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Amino acid-catalyzed synthesis of amino acid derivatives: Application and semi-synthesis of Paclitaxel, Docetaxel and their derivatives
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Armando Córdova)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with different applications of organocatalysis, where amino acid derivatives and small peptides are applied as catalysts. First, the development of environmentally friendly aldol reactions, carried out in aqueous media is illustrated. The corresponding β-hydroxy ketones are formed with ee´s up to 99%. Chapter 3 describes the ability of β3-amino acids to selectively catalyze Mannich-type reactions and govern the formation of products with high anti-selectivity (up to >19:1) and ee´s up to 99%. In the following chapter, an amino acid-catalyzed one-pot three component Mannich reaction between dihydroxyacetone and PMP-protected imines, is presented. The corresponding a,a’-dihydroxy-b-aminoketones are obtained in high yields and with 82-95% ee. Next, an aza-Morita-Baylis-Hillman reaction was investigated where L-proline is the catalyst. The reaction proceeds with excellent chemo- and enantioselectivity to give the corresponding compounds in good yields and with 97-99% ee. Finally, the last part describes development of a proline-catalyzed Mannich reation between N-acyl imines and protected α-hydroxyaldehyes, providing access to different α-hydroxy-β-amino acids in good yields and high enantioselctivity (92-99% ee). The obtained amino acids were further applied in the semisynthesis of paclitaxel and docetaxel derivatives.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2010. , 73 p.
Keyword [en]
Organocatlysis, amino acids, syntesis, Taxol and Taxotere derivatives
National Category
Other Basic Medicine
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-39138ISBN: 978-91-7447-091-8 (print)OAI: oai:DiVA.org:su-39138DiVA: diva2:318680
Public defence
2010-06-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16b, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 7: Manuscript.Available from: 2010-05-20 Created: 2010-05-10 Last updated: 2010-05-12Bibliographically approved
List of papers
1. The small peptide-catalyzed direct asymmetric aldol reaction in water
Open this publication in new window or tab >>The small peptide-catalyzed direct asymmetric aldol reaction in water
2006 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, 38-40 p.Article in journal (Refereed) Published
National Category
Other Basic Medicine
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-39047 (URN)10.1039/b515880j (DOI)
Available from: 2010-05-06 Created: 2010-05-06 Last updated: 2017-12-12Bibliographically approved
2. Acyclic beta-amino acid catalyzed asymmetric anti-selective Mannich-type reactions
Open this publication in new window or tab >>Acyclic beta-amino acid catalyzed asymmetric anti-selective Mannich-type reactions
2007 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 18, no 9, 1033-1037 p.Article in journal (Refereed) Published
Abstract [en]

 The ability of a primary amine containing acyclic beta(3)-amino acids to catalyze direct asymmetric anti-selective Mannich-type reactions is presented. The reactions are generally highly diastereo- and enantioselective to give the corresponding Mannich products with up to >19:1 dr (anti/syn) and 88-99% ee.

Identifiers
urn:nbn:se:su:diva-19291 (URN)10.1016/j.tetasy.2007.04.024 (DOI)000247898000001 ()
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2010-05-12Bibliographically approved
3. Direct catalytic asymmetric three-component Mannich reactions with dihydroxyacetone: enantioselective synthesis of amino sugar derivatives
Open this publication in new window or tab >>Direct catalytic asymmetric three-component Mannich reactions with dihydroxyacetone: enantioselective synthesis of amino sugar derivatives
2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1873-3581, Vol. 49, no 5, 803-807 p.Article in journal (Refereed) Published
Abstract [en]

Highly enantioselective, amino acid-catalyzed, one-pot three-component asymmetric Mannich reactions between dihydroxyacetone, p-anisidine, and aldehydes are presented. The reactions proceeded with high chemo- and stereoselectivity and furnished the corresponding α,α′-dihydroxy-β-aminoketones in high yields with 82–95% ee.

Identifiers
urn:nbn:se:su:diva-13153 (URN)10.1016/j.tetlet.2007.11.196 (DOI)000253170200014 ()
Available from: 2008-12-03 Created: 2008-12-03 Last updated: 2010-05-12Bibliographically approved
4. Aza-Morita-Baylis-Hillman-type reactions: highly enantioselective organocatalytic addition of unmodified alpha-beta-unsaturated aldehydes to N-Boc protected imines
Open this publication in new window or tab >>Aza-Morita-Baylis-Hillman-type reactions: highly enantioselective organocatalytic addition of unmodified alpha-beta-unsaturated aldehydes to N-Boc protected imines
2007 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1873-3581, Vol. 48, no 39, 6900-6904 p.Article in journal (Refereed) Published
Abstract [en]

Highly enantioselective catalytic routes to Boc protected aza-Morita-Baylis-Hiliman-type products are presented. The organocatalytic asymmetric reactions between unmodified alpha,beta-unsaturated aldehydes and N-Boc protected aryl imines proceed with excellent chemo- and enantioselectivity to give the corresponding compounds in good yields with 97-99% ee

Identifiers
urn:nbn:se:su:diva-19364 (URN)10.1016/j.tetlet.2007.07.154 (DOI)000249752500016 ()
Available from: 2007-11-07 Created: 2007-11-07 Last updated: 2010-05-12Bibliographically approved
5. Catalytic asymmetric synthesis of the docetaxel (Taxotere) side chain: organocatalytic highly enantioselective synthesis of esterification-ready alpha-hydroxy-beta-amino acids
Open this publication in new window or tab >>Catalytic asymmetric synthesis of the docetaxel (Taxotere) side chain: organocatalytic highly enantioselective synthesis of esterification-ready alpha-hydroxy-beta-amino acids
2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, Vol. 49, no 47, 6631-6634 p.Article in journal (Refereed) Published
Abstract [en]

A highly enantioselective catalytic route to protected β-amino-α-hydroxy acids, such as the side chain of Taxotere, is presented. The organocatalytic asymmetric reactions between unmodified protected α-oxyaldehydes and N-Boc-protected aryl imines give the corresponding compound with up to >19:1 dr and 99–99% ee.

Identifiers
urn:nbn:se:su:diva-15773 (URN)10.1016/j.tetlet.2008.09.038 (DOI)000260944900008 ()
Available from: 2008-12-10 Created: 2008-12-10 Last updated: 2010-05-12Bibliographically approved
6. Highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides: Asymmetric synthesis of the paclitaxel side chain and its analogues
Open this publication in new window or tab >>Highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides: Asymmetric synthesis of the paclitaxel side chain and its analogues
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 16, 4044-4048 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2009
Keyword
aldehydes, asymmetric catalysis, (phenylmethylene)benzamides, organocatalysis, taxol
National Category
Chemical Sciences
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-28211 (URN)10.1002/chem.200900078 (DOI)000265509700013 ()
Available from: 2009-06-10 Created: 2009-06-10 Last updated: 2010-05-12Bibliographically approved
7. Practical amino acid-catalyzed asymmetric synthesis pf protected α-hydroxy-amino aldehydes and acids
Open this publication in new window or tab >>Practical amino acid-catalyzed asymmetric synthesis pf protected α-hydroxy-amino aldehydes and acids
(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-39028 (URN)
Available from: 2010-05-06 Created: 2010-05-06 Last updated: 2010-05-12Bibliographically approved

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