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Dynamic Asymmetric Multicomponent Resolution: Lipase-Mediated Amidation of a Double Dynamic Covalent System
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2009 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 131, no 40, 14419-14425 p.Article in journal (Refereed) Published
Abstract [en]

The Strecker reaction is one of the most important multicomponent reactions developed, leading to alpha-aminonitriles that are versatile substrates for many synthetic applications. In the present study, this reaction type has been applied to a double dynamic covalent resolution protocol, leading to efficient C-C- and C-N-bond generation as well as chiral discrimination. The combination of transimination with iminecyanation enabled the dynamic exchange in more,than one direction around a single stereogenic center of restricted structure. This multiple exchange process could generate a vast range of compounds from a low number of starting materials in very short time. The resulting double dynamic covalent systems, created under thermodynamic control, were subsequently coupled in a one-pot process with kinetically controlled lipase-mediated transacylation. This resulted in complete resolution of the dynamic systems, yielding the optimal N-acyl-alpha-aminonitriles for the enzyme, where the individual chemoenzymatic reactions could produce enantiomerically pure acylated N-substituted alpha-aminonitriles in good yields.

Place, publisher, year, edition, pages
2009. Vol. 131, no 40, 14419-14425 p.
Keyword [en]
strecker reaction; combinatorial libraries; enantioselective synthesis; catalytic addition; amino-acids; imines; chemistry; receptors; selection; molecules
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-18907DOI: 10.1021/ja9052015ISI: 000271271500081Scopus ID: 2-s2.0-70349914540OAI: oai:DiVA.org:kth-18907DiVA: diva2:336954
Note
QC 20100525Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically 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

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