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Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenationof Imines: A Density Functional Theory Study of Reaction Mechanismand the Origins of Enantioselectivity
KTH, School of Biotechnology (BIO), Theoretical Chemistry. (Theoretical Chemistry)
KTH, School of Biotechnology (BIO), Theoretical Chemistry. (Theoretical Chemistry)
KTH, School of Biotechnology (BIO), Theoretical Chemistry. (Theoretical Chemistry)
2008 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 14, 8562-8571 p.Article in journal (Refereed) Published
Abstract [en]

The phosphoric acid catalyzedreaction of 1,4-dihydropyridineswith N-arylimines has been investigatedby using density functional theory.We first considered the reaction of acetophenonePMP-imine (PMP=p-methoxyphenyl)with the dimethylHantzsch ester catalyzed by diphenylphosphate. Our study showed that, inagreement with what has previouslybeen postulated for other reactions, diphenylphosphate acts as a Lewis base/Brønsted acid bifunctional catalyst inthis transformation, simultaneously activatingboth reaction partners. The calculationsalso showed that the hydridetransfer transition states for the E andZ isomers of the iminium ion havecomparable energies. This observationturned out to be crucial to the understandingof the enantioselectivity of theprocess. Our results indicate that whenusing a chiral 3,3’-disubstituted biarylphosphoric acid, hydride transfer to theRe face of the (Z)-iminium is energeticallymore favorable and is responsiblefor the enantioselectivity, whereas thecorresponding transition states for nucleophilicattack on the two faces ofthe (E)-iminium are virtually degenerate.Moreover, model calculations predictthe reversal in enantioselectivityobserved in the hydrogenation of 2-arylquinolines,which during the catalyticcycle are converted into (E)-iminiumions that lack the flexibility of thosederived from acyclic N-arylimines. Inthis respect, the conformational rigidityof the dihydroquinolinium cation imposesan unfavorable binding geometryon the transition state for hydridetransfer on the Re face and is thereforeresponsible for the high enantioselectivity.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH&Co. KGaA , 2008. Vol. 14, 8562-8571 p.
Keyword [en]
ensity functional calculations; hydrogenation; imines; organocatalysis; pyridines
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-11611DOI: 10.1002/chem.200800890ISI: 000260035900018Scopus ID: 2-s2.0-53849122697OAI: oai:DiVA.org:kth-11611DiVA: diva2:278322
Note
QC 20100719Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
Open this publication in new window or tab >>Quantum Chemical Studies of Mechanisms and Stereoselectivities of Organocatalytic Reactions
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As the field of organocatalysis is growing, it is becoming more important to understand the specific modes of action of these new organic catalysts. Quantum chemistry, in particular density functional theory, has proven very powerful in exploring reaction mechanisms as well as selectivities in organocatalytic reactions, and is the tool used in this thesis. Different reaction mechanisms of several organocatalytic reactions have been examined, and we have been able to exclude various reaction pathways based on the calculated reaction barriers. The origins of stereoselection in a number of reactions have been rationalized. The computational method has generally reproduced the experimental stereoselectivities satisfactorily.

The amino acid-catalyzed aldol reaction has previously been established to go through an enamine intermediate. In the first study of this thesis the understanding of this kind of reactions has been expanded to the dipeptide-catalyzed aldol reaction. The factors governing the enantioselection have been studied, showing how the chirality of the amino acids controls the conformation of the transition state, thereby determining the configuration of the product.

In the cinchona thiourea-catalyzed Henry reaction two reaction modes regarding substrate binding to the two sites of the catalyst have been investigated, showing the optimal arrangement for this reaction. This enabled the rationalization of the observed stereoselectivity.

The hydrophosphination of α,β-unsaturated aldehydes was studied. The bulky substituent of the chiral prolinol-derived catalyst was shown to effectively shield one face of the reactive iminium intermediate, thereby inducing the stereoselectivity.

The transfer hydrogenation of imines using Hantzsch esters as hydride source and axially chiral phosphoric acid catalyst has also been explored. A reaction mode where both the Hantzsch ester and the protonated imine are hydrogen bonded to the phosphoric acid is demonstrated to be the preferred mode of action. The different arrangements leading to the two enantiomers of the product are evaluated for several cases, including the hydride transfer step in the reductive amination of α-branched aldehydes via dynamic kinetic resolution.

Finally, the intramolecular aldol reaction of ketoaldehydes catalyzed by guanidinebased triazabicyclodecene (TBD) has been studied. Different mechanistic proposals have been assessed computationally, showing that the favoured reaction pathway is catalyzed by proton shuttling. The ability of a range of guanidines to catalyze this reaction has been investigated. The calculated reaction barriers reproduced the experimental reactivities quite well.

Place, publisher, year, edition, pages
Stockholm: KTH, 2009. viii, 72 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2009:27
National Category
Theoretical Chemistry Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-11616 (URN)978-91-7415-498-6 (ISBN)
Public defence
2009-12-18, Svedbergsalen, FD5, Roslagstullsbacken 21, AlbaNova, Stockholm, 14:00 (English)
Opponent
Supervisors
Note
QC 20100719Available from: 2009-12-04 Created: 2009-11-25 Last updated: 2011-11-23Bibliographically approved

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