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Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis and Nitroaldol (Henry) Reaction
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
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.

Place, publisher, year, edition, pages
2008. Vol. 350, no 3, 448-452 p.
Keyword [en]
Dynamic kinetic resolution; Enzyme catalysis; Nitroaldol (Henry) reaction; Secondary alcohols
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-8264DOI: 10.1002/adsc.200700432ISI: 000253600600018Scopus ID: 2-s2.0-49049106632OAI: oai:DiVA.org:kth-8264DiVA: diva2:13541
Note
QC 20100818Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
Open this publication in new window or tab >>Dynamic Systems for Screening, Control and Identification of Protein-Ligand Interactions
2008 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Dynamic systems for screening, control and identification of different protein-ligand interactions are presented. Dynamic chemistry is used to produce new compounds/constituents in situ that can interact with a target molecule. Several entities can be introduced at the same time and interact with one another. These molecules make a dynamic combinatorial library (DCL) which is used in dynamic combinatorial chemistry (DCC). DCC is a recently introduced approach to generate dynamically interchanging libraries of compounds. These libraries are made of different building blocks that reversibly interact with one another and spontaneously assemble to encompass all possible combinations. If a target molecule, for instance a receptor is added to the system and one or more molecules show affinity to the target species, these compounds will, according to Le Châtelier´s principle, be amplified on the expense of the other non-bonding constituents. To further advance the technique, especially when biological systems are targeted, new reaction types and new screening methods are necessary. This thesis describes the development of different reversible reactions, thiol/disulfide interchange, transthiolesterification and the nitroaldol (Henry) reaction as means of generating reversible covalent bond reactions. Two different types of target proteins are used, enzymes belonging to the hydrolase family and the plant lectin Concanavalin A.

Dynamic combinatorial resolution (DCR) is presented. This new concept relies on the consecutive kinetic resolution of dynamic combinatorial libraries, leading to complete amplification and control of dynamically interchangeable processes. By applying a kinetically controlled step to a thermodynamically controlled system, complete transformation and amplification can be obtained. The concept has been demonstrated by developing transthiolesterification and nitroaldol exchange reactions to generate diversity, forming libraries under thermodynamic control, and used in one-pot processes with kinetically controlled enzyme-mediated resolution. The results demonstrate that the reaction types are useful for the generation of dynamic libraries, and that the dynamic combinatorial resolution concept is highly valuable for efficient substrate identification, asymmetric synthesis, and library screening.

The thesis also describes three other dynamic chemistry protocols. The first one describes dynamic kinetic resolution (DKR) of nitroaldol adducts by combined lipase catalysis. The second one describes finding lectin inhibitors from a glycodisulfide library and the third one describes finding an inhibitor of acetylcholinesterase using a tandem driven dynamic self-inhibition approach.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. 64 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2008:31
Keyword
Dynamic combinatorial chemistry, Dynamic kinetic/combinatorial resolution, Catalytic screening, Transthiolesterification, Thiol/disulfide interchange, Nitroaldol reaction, Lectins, Hydrolases, Dynamic self-inhibition
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-4709 (URN)978-91-7178-944-0 (ISBN)
Public defence
2008-05-09, F3, Lindstedtsvägen 26, Stockholm, 13:00
Opponent
Supervisors
Note

QC 20100818

Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-02-23Bibliographically approved
2. Dynamic Covalent Resolution: Applications in System Screening and Asymmetric Synthesis
Open this publication in new window or tab >>Dynamic Covalent Resolution: Applications in System Screening and Asymmetric Synthesis
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
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:nbn:se:kth:diva-11200 (URN)978-91-7415-442-9 (ISBN)
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

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Publisher's full textScopushttp://www3.interscience.wiley.com.focus.lib.kth.se/cgi-bin/abstract/117910279/ABSTRACT

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