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Dynamic Covalent Resolution: Applications in System Screening and Asymmetric Synthesis
KTH, School of Chemical Science and Engineering (CHE), Chemistry. (Olof Ramström)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Combined thermodynamic/kinetic events amount to a kinetically controlled Dynamic Combinatorial Resolution (DCR) process, where the lability of themolecules/aggregates are used to generate dynamics, and the species experiencing the lowest activation energy is selected via kinetic process. Bothinter- and intramolecular processes can be performed using this concept,resulting in complete resolution and associated amplification of the selected species. When intermolecular processes are resolved using this method, an additional advantage is that only a catalytic amount of selector is required tocontrol the system.In this thesis, the Henry and Strecker reactions were developed as efficient C–C bond-forming routes to single and multi-level dynamic covalent systems.These methods efficiently provided a vast variety of substrates from smallnumbers of starting compounds. These dynamic systems, generated underthermodynamic control at mild conditions, were coupled in one-pot processes with kinetically controlled lipase-mediated transacylation. The enzym emediated resolution of the dynamic nitroaldol system led to enantiomericallypure β-nitroacetates in high yield. Furthermore, combination of multi-leveldynamic Strecker systems and lipase-mediated acylation resulted in theresolution of specific α-aminonitriles from the pool.In addition, the asymmetric synthesis of discrete β-nitroalkanol derivatives wassimply achieved, resulting in high yields and high enantiomeric purities through the direct one-pot procedure. Moreover, racemase type activity oflipase enzyme through N-substituted α-aminonitrile structure has been discovered. By use of control experiments together with molecular modeling,the mechanism of the racemization process has been established. Asymmetric synthesis of N-methyl α-aminonitriles was also performed through the dualfunction of lipase, resulting in high yield and good enantio selectivity.

Place, publisher, year, edition, pages
Stockholm: KTH , 2009. , 72 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2009:52
Keyword [en]
dynamic covalent/kinetic/combinatorial resolution, Self-screening, Transesterification, Amidation, Enzyme catalysis, Nitroaldol reaction, Secondary alcohols, Strecker reaction, Aminonitriles, Racemase, Enzyme catalytic promiscuity
National Category
Chemical Sciences Organic Chemistry Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-11200ISBN: 978-91-7415-442-9 (print)OAI: oai:DiVA.org:kth-11200DiVA: diva2:241452
Public defence
2009-10-15, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20100818

Available from: 2009-10-05 Created: 2009-10-02 Last updated: 2012-09-03Bibliographically approved
List of papers
1. Dynamic Combinatorial Resolution: Direct Asymmetric Lipase-Mediated Screening of a Dynamic Nitroaldol Library
Open this publication in new window or tab >>Dynamic Combinatorial Resolution: Direct Asymmetric Lipase-Mediated Screening of a Dynamic Nitroaldol Library
2007 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 46, no 6, 948-950 p.Article in journal (Refereed) Published
Abstract [en]

(Chemical Equation Presented) A disturbance in the library: The nitroaldol (Henry) reaction was developed as an efficient C-C bond-forming route to dynamic combinatorial libraries (DCLs). These DCLs generated under thermodynamic control were coupled in a one-pot process with kinetically controlled lipase-mediated transesterification (see scheme). The asymmetric resolution of the DCLs by the enzyme led to enantiomerically pure β-nitroacetates in high yield.

Keyword
Aldol reaction; Combinatorial chemistry; Dynamic chemistry; Enzyme catalysis; Reversible reactions
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-8267 (URN)10.1002/anie.200603740 (DOI)000244146500026 ()2-s2.0-33846687723 (Scopus ID)
Note
QC 20100506Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2010-08-18Bibliographically approved
2. Tandem driven dynamic combinatorial resolution via Henry–iminolactone rearrangement
Open this publication in new window or tab >>Tandem driven dynamic combinatorial resolution via Henry–iminolactone rearrangement
2008 (English)In: ChemComm, ISSN 1359-7345, 768-770 p.Article in journal (Refereed) Published
Abstract [en]

An unexplored type of tandem reaction is used to kinetically resolve a dynamic combinatorial library resulting in quantitative amplification of an interesting 3-substituted isoindolinone.

