
2010 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 20, 3927-3933 p.Article in journal (Refereed) Published
Abstract [en]

The formal 1,3-dipolar cycloaddition of azomethine ylides and aldehydes is explored, as hydrolysis of the resulting oxazolidine product gives facile access to valuable syn-beta-aryl-beta-hydroxy-alpha-amino esters. The use of using benzaldehyde-derived imines as the ylide precursor results in 1,3-dipolar cycloaddition with high conversions but low diastereoselectivity. In contrast, the employment of benzophenone-derived imines as the ylide precursor results in an aldol reaction, which gives the intermediate oxazolidine in high diastereoselectivity and requires a weak acid catalyst to achieve higher conversions.

Keyword
Amino alcohols, Azomethine ylides, Aldol reaction, Cycloaddition
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-29445 (URN)10.1002/ejoc.201000377 (DOI)000280428700019 ()2-s2.0-77954263292 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note
QC 20110211Available from: 2011-02-11 Created: 2011-02-02 Last updated: 2017-12-11Bibliographically approved
2. Domino Carbopalladation-Carbonylation: Generating Quaternary Stereocenters while Controlling beta-Hydride Elimination
Open this publication in new window or tab >>Domino Carbopalladation-Carbonylation: Generating Quaternary Stereocenters while Controlling beta-Hydride Elimination
2010 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, no 17, 3732-3735 p.Article in journal (Refereed) Published
Abstract [en]

A domino carbopalladation-carbonylation sequence for substrates possessing beta-hydrogens is explored. This allows for the construction of complex architectures with vicinal stereocenters in a concise and rapid fashion via the stereocontrolled formation of two carbon carbon bonds. An integral aspect of this domino reaction is the ability to control beta-hydride elimination of the organopalladium intermediate and instead form the carbonylation product.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-26818 (URN)10.1021/ol1009703 (DOI)000281180700002 ()2-s2.0-77956224503 (Scopus ID)
Note
QC 20101208Available from: 2010-12-08 Created: 2010-11-29 Last updated: 2017-12-11Bibliographically approved
3. Enantioselective Synthesis of anti-beta-Hydroxy-alpha-amido Esters via Transfer Hydrogenation
Open this publication in new window or tab >>Enantioselective Synthesis of anti-beta-Hydroxy-alpha-amido Esters via Transfer Hydrogenation
2010 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, no 22, 5274-5277 p.Article in journal (Refereed) Published
Abstract [en]

The asymmetric transfer hydrogenation of alpha-amido-beta-keto esters to provide the corresponding anti-beta-hydroxy-alpha-amido esters in good to excellent yields, diastereoselectivity, and enantioselectivity is reported. The procedure is operationally simple, and delicate handling of the catalyst is not necessary.

Keyword
dynamic kinetic resolution, asymmetric transfer hydrogenation, amino acid-derivatives, aldol reactions, stereoselective hydrogenation, catalyzed hydrogenation, functionalized ketones, efficient approach, organic-synthesis, aldehydes
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-27357 (URN)10.1021/ol102323k (DOI)000284080400050 ()2-s2.0-78449267573 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note
QC 20101214Available from: 2010-12-14 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
4. Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
Open this publication in new window or tab >>Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
2012 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 354, no 1, 205-216 p.Article in journal (Refereed) Published
Abstract [en]

This work gives an in depth account of our domino carbopalladation-carbonylation method for substrates possessing beta-hydrogens. The scope of the method is examined for allylic amines containing trisubstituted olefins and we detail our attempts toward the diastereospecific synthesis of contiguous quaternary centers using this technology. The results give key insights into the relative rates of the competing reactions of the alkyl palladium intermediates, which is crucial for the understanding and development of new domino processes.

Keyword
carbonylation, domino reactions, Heck reaction, oxindoles, quaternary stereocenters
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-90663 (URN)10.1002/adsc.201100678 (DOI)000299331300020 ()2-s2.0-84856833104 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note
QC 20120228Available from: 2012-02-28 Created: 2012-02-27 Last updated: 2017-12-07Bibliographically approved
5. Enantioselective Synthesis of anti-β-Hydroxy-α-Amido Esters by Asymmetric Transfer Hydrogenation in Emulsions
Open this publication in new window or tab >>Enantioselective Synthesis of anti-β-Hydroxy-α-Amido Esters by Asymmetric Transfer Hydrogenation in Emulsions
2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 23, 2719-2723 p.Article in journal (Refereed) Published
Abstract [en]

Herein, we present two methods for an asymmetric transfer hydrogenation through the dynamic kinetic resolution of α-amido-β-ketoesters. These procedures yield the corresponding anti-β-hydroxy-α-amido esters in good yields and with good diastereo- and enantioselectivities. First, the scope of the reduction of α-amido-β-ketoesters by using triethylammonium formate azeotrope is examined. Then, an emulsion technology with sodium formate is explored, which allows for broader substrate scope, faster reaction times, and lower catalyst loading. Furthermore, these reactions are operationally simple and can be set up in air.

Keyword
amino acids, asymmetric synthesis, emulsions, kinetic resolution, transfer hydrogenation
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-96516 (URN)10.1002/chem.201103739 (DOI)000304438000026 ()2-s2.0-84861634727 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note
QC 20120605Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2017-12-07Bibliographically approved
6. Domino carbopalladation-cross-coupling for the synthesis of 3,3-disubstituted oxindoles
Open this publication in new window or tab >>Domino carbopalladation-cross-coupling for the synthesis of 3,3-disubstituted oxindoles
2012 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, no 15, 3858-3861 p.Article in journal (Refereed) Published
Abstract [en]

This study examines a domino carbopalladation-cross-coupling reaction for the formation of valuable oxindole scaffolds. Furthermore, the reaction sequence forges vicinal stereocenters in a stereospecific manner through the formation of two carbon-carbon bonds and, thereby, rapidly generates complexity. The reaction gives high yields for a variety of acrylamide substrates, and various organoboranes have also been evaluated for the cross-coupling. This work offers insight into the relative rates determining a successful carbopalladation-cross- coupling reaction and how to favor the desired reaction pathway.

Keyword
Cyclization-Anion Capture, Structure-Based Design, Organic-Synthesis, Natural-Products, Boronic Acid, Inhibitors, Catalysis, Potent, Agents, Leads
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-96517 (URN)10.1021/ol301539p (DOI)000307041600012 ()2-s2.0-84864623336 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council
Note

QC 20120905. Updated from submitted to published.

Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2017-12-07Bibliographically approved

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