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Methods for Asymmetric Olefination Reactions; Development and Application to Natural Product Synthesis
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

This thesis deals with the development and application of methods for asymmetric olefinations, in particular Horner-Wadsworth-Emmons (HWE) reactions, in the synthesis of certain natural products.

Relying on asymmetric HWE reactions to access key building blocks, two natu-ral products, pyranicin and pyragonicin, were synthesized from common late intermediates. The utility of the HWE reactions is highlighted through a desymmetrization of a meso-dialdehyde as well as a stereoconvergent reaction sequence employing the sequential use of a HWE parallel kinetic resolution fol-lowed by a Pd-catalyzed allylic substitution to convergently transform a race-mate to a single stereoisomer of the product. Methodological extensions of these syntheses include a divergent synthesis of 2,3,6-substituted tetrahydropyran derivatives and application of Zn-mediated asymmetric alkynylations to install key stereocenters.

Synthetic studies directed towards a more complex target, mucocin, employing a triply convergent strategy, have also been performed. Expedient and reliable routes to three key fragments were developed, as well as methodology to access to all nine stereocenters. The fragment coupling to assemble the oligonuclear core still remains a challenge, however. Key features of the synthesis include the formation of two fragments from a common precursor derived from an asymmetric HWE desymmetrization, Zn-mediatedated asymmetric alkynylations, a stereoselective oxa-Michael cyclization dependent on a simultaneous protective group migration and a one-pot procedure for the synthesis of a TBS protected iodohydrin from a terminal epoxide.

An investigation of the possibilities for developing a transition metal catalyzed asymmetric olefination using a chiral Re-complex is outlined. An enantioen-riched BINAP-Re complex was synthesized and characterized by X-ray. An efficient protocol for the olefination of functionalized aldehydes employing this catalyst was developed, but gave racemic products in two attempted kinetic resolutions of racemic substrates, most likely due to a reaction pathway proceeding via a non-metal associated phosphonium ylide.

Place, publisher, year, edition, pages
Stockholm: KTH , 2006.
Series
Trita-IOK, ISSN 1100-7974 ; 2006:103
Keyword [en]
Antitumor agents, Asymmetric Horner-Wadsworth-Emmons, Desymmetrization, Metal-catalyzed olefination, Mucocin, Palladium-catalyzed allylic substitution, Parallel kinetic resolution, Pyranicin, Pyragonicin, Rhenium, Stereoconvergent synthesis, Stereodivergent synthesis, Stereoselective synthesis, Tetrahydropyran, Wittig reaction
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4088ISBN: 91-7178-427-6 (print)OAI: oai:DiVA.org:kth-4088DiVA: diva2:10674
Public defence
2006-09-20, F3, Lindstetsvägen 26, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100921Available from: 2006-08-28 Created: 2006-08-28 Last updated: 2010-09-21Bibliographically approved
List of papers
1. Total Synthesis of Pyranicin
Open this publication in new window or tab >>Total Synthesis of Pyranicin
2005 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 7, no 2, 199-202 p.Article in journal (Refereed) Published
Abstract [en]

A stereocontrolled convergent synthesis of the annonaceous acetogenin pyranicin (1) is presented. Asymmetric Horner-Wadsworth-Emmons (HWE) reactions were used to access key intermediates. The tetrahydropyran derivative 2 was obtained via an asymmetric desymmetrization of the meso-dialdehyde 6, and the butenolide fragment was constructed using a stereoconvergent reaction sequence involving a parallel kinetic HWE resolution followed by a Pd-catalyzed allylic substitution. The C10/C15 1,6-diol motif was installed using Carreira's asymmetric acetylide addition methodology.

Keyword
horner-wadsworth-emmons, annonaceous acetogenins, antitumor agent, aldehydes, ethers
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6066 (URN)10.1021/ol0479242 (DOI)000226330300009 ()2-s2.0-13444249837 (Scopus ID)
Note
QC 20100921Available from: 2006-08-28 Created: 2006-08-28 Last updated: 2010-09-21Bibliographically approved
2. Synthesis of Pyragonicin
Open this publication in new window or tab >>Synthesis of Pyragonicin
2005 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 7, no 13, 2779-2781 p.Article in journal (Refereed) Published
Abstract [en]

A stereocontrolled convergent synthesis of the annonaceous acetogenin pyragonicin (1) is presented. The key intermediates were accessed using asymmetric Horner-Wadsworth-Emmons (HWE) methodology. A reagent controlled zinc-mediated stereoselective coupling, joining the two highly functionalized intermediates 3 and 4, then provided the core structure.

Keyword
annonaceous acetogenins, epimerization, pyranicin, ring
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6067 (URN)10.1021/ol050997g (DOI)000229952100066 ()2-s2.0-29844439833 (Scopus ID)
Note
QC 20100921Available from: 2006-08-28 Created: 2006-08-28 Last updated: 2010-09-21Bibliographically approved
3. Divergence en Route to Nonclassical Annonaceous Acetogenins. Synthesis of Pyranicin and Pyragonicin
Open this publication in new window or tab >>Divergence en Route to Nonclassical Annonaceous Acetogenins. Synthesis of Pyranicin and Pyragonicin
2006 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, no 5, 1879-1891 p.Article in journal (Refereed) Published
Abstract [en]

Syntheses of the nonclassical annonaceous acetogenins, pyranicin, and pyragonicin from common late-stage intermediates are presented. The construction of key elements relies on asymmetric HWE reactions, including the desymmetrization of a meso-dialdehyde and a parallel kinetic resolution of a racemic aldehyde. A stereoconvergent Pd-catalyzed substitution serves to install the C4 stereocenter in protected form with different orthogonal protective groups. A divergent strategy to form 1.4- and 1.6-diols, employing stereoselective Zn-mediated alkynylations, is used for completion of the core structures. Notably, the stereoselective coupling reaction toward pyragonicin proceeds with highly functionalized fragments. The methodology is further expanded by a divergent synthesis of all stereoisomers of the 2,3,6-trisubstituted tetrahydropyran subunit.

Keyword
horner-wadsworth-emmons, molecular mechanics, tetrahydropyran ring, cytotoxic acetogenin, recent progress, complex-i, efficient, stereodivergent, aldehydes, ethers
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6068 (URN)10.1021/jo052233k (DOI)000235896800015 ()2-s2.0-33644652277 (Scopus ID)
Note

QC 20100921

Available from: 2006-08-28 Created: 2006-08-28 Last updated: 2017-06-13Bibliographically approved
4. Towards the Synthesis of (-) -Mucocin
Open this publication in new window or tab >>Towards the Synthesis of (-) -Mucocin
(English)Manuscript (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6069 (URN)
Note
QC 20100921Available from: 2006-08-28 Created: 2006-08-28 Last updated: 2010-09-21Bibliographically approved
5. Evaluation of (+)-[BINAP]Re(0)Cl3 as a Catalyst for the Olefination of Aldehydes
Open this publication in new window or tab >>Evaluation of (+)-[BINAP]Re(0)Cl3 as a Catalyst for the Olefination of Aldehydes
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6070 (URN)
Note
QC 20100921Available from: 2006-08-28 Created: 2006-08-28 Last updated: 2010-09-21Bibliographically approved

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