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Stereoselective Synthesis of Amino Alcohols: Applications to Natural Product Synthesis
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

This thesis is divided into four separate parts with amino alcohols as the common feature.

The first part of the thesis describes the development of an efficient three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral α-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-amino esters. This methodology was also applied on a short asymmetric synthesis of the paclitaxel side-chain as well as in an asymmetric synthetic approach towards the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II) carboxylates furnishes the syn-α-hydroxy-β-amino esters in moderate enantioselectivity (er up to 82:18), which indicates that the reaction proceeds via a metal-associated carbonyl ylide.

The second part describes the development of a 1,3-dipolar cycloaddition reaction of azomethine ylides to aldehydes for the synthesis of α-amino-β-hydroxy esters. Different methods for the generation of the ylides, including Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have been evaluated. The best results were obtained with the Ag(I)/phosphine approach, which yielded the desired α-amino-β-hydroxy ester in 68% yield and 3.4:1 syn:anti-selectivity.

The last two parts deals with the total synthesis of the amino alcohol-containing natural products D-erythro-sphingosine and (−)-stemoamide. The key transformation in the sphingosine synthesis is a cross-metathesis reaction for the assembly of the polar head group and the aliphatic chain. In the stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-sequence for the construction of the β,γ-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry.

Place, publisher, year, edition, pages
Stockholm: KTH , 2007. , 71 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2007:52
Keyword [en]
Amino alcohol, asymmetric 1.3-dipolar cycloaddition, azomethine ylide, carbenoid, carbonyl ylide, cross-metathesis, omuralide, oxazolidine, rhodium, sphingosine, stemoamide, stereoselective synthesis, total synthesis.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4472ISBN: 978-91-7178-734-7 (print)OAI: oai:DiVA.org:kth-4472DiVA: diva2:12426
Public defence
2007-09-14, F3, Lindstedtsvägen 26, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100820Available from: 2007-08-23 Created: 2007-08-23 Last updated: 2010-08-20Bibliographically approved
List of papers
1. 1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines: A Three Component Approach to syn-α-Hydroxy-β-amino Esters
Open this publication in new window or tab >>1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines: A Three Component Approach to syn-α-Hydroxy-β-amino Esters
2005 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 44, no 20, 3096-3099 p.Article in journal (Refereed) Published
Abstract [en]

(Chemical Equation Presented) A highly diastereoselective Rh II-catalyzed 1,3-dipolar cycloaddition leads to the formation of syn-β-amino alcohols and syn-α-hydroxy-β-amino acids in high yields (see scheme; p-TSA = poro-toluenesulfonic acid, Bn = benzyl). This three-component approach to the addition of metal-associated carbonyl ylides to aldimines was applied to a short enantioselective synthesis of the C13 side chain of taxol.

Keyword
amino alcohols; carbenoids; cycloaddition; multicomponent reactions; ylides
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-7403 (URN)10.1002/anie.200500296 (DOI)000229342600020 ()2-s2.0-18944380156 (Scopus ID)
Note
QC 20100817Available from: 2007-08-23 Created: 2007-08-23 Last updated: 2010-12-22Bibliographically approved
2. 1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines:  Scope, Limitations and Asymmetric Cycloadditions
Open this publication in new window or tab >>1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines:  Scope, Limitations and Asymmetric Cycloadditions
2006 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 348, no 16-17, 2421-2430 p.Article in journal (Refereed) Published
Abstract [en]

The development of a diastereoselective 1,3-dipolar cycloaddition of carbonyl ylides and imines for the synthesis of alpha-hydroxy-beta-amino esters is described. The methodology is successfully applied to chiral alpha-methylbenzylimines affording enantiomerically pure syn-beta-amino alcohols, which is exemplified with a short asymmetric synthesis of the paclitaxel side-chain. The use of chiral Rh(11) carboxylate catalysts for the development of a catalytic enantioselective 1,3-dipolar cycloaddition is also described, affording syn-beta-amino alcohols in modest enantiomeric purity (e.r. up to 82:18).

Keyword
amino alcohols; asymmetric 1, 3-dipolar cycloadditions; carbenoids; carbonyl ylides; imines; multicomponent reactions
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-7404 (URN)10.1002/adsc.200600324 (DOI)000242471700017 ()2-s2.0-33845293766 (Scopus ID)
Note
QC 20100817Available from: 2007-08-23 Created: 2007-08-23 Last updated: 2010-08-17Bibliographically approved
3. 1,3-Dipolar Cycloadditions of Azomethine Ylides to Aldehydes: Synthesis of α-Amino-β-hydroxy Esters
Open this publication in new window or tab >>1,3-Dipolar Cycloadditions of Azomethine Ylides to Aldehydes: Synthesis of α-Amino-β-hydroxy Esters
(English)Manuscript (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-7405 (URN)
Note
QC 20100820Available from: 2007-08-23 Created: 2007-08-23 Last updated: 2010-08-20Bibliographically approved
4. A Practical Synthesis of D-erythro-Sphingosine Using a Cross-Metathesis Approach
Open this publication in new window or tab >>A Practical Synthesis of D-erythro-Sphingosine Using a Cross-Metathesis Approach
2004 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, no 11, 1643-1646 p.Article in journal (Refereed) Published
Abstract [en]

Starting from a vinylepoxide, a short and practical synthesis of D-erythro-sphingosine is described. The key transformations are a regioselective opening of the vinylepoxide and an E-selective cross-metathesis, affording the target molecule in 5 steps and 51% overall yield.

Keyword
ring-closing metathesis, glycosphingolipid precursors, stereoselective synthesis, ceramide, epoxy-4-pentenols, diastereomers, selectivity, alcohols, products, support
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-7406 (URN)10.1039/b403568b (DOI)000221664600014 ()2-s2.0-2942752245 (Scopus ID)
Note
QC 20100825Available from: 2007-08-23 Created: 2007-08-23 Last updated: 2010-12-22Bibliographically approved
5. Total Synthesis of (-)-Stemoamide
Open this publication in new window or tab >>Total Synthesis of (-)-Stemoamide
2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 11, 4246-4249 p.Article in journal (Refereed) Published
Abstract [en]

A stereocontrolled total synthesis of (-)-stemoamide (1) is presented. The synthesis starts from commercially available (S)-pyroglutaminol (4). A chemoselective iodoboration of 5 was used to access key intermediate 3. The beta,gamma-unsaturated azepine derivative 2 was obtained via a Pd(0)-catalyzed sp(2)-sp(3) Negishi cross-coupling using a Reformatsky nucleophile followed by a ring-closing metathesis reaction. The required C8-C9 trans-stereochemistry of 1 was accessed through a stereoselective bromolactonization/1,4-reduction sequence.

Keyword
Chemoselective iodoboration; Metathesis reaction; Reduction sequences; Alcohols; Derivatives; Reduction; Synthesis (chemical); Amides; alkaloid derivative; azepine derivative; glutamine derivative; palladium; pyroglutaminol; stemoamide; unclassified drug; article; catalysis; cross coupling reaction; drug structure; drug synthesis; reduction; Reformatsky reaction; ring closing metathesis; stereochemistry; Alkaloids; Azepines; Catalysis; Heterocyclic Compounds, 3-Ring; Lactones; Models, Molecular; Molecular Conformation; Molecular Structure; Stereoisomerism
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-7407 (URN)10.1021/jo070498o (DOI)000246570200034 ()17451274 (PubMedID)2-s2.0-34249812712 (Scopus ID)
Note
QC 20100820Available from: 2007-08-23 Created: 2007-08-23 Last updated: 2010-08-20Bibliographically approved

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