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Tandem driven dynamic combinatorial resolution via Henry–iminolactone rearrangement
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.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
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.

Place, publisher, year, edition, pages
2008. 768-770 p.
Keyword [en]
iminolactone; indole derivative; lactone derivative; unclassified drug
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-11208DOI: 10.1039/b716521hISI: 000252757100032Scopus ID: 2-s2.0-38849163008OAI: oai:DiVA.org:kth-11208DiVA: diva2:241646
Note
QC 20100506Available from: 2009-10-05 Created: 2009-10-05 Last updated: 2010-08-18Bibliographically approved
In thesis
1. 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
2. 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

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