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Dynamic Asymmetric Hemithioacetal Transformation by Lipase-Catalyzed gamma-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one Derivatives
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 20, 6129-6132 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic hemithioacetal systems were efficiently generated in organic solvents and subsequently allowed to react with a range of lipases. This resulted in direct, dynamic asymmetric transformation of the systems, leading to optically active 1,3-oxathiolan-5-one products. The tandem process identified lipase-catalyzed lactonization as a useful method for the resolution of optimal constituents with high chemo- and stereoselectivities.

Place, publisher, year, edition, pages
2012. Vol. 18, no 20, 6129-6132 p.
Keyword [en]
asymmetric transformation, dynamic chemistry, enzyme catalysis, hemithioacetal, lactone, lipase
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-34125DOI: 10.1002/chem.201102139ISI: 000303497600002Scopus ID: 2-s2.0-84860758898OAI: oai:DiVA.org:kth-34125DiVA: diva2:419256
Funder
Swedish Research Council, 621-2010-4866
Note
Updated from in press to published. Previous title: Dynamic Asymmetric Hemithioacetal Resolution by Lipase-Catalyzed γ-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one DerivativesAvailable from: 2011-05-26 Created: 2011-05-26 Last updated: 2017-12-11Bibliographically approved
In thesis
1. 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
2. Chemoenzymatic Resolution in Dynamic Systems: Screening, Classification and Asymmetric Synthesis
Open this publication in new window or tab >>Chemoenzymatic Resolution in Dynamic Systems: Screening, Classification and Asymmetric Synthesis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This  thesis  is  divided  into  four  parts,  all  centered  around  Constitutional Dynamic  Chemistry  (CDC)  and  Dynamic  Kinetic  Resolution  (DKR)  using biocatalysts for selective transformations, and their applications in screening of bioactive compounds, organic synthesis, and enzyme classification.   

In  part  one,  an  introduction  to  CDC  and  DKR  is  presented,  illustrating  the basic  concepts,  practical  considerations  and  potential  applications  of  such dynamic systems, thus providing the background information for the studies in the following chapters.  

In part two, Dynamic Systemic Resolution (DSR), a concept based on CDC is exemplified.  With  enzyme-catalyzed  transformations  as  external  selection pressure,  optimal  structures  can  be  selected  and  amplified  from  the  system. This  concept  is  expanded  to  various  types  of  dynamic  systems  containing single, double cascade/parallel, and multiple reversible reactions. In addition, the  substrate  selectivity  and  catalytic  promiscuity  of  target  enzymes  are  also investigated.  

In   part   three,   DKR   protocols   using   reversible   reactions   for   substrate racemizations  are  illustrated.  Biocatalysts  are  here  employed  for  asymmetric transformations,  resulting  in  efficient  synthetic  pathways  for  enantioenriched organic compounds.  

Part  four  demonstrates  two  unique  applications  of  CDC:  one  resulting  in enzyme  classification  by  use  of  pattern  recognition  methodology;  the  other involving  enzyme  self-inhibition  through  in  situ  transformation  of  stealth inhibitors employing the catalytic activity of the target enzyme.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2013. 71 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2013:29
Keyword
constitutional dynamic chemistry, dynamic systemic resolution, dynamic kinetic resolution, enzyme catalysis, transesterification, enzyme promiscuity, asymmetric synthesis, pattern recognition, self-inhibition.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-123089 (URN)978-91-7501-804-1 (ISBN)
Public defence
2013-08-23, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20130614

Available from: 2013-06-14 Created: 2013-05-31 Last updated: 2013-06-14Bibliographically approved

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