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Tandem reversible addition-intramolecular lactonization for the synthesis of 3-functionalized phthalides
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 1, 75-78 p.Article in journal (Refereed) Published
Abstract [en]

A new tandem process based on reversible nucleophilic addition and intramolecular lactonization of methyl 2-formylbenzoate leads to the efficient synthesis of 3-functionalized phthalides, which are important precursors for the synthesis of quinone skeletons via Hauser–Kraus annulation. The reactions are successfully carried out under mild conditions in single operations.

Place, publisher, year, edition, pages
2010. Vol. 51, no 1, 75-78 p.
Keyword [en]
DYNAMIC COMBINATORIAL RESOLUTION, ANNULATION REACTIONS, CHEMISTRY, ANNELATION
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-12736DOI: 10.1016/j.tetlet.2009.10.079ISI: 000274232200018Scopus ID: 2-s2.0-70649083235OAI: oai:DiVA.org:kth-12736DiVA: diva2:318438
Funder
Swedish Research Council
Note
QC 20110126Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Discovery-Oriented Screening of Dynamic Systems: Combinatorial and Synthetic Applications
Open this publication in new window or tab >>Discovery-Oriented Screening of Dynamic Systems: Combinatorial and Synthetic Applications
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is divided into six parts, all centered around the development of dynamic (i.e., reversibly interacting) systems of molecules and their applications in dynamic combinatorial chemistry (DCC) and organic synthesis.

Part one offers a general introduction, as well as a more detailed description of DCC, being the central concept of this thesis. Part two explores the potential of the nitroaldol reaction as a tool for constructing dynamic systems, employing benzaldehyde derivatives and nitroalkanes. This reaction is then applied in part three where a dynamic nitroaldol system is resolved by lipase-catalyzed transacylation, selecting two out of 16 components.

In part four, reaction and crystallization driven DCC protocols are developed and demonstrated. The discovery of unexpected crystalline properties of certain pyridine β-nitroalcohols is used to resolve a dynamic system and further expanded into asynthetic procedure. Furthermore, a previously unexplored tandem nitroaldol-iminolactone rearrangement reaction between 2-cyanobenzaldehyde and primarynitroalkanes is used for the resolution of dynamic systems. It is also coupled with diastereoselective crystallization to demonstrate the possibility to combine several selection processes. The mechanism of this reaction is investigated and a synthetic protocol is developed for asymmetric synthesis of 3-substituted isoindolinones.

Part five continues the exploration of tandem reactions by combining dynamic hemithioacetal or cyanohydrin formation with intramolecular cyclization to synthesize a wide range of 3-functionalized phthalides.

Finally, part six deals with the construction of a laboratory experiment to facilitate the introduction of DCC in undergraduate chemistry education. The experiment is based on previous work in our group and features an acetylcholinesterase-catalyzed resolution of a dynamic transthioacylation system.

Place, publisher, year, edition, pages
Stockholm: KTH, 2010. 82 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2010:13
Keyword
chemical education, crystallization, dynamic combinatorial chemistry, dynamic combinatorial resolution, dynamic system, enzyme catalysis, isoindolinone, lipase, nitroalcohol, nitroaldol reaction, phthalide, reversible, secondary alcohol, systems chemistry, tandem reaction
National Category
Organic Chemistry Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-12524 (URN)978-91-7415-617-1 (ISBN)
Public defence
2010-05-28, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100628Available from: 2010-05-12 Created: 2010-05-03 Last updated: 2011-02-11Bibliographically approved
2. Dynamic Systems: Evaluation, Screening and Synthetic Application
Open this publication in new window or tab >>Dynamic Systems: Evaluation, Screening and Synthetic Application
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research work reported in the thesis deals with the development of dynamic covalent systems and their applications in evaluation and screening of protein-ligands and enzyme inhibitors, as well as in synthetic methodologies. The thesis is divided into four parts as described below.

In part one, synthetic methodologies to access 3-functionalized phthalides and 3-thioisoindolinones using the concept of cascade reactions are demonstrated. Efficient syntheses of the target products are designed and performed in one-pot process under mild reaction conditions.

 In part two, phosphine-catalyzed disulfide metathesis for the generation of dynamic carbohydrate system in aqueous solution is demonstrated. In the presence of biological target (Concanavalin A), the optimal dynamic ligand is successfully identified in situ by the 1H STD-NMR spectroscopy.

In part three, lipase-catalyzed resolutions of dynamic reversible systems using reversible cyanohydrin and hemithioacetal reactions in one-pot processes are demonstrated. The dynamic systems are generated under thermodynamic control in organic solution and subsequently resolved by lipase-mediated resolution under kinetic control. The resolution processes resulted in the lipase-selected substrates with high structural and stereochemical specificities.

In the last part, dynamic fragment-based strategy is presented using β-galactosidase as a model target enzyme. Based on our previous study, the best dynamic inhibitor of β-galactosidase was identified using 1H STD-NMR technique from dynamic hemithioacetal systems. The structure of the dynamic inhibitor is tailored by fragment linking and optimization processes. The designed inhibitor structures are then synthesized and tested for inhibition activities against β-galactosidase. 

 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2011. 69 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2011:33
Keyword
constitutional dynamic chemistry; dynamic combinatorial chemistry/ resolution; dynamic fragment-based approach; dynamic kinetic resolution; dynamic reversible systems; 1H STD-NMR; multicomponent reaction; tandem reaction
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-34100 (URN)978-91-7415-986-8 (ISBN)
Public defence
2011-06-07, F3, KTH, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
EU, European Research Council, MRTN-CT-2006-035614
Note
QC 20110526Available from: 2011-05-26 Created: 2011-05-25 Last updated: 2011-05-26Bibliographically approved

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