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Tandem driven dynamic combinatorial resolution via Henry–iminolactone rearrangement
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
2008 (engelsk)Inngår i: ChemComm, ISSN 1359-7345, s. 768-770Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2008. s. 768-770
Emneord [en]
iminolactone; indole derivative; lactone derivative; unclassified drug
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-11208DOI: 10.1039/b716521hISI: 000252757100032Scopus ID: 2-s2.0-38849163008OAI: oai:DiVA.org:kth-11208DiVA, id: diva2:241646
Merknad
QC 20100506Tilgjengelig fra: 2009-10-05 Laget: 2009-10-05 Sist oppdatert: 2010-08-18bibliografisk kontrollert
Inngår i avhandling
1. Dynamic Covalent Resolution: Applications in System Screening and Asymmetric Synthesis
Åpne denne publikasjonen i ny fane eller vindu >>Dynamic Covalent Resolution: Applications in System Screening and Asymmetric Synthesis
2009 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: KTH, 2009. s. 72
Serie
Trita-CHE-Report, ISSN 1654-1081 ; 2009:52
Emneord
dynamic covalent/kinetic/combinatorial resolution, Self-screening, Transesterification, Amidation, Enzyme catalysis, Nitroaldol reaction, Secondary alcohols, Strecker reaction, Aminonitriles, Racemase, Enzyme catalytic promiscuity
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-11200 (URN)978-91-7415-442-9 (ISBN)
Disputas
2009-10-15, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

QC 20100818

Tilgjengelig fra: 2009-10-05 Laget: 2009-10-02 Sist oppdatert: 2012-09-03bibliografisk kontrollert
2. Discovery-Oriented Screening of Dynamic Systems: Combinatorial and Synthetic Applications
Åpne denne publikasjonen i ny fane eller vindu >>Discovery-Oriented Screening of Dynamic Systems: Combinatorial and Synthetic Applications
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: KTH, 2010. s. 82
Serie
Trita-CHE-Report, ISSN 1654-1081 ; 2010:13
Emneord
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
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-12524 (URN)978-91-7415-617-1 (ISBN)
Disputas
2010-05-28, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad
QC 20100628Tilgjengelig fra: 2010-05-12 Laget: 2010-05-03 Sist oppdatert: 2011-02-11bibliografisk kontrollert

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