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Diastereoselective One-Pot Tandem Synthesis of 3-Substituted Isoindolinones: A Mechanistic Investigation
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.
KTH, School of Chemical Science and Engineering (CHE), Chemistry.ORCID iD: 0000-0003-2673-075X
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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.

Place, publisher, year, edition, pages
2010. Vol. 75, no 17, 5882-5887 p.
Keyword [en]
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: urn:nbn:se:kth:diva-26826DOI: 10.1021/jo100868zISI: 000281180100011Scopus ID: 2-s2.0-77956142428OAI: oai:DiVA.org:kth-26826DiVA: diva2:375180
Funder
Swedish Research Council
Note
QC 20101207Available from: 2010-12-07 Created: 2010-11-29 Last updated: 2017-12-11Bibliographically approved
In thesis
1. 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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