Center for Molecular Modeling - N. De Kimpe

Nucleophile-Dependent Regio- and Stereoselective Ring Opening of 1-Azoniabicyclo-[3.1.0]hexane Tosylate

michel — Sat, 30 Nov 2013 15:23:21 +0000

Mi-Kyung Ji, D. Hertsen, D.-H. Yoon, H. Eum, H. Goossens, M. Waroquier, V. Van Speybroeck, M. D'Hooghe, N. De Kimpe, H.-J. Ha

Chemistry - An Asian Journal

2014 (9), 1060-1067

2014

Abstract

1-[(1R)-(1-Phenylethyl)]-1-azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2-(3-hydroxypropyl)aziridine upon reaction with p-toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH3CN to afford either piperidines or pyrrolidines through regio- and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring-opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways.

DOI

http://dx.doi.org/10.1002/asia.201301551

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14_chemasianjournal_2014(9)1060_Ji.pdf

Synthesis of 2-Hydroxy-1,4-oxazin-3-ones through Ring Transformation of 3-Hydroxy-4-(1,2-dihydroxyethyl)--lactams and a Study of Their Reactivity

michel — Fri, 13 Jul 2012 11:46:22 +0000

K. Mollet, H. Goossens, N. Piens, S. Catak, M. Waroquier, V. Van Speybroeck, M. D'Hooghe, N. De Kimpe

Chemistry - A European Journal

19 (10), 3383-3396

2013

Abstract

The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-β-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-β-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO4-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-β-lactams, which exclusively leads to the corresponding 4-formyl-β-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3-ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations.

DOI

http://dx.doi.org/10.1002/chem.201203314

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13_chem_eur_ j_19(10)3383_Mollet.pdf

Diastereoselective aldol reaction of zincated 3-chloro-3-methyl-1- azaallylