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Discovery-Oriented Screening of Dynamic Systems: Combinatorial and Synthetic Applications
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry. (Olof Ramström)
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 [en]
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: urn:nbn:se:kth:diva-12524ISBN: 978-91-7415-617-1 (print)OAI: oai:DiVA.org:kth-12524DiVA: diva2:317313
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
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: 2017-12-14Bibliographically approved
2. Crystallization Driven Asymmetric Synthesis of Pyridine β-Nitroalcoholsvia Discovery-Oriented Self-Resolution of a Dynamic System
Open this publication in new window or tab >>Crystallization Driven Asymmetric Synthesis of Pyridine β-Nitroalcoholsvia Discovery-Oriented Self-Resolution of a Dynamic System
2010 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 33, 6315-6318 p.Article in journal (Refereed) Published
Abstract [en]

The study of dynamic nitroaldol systems aided the discovery of a diastereoselective crystallization process through amplification of 2-nitro-1-(pyridine-4-yl)propan-1-ol. The phenomenon was further developed into an effective procedure for asymmetic synthesis of pyridine-nitroalcohols and several substrates were screened to this end. These results demonstrate how work with larger dynamic systems facilitates and increases the likelihood of serendipitous discoveries.

Keyword
Dynamic combinatorial chemistry, Systems chemistry, Aldol reactions, Asymmetric synthesis, Crystallization
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-13741 (URN)10.1002/ejoc.201000907 (DOI)000285229700002 ()2-s2.0-78649310287 (Scopus ID)
Funder
Swedish Research Council
Note
Updated from submitted to published. QC 20120326Available from: 2010-06-28 Created: 2010-06-28 Last updated: 2017-12-12Bibliographically approved
3. 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
4. Crystallization-induced secondary selection from a tandem driven dynamic combinatorial resolution process
Open this publication in new window or tab >>Crystallization-induced secondary selection from a tandem driven dynamic combinatorial resolution process
2008 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 73, no 9, 3593-3595 p.Article in journal (Refereed) Published
Abstract [en]

Crystallization-induced secondary selection from a tandem driven dynamic combinatorial library is presented. In a one-pot experiment, an initial nitroaldol equilibrium was kinetically driven by a tandem reaction resulting in a subsequent dynamic library of diastereoisomers. This library was then further driven by a phase change, resulting in amplification and isolation of a highly diastereomerically enriched and synthetically interesting isoindolinone.

Keyword
ASYMMETRIC-SYNTHESIS, DRUG DISCOVERY, SOLID-STATE, CHEMISTRY, LIBRARIES, REARRANGEMENT, LIGANDS
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-12713 (URN)000255339600042 ()2-s2.0-43449087343 (Scopus ID)
Note

QC 20100507

Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2017-04-28Bibliographically approved
5. Diastereoselective One-Pot Tandem Synthesis of 3-Substituted Isoindolinones: A Mechanistic Investigation
Open this publication in new window or tab >>Diastereoselective One-Pot Tandem Synthesis of 3-Substituted Isoindolinones: A Mechanistic Investigation
Show others...
2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 17, 5882-5887 p.Article in journal (Refereed) Published
Abstract [en]

The mechanism of a base-catalyzed one-pot reaction of 2-cyanobenzaldehyde and primary nitroalkanes, to produce 3-substituted isoindolinones, has been investigated. A route starting with a nitroaldol (Henry) reaction, followed by a subsequent cyclization and rearrangement, was supported by intermediate analogue synthesis and DFT calculations. Direct diastereoselective crystallization from the reaction mixture was also achieved and studied for a number of substrates. Furthermore, the 3-substituted isoindolinones are an interesting group of compounds, both present important natural products, as well as being precursors to other valuable building blocks.

Keyword
DYNAMIC COMBINATORIAL CHEMISTRY, DIELS-ALDER REACTIONS, ASYMMETRIC-SYNTHESIS, DRUG DISCOVERY, DERIVATIVES, RECEPTOR, ISOINDOLOBENZAZEPINE, 2-CYANOBENZALDEHYDE, ISOINDOLIN-1-ONES, AUXILIARIES
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-26826 (URN)10.1021/jo100868z (DOI)000281180100011 ()2-s2.0-77956142428 (Scopus ID)
Funder
Swedish Research Council
Note
QC 20101207Available from: 2010-12-07 Created: 2010-11-29 Last updated: 2017-12-11Bibliographically approved
6. Tandem reversible addition-intramolecular lactonization for the synthesis of 3-functionalized phthalides
Open this publication in new window or tab >>Tandem reversible addition-intramolecular lactonization for the synthesis of 3-functionalized phthalides
2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 1, 75-78 p.Article in journal (Refereed) Published
Abstract [en]

A new tandem process based on reversible nucleophilic addition and intramolecular lactonization of methyl 2-formylbenzoate leads to the efficient synthesis of 3-functionalized phthalides, which are important precursors for the synthesis of quinone skeletons via Hauser–Kraus annulation. The reactions are successfully carried out under mild conditions in single operations.

Keyword
DYNAMIC COMBINATORIAL RESOLUTION, ANNULATION REACTIONS, CHEMISTRY, ANNELATION
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-12736 (URN)10.1016/j.tetlet.2009.10.079 (DOI)000274232200018 ()2-s2.0-70649083235 (Scopus ID)
Funder
Swedish Research Council
Note
QC 20110126Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2017-12-12Bibliographically approved
7. Introducing Dynamic Combinatorial Chemistry: Probing the Substrate Selectivity of Acetylcholinesterase
Open this publication in new window or tab >>Introducing Dynamic Combinatorial Chemistry: Probing the Substrate Selectivity of Acetylcholinesterase
2010 (English)In: Journal of Chemical Education, ISSN 0021-9584, E-ISSN 1938-1328, Vol. 87, no 11, 1248-1251 p.Article in journal (Refereed) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-13743 (URN)10.1021/ed100400v (DOI)000282868100032 ()2-s2.0-78449272682 (Scopus ID)
Note
QC20100628, QC 20111109. Ändrad från accepted till published 20111109Available from: 2010-06-28 Created: 2010-06-28 Last updated: 2017-12-12Bibliographically approved

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