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Racemase Activity of B. cepacia Lipase Leads to Dual-Function Asymmetric Dynamic Kinetic Resolution of alpha-Aminonitriles
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Physical Chemistry (closed 20110630).
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Biotechnology (BIO), Biochemistry.ORCID iD: 0000-0003-2371-8755
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2011 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 50, no 29, 6592-6595 p.Article in journal (Refereed) Published
Abstract [en]

Applaudable promiscuity: Racemase-type activity discovered for B. cepacia lipase with N-substituted α-aminonitriles is proposed to involve a C-C bond-breaking/forming mechanism in the hydrolase site of the enzyme, as supported by experimental data and calculations. This promiscuous activity in combination with the transacylation activity of the enzyme enabled the asymmetric synthesis of N-methyl α-aminonitrile amides in high yield (see scheme).

Place, publisher, year, edition, pages
2011. Vol. 50, no 29, 6592-6595 p.
Keyword [en]
dynamic kinetic resolution, enzyme catalysis, racemase activity, secondary amines, Strecker reaction
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-37184DOI: 10.1002/anie.201007373ISI: 000292644400026Scopus ID: 2-s2.0-79959992526OAI: oai:DiVA.org:kth-37184DiVA: diva2:432472
Note

Uppdated from Manuscript to Article. QC 20120903

Available from: 2011-08-03 Created: 2011-08-03 Last updated: 2017-12-08Bibliographically 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. Computational Studies and Design of Biomolecular Diels-Alder Catalysis
Open this publication in new window or tab >>Computational Studies and Design of Biomolecular Diels-Alder Catalysis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Diels-Alder reaction is one of the most powerful synthetic tools in organic chemistry, and asymmetric Diels-Alder catalysis allows for rapid construction of chiral carbon scaffolds. For this reason, considerable effort has been invested in developing efficient and stereoselective organo- and biocatalysts. However, Diels-Alder is a virtually unknown reaction in Nature, and to engineer an enzyme into a Diels-Alderase is therefore a challenging task. Despite several successful designs of catalytic antibodies since the 1980’s, their catalytic activities have remained low, and no true artificial ’Diels-Alderase’ enzyme was reported before 2010.

In this thesis, we employ state-of-the-art computational tools to study the mechanism of organocatalyzed Diels-Alder in detail, and to redesign existing enzymes into intermolecular Diels-Alder catalysts. Papers I–IV explore the mechanistic variations when employing increasingly activated reactants and the effect of catalysis. In particular, the relation between the traditionally presumed concerted mechanism and a stepwise pathway, forming one bond at a time, is probed. Papers V–X deal with enzyme design and the computational aspects of predicting catalytic activity. Four novel, computationally designed Diels-Alderase candidates are presented in Papers VI–IX. In Paper X, a new parameterization of the Linear Interaction Energy model for predicting protein-ligand affinities is presented.

A general finding in this thesis is that it is difficult to attain large transition state stabilization effects solely by hydrogen bond catalysis. In addition, water (the preferred solvent of enzymes) is well-known for catalyzing Diels- Alder by itself. Therefore, an efficient Diels-Alderase must rely on large binding affinities for the two substrates and preferential binding conformations close to the transition state geometry. In Papers VI–VIII, we co-designed the enzyme active site and substrates in order to achieve the best possible complementarity and maximize binding affinity and pre-organization. Even so, catalysis is limited by the maximum possible stabilization offered by hydrogen bonds, and by the inherently large energy barrier associated with the [4+2] cycloaddition.

The stepwise Diels-Alder pathway, proceeding via a zwitterionic intermediate, may offer a productive alternative for enzyme catalysis, since an enzyme active site may be more differentiated towards stabilizing the high-energy states than for the standard mechanism. In Papers I and III, it is demonstrated that a hydrogen bond donor catalyst provides more stabilization of transition states having pronounced charge-transfer character, which shifts the preference towards a stepwise mechanism.

Another alternative, explored in Paper IX, is to use an α,β -unsaturated ketone as a ’pro-diene’, and let the enzyme generate the diene in situ by general acid/base catalysis. The results show that the potential reduction in the reaction barrier with such a mechanism is much larger than for conventional Diels-Alder. Moreover, an acid/base-mediated pathway is a better mimic of how natural enzymes function, since remarkably few catalyze their reactions solely by non-covalent interactions.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. xii, 138 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2012:34
Keyword
Computational chemistry, density functional theory, enzyme design, molecular modeling, organocatalysis, stepwise Diels-Alder, oxyanion hole
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-101706 (URN)978-91-7501-435-7 (ISBN)
Public defence
2012-09-21, K1, Teknikringen 56, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20120903

Available from: 2012-09-03 Created: 2012-08-31 Last updated: 2012-09-03Bibliographically approved

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