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Stepwise Diels-Alder: More than Just an Oddity? A Computational Mechanistic Study
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry. (Brinck)
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry. (Brinck)ORCID iD: 0000-0003-2673-075X
2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 15, 6563-6573 p.Article in journal (Refereed) Published
Abstract [en]

We have employed hybrid DFT and SCS-MP2 calculations at the SMD-PCM–6-311++G(2d,2p)//6-31+G(d) level to investigate the relationship between three possible channels for forming a Diels–Alder adduct from a highly nucleophilic diene and moderately to highly electrophilic dienophiles. We discuss geometries optimized using the B3LYP and M06-2X functionals with the 6-31+(d) basis set. The transition states and intermediates are characterized on the basis of geometric and electronic properties, and we also address the possibility of predicting detectability of a zwitterionic intermediate based on its relative stability. Our results show that a conventional Diels–Alder transition state conformation yields intermediates in all four investigated cases, but that these are too short-lived to be detected experimentally for the less activated reactants. The stepwise trans pathway, beginning with a conjugate addition-like transition state, becomes increasingly competitive with more activated reactants and is indeed favored for the most electrophilic dienophiles. Addition of a trans diene leads to a dead-end as the trans intermediates have insurmountable rotation barriers that prohibit formation of the second bond, unless another, heterocyclic intermediate is formed. We also show that introduction of a hydrogen bond donating catalyst favors a stepwise pathway even for less activated dienophiles.

Place, publisher, year, edition, pages
2012. Vol. 77, no 15, 6563-6573 p.
Keyword [en]
Density-Functional Theory, Main-Group Thermochemistry, Noncovalent Interactions, Quantitative Characterization, Cycloaddition Reactions, Organic-Molecules, Metal-Free, M06 Suite, Energies, Butadiene
National Category
Organic Chemistry
URN: urn:nbn:se:kth:diva-101708DOI: 10.1021/jo301176tISI: 000307037700021ScopusID: 2-s2.0-84864609647OAI: diva2:548767
Swedish Research Council

QC 20120903

Available from: 2012-09-03 Created: 2012-08-31 Last updated: 2012-10-10Bibliographically approved
In thesis
1. 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.
Trita-CHE-Report, ISSN 1654-1081 ; 2012:34
Computational chemistry, density functional theory, enzyme design, molecular modeling, organocatalysis, stepwise Diels-Alder, oxyanion hole
National Category
Physical Chemistry
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)

QC 20120903

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

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