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Chemoenzymatic Resolution in Dynamic Systems: Screening, Classification and Asymmetric Synthesis
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
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 [en]
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: urn:nbn:se:kth:diva-123089ISBN: 978-91-7501-804-1 (print)OAI: oai:DiVA.org:kth-123089DiVA: diva2:624519
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
List of papers
1. Dynamic Asymmetric Hemithioacetal Transformation by Lipase-Catalyzed gamma-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one Derivatives
Open this publication in new window or tab >>Dynamic Asymmetric Hemithioacetal Transformation by Lipase-Catalyzed gamma-Lactonization: In Situ Tandem Formation of 1,3-Oxathiolan-5-one Derivatives
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.

Keyword
asymmetric transformation, dynamic chemistry, enzyme catalysis, hemithioacetal, lactone, lipase
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-34125 (URN)10.1002/chem.201102139 (DOI)000303497600002 ()2-s2.0-84860758898 (Scopus ID)
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
2. Biocatalyzed Dynamic Systemic Domino Thia-Michael--Henry Resolution to Substituted Asymmetric Thiolanes
Open this publication in new window or tab >>Biocatalyzed Dynamic Systemic Domino Thia-Michael--Henry Resolution to Substituted Asymmetric Thiolanes
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Dynamic systems based on consecutive thia-Michael and Henry reactions were generated and transformed using lipase-catalyzed asymmetric transformation. Substituted thiolane structures with three contiguous stereocenters were resolved in the process in high yields and high enantiomeric excesses.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-123669 (URN)
Note

QS 2013

Available from: 2013-06-14 Created: 2013-06-14 Last updated: 2013-06-14Bibliographically approved
3. Double parallel dynamic resolution through lipase-catalyzed asymmetric transformation
Open this publication in new window or tab >>Double parallel dynamic resolution through lipase-catalyzed asymmetric transformation
2013 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, no 18, 1805-1807 p.Article in journal (Refereed) Published
Abstract [en]

Dynamic systems based on double parallel reactions have been generated and resolved in situ by secondary lipase-catalyzed asymmetric transformation, resulting in high chemo- and enantioselectivities.

Place, publisher, year, edition, pages
RSC Publishing, 2013
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-119127 (URN)10.1039/c3cc38203f (DOI)000314650100006 ()2-s2.0-84873606019 (Scopus ID)
Funder
Swedish Research Council
Note

QC 20130311

Available from: 2013-03-11 Created: 2013-03-07 Last updated: 2017-12-06Bibliographically approved
4. Lipase-Catalyzed Dynamic Systemic Resolution from Reversible Reaction Networks
Open this publication in new window or tab >>Lipase-Catalyzed Dynamic Systemic Resolution from Reversible Reaction Networks
(English)Article in journal (Other academic) Submitted
Abstract [en]

A dynamic system based on a network of multiple reversible reactions has been established. The network was applied to a dynamic systemic resolution protocol based on two kinetically controlled lipase-catalyzed transformations, where two compounds were efficiently selected from a pool of potential products.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-123671 (URN)
Note

QS 2013

Available from: 2013-06-14 Created: 2013-06-14 Last updated: 2013-06-14Bibliographically approved
5. Asymmetric Dynamic Kinetic Resolution for the Synthesis of 1,3-Oxathiolan-5-one Derivatives
Open this publication in new window or tab >>Asymmetric Dynamic Kinetic Resolution for the Synthesis of 1,3-Oxathiolan-5-one Derivatives
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Synthesis of 1,3-oxathiolan-5-one derivatives through dynamic kinetic resolution strategy has been illustrated, resulting in moderate to good enantioselectivities of the final products. In addition, the substrate scope and potential access to lamivudine (3TC) have also been explored.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-123683 (URN)
Note

QS 2013

Available from: 2013-06-14 Created: 2013-06-14 Last updated: 2013-06-14Bibliographically approved
6. Lipase-Catalyzed Dynamic Kinetic Asymmetric Transformation to Oxathiazinanones
Open this publication in new window or tab >>Lipase-Catalyzed Dynamic Kinetic Asymmetric Transformation to Oxathiazinanones
(English)Article in journal (Other academic) Submitted
Abstract [en]

A domino addition-lactonization pathway has been applied to a dynamic covalent resolution protocol, leading to efficient oxathiazinanone formation as well as chiral discrimination. A new, double biocatalytic pathway has furthermore been proposed and evaluated where initial product inhibition could be efficiently circumvented.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-123685 (URN)
Note

QS 2013

Available from: 2013-06-14 Created: 2013-06-14 Last updated: 2013-06-14Bibliographically approved
7. Classification of Lipases Using Pattern Recognition through Transformation of Dynamic Hemithioacetal Systems
Open this publication in new window or tab >>Classification of Lipases Using Pattern Recognition through Transformation of Dynamic Hemithioacetal Systems
(English)Article in journal (Other academic) Submitted
Abstract [en]

A complex dynamic hemithioacetal system was generated for the evaluation of lipase reactivities. In combination with pattern recognition methodology, twelve different lipases were successfully classified into three distinct groups following their reaction selectivities and reactivities. A probe lipase was further categorized using the training matrix with predicted reactivity.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-123686 (URN)
Note

QS 2013

Available from: 2013-06-14 Created: 2013-06-14 Last updated: 2013-06-14Bibliographically approved
8. Tandem driven dynamic self-inhibition of acetylcholinesterase
Open this publication in new window or tab >>Tandem driven dynamic self-inhibition of acetylcholinesterase
Show others...
2010 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 46, no 44, 8457-8459 p.Article in journal (Refereed) Published
Abstract [en]

A concept of tandem driven dynamic self-inhibition is demonstrated through dynamic inhibitors of acetylcholinesterase (AChE) using reversible transthiolesterification.

Keyword
SITU CLICK CHEMISTRY, IN-SITU, COMBINATORIAL RESOLUTION, LIBRARIES, EXCHANGE
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-27093 (URN)10.1039/c0cc02479a (DOI)000283690400044 ()2-s2.0-78049383176 (Scopus ID)
Note
QC 20101210Available from: 2010-12-10 Created: 2010-12-06 Last updated: 2017-12-11Bibliographically approved

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