Keyword
iminolactone; indole derivative; lactone derivative; unclassified drug
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-11208 (URN)10.1039/b716521h (DOI)000252757100032 ()2-s2.0-38849163008 (Scopus ID)
Note
QC 20100506Available from: 2009-10-05 Created: 2009-10-05 Last updated: 2010-08-18Bibliographically approved
3. Dynamic Asymmetric Multicomponent Resolution: Lipase-Mediated Amidation of a Double Dynamic Covalent System
Open this publication in new window or tab >>Dynamic Asymmetric Multicomponent Resolution: Lipase-Mediated Amidation of a Double Dynamic Covalent System
2009 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 131, no 40, 14419-14425 p.Article in journal (Refereed) Published
Abstract [en]

The Strecker reaction is one of the most important multicomponent reactions developed, leading to alpha-aminonitriles that are versatile substrates for many synthetic applications. In the present study, this reaction type has been applied to a double dynamic covalent resolution protocol, leading to efficient C-C- and C-N-bond generation as well as chiral discrimination. The combination of transimination with iminecyanation enabled the dynamic exchange in more,than one direction around a single stereogenic center of restricted structure. This multiple exchange process could generate a vast range of compounds from a low number of starting materials in very short time. The resulting double dynamic covalent systems, created under thermodynamic control, were subsequently coupled in a one-pot process with kinetically controlled lipase-mediated transacylation. This resulted in complete resolution of the dynamic systems, yielding the optimal N-acyl-alpha-aminonitriles for the enzyme, where the individual chemoenzymatic reactions could produce enantiomerically pure acylated N-substituted alpha-aminonitriles in good yields.

Keyword
strecker reaction; combinatorial libraries; enantioselective synthesis; catalytic addition; amino-acids; imines; chemistry; receptors; selection; molecules
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-18907 (URN)10.1021/ja9052015 (DOI)000271271500081 ()2-s2.0-70349914540 (Scopus ID)
Note
QC 20100525Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2011-01-17Bibliographically approved
4. In Situ Evaluation of Lipase Performances Through Dynamic Asymmetric Cyanohydrin Resolution
Open this publication in new window or tab >>In Situ Evaluation of Lipase Performances Through Dynamic Asymmetric Cyanohydrin Resolution
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-24147 (URN)
Note
QC 20100818Available from: 2010-08-18 Created: 2010-08-18 Last updated: 2011-05-26Bibliographically approved
5. Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis and Nitroaldol (Henry) Reaction
Open this publication in new window or tab >>Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis and Nitroaldol (Henry) Reaction
2008 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 350, no 3, 448-452 p.Article in journal (Refereed) Published
Abstract [en]

The asymmetric synthesis of β-nitroalkanol derivatives was simply achieved by a combined nitroaldol (Henry) reaction with lipase-catalyzed transesterification in high yield and enantiomeric purity (up to 92% and 99% ee) through a direct one-pot procedure.

Keyword
Dynamic kinetic resolution; Enzyme catalysis; Nitroaldol (Henry) reaction; Secondary alcohols
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-8264 (URN)10.1002/adsc.200700432 (DOI)000253600600018 ()2-s2.0-49049106632 (Scopus ID)
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2010-08-18Bibliographically approved
6. Racemase Activity of B. cepacia Lipase Leads to Dual-Function Asymmetric Dynamic Kinetic Resolution of alpha-Aminonitriles
Open this publication in new window or tab >>Racemase Activity of B. cepacia Lipase Leads to Dual-Function Asymmetric Dynamic Kinetic Resolution of alpha-Aminonitriles
Show others...
2011 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 50, no 29, 6592-6595 p.Article in journal (Refereed) Published
Abstract [en]

Applaudable promiscuity: Racemase-type activity discovered for B. cepacia lipase with N-substituted α-aminonitriles is proposed to involve a C-C bond-breaking/forming mechanism in the hydrolase site of the enzyme, as supported by experimental data and calculations. This promiscuous activity in combination with the transacylation activity of the enzyme enabled the asymmetric synthesis of N-methyl α-aminonitrile amides in high yield (see scheme).

Keyword
dynamic kinetic resolution, enzyme catalysis, racemase activity, secondary amines, Strecker reaction
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-37184 (URN)10.1002/anie.201007373 (DOI)000292644400026 ()2-s2.0-79959992526 (Scopus ID)
Note

Uppdated from Manuscript to Article. QC 20120903

Available from: 2011-08-03 Created: 2011-08-03 Last updated: 2017-12-08Bibliographically approved

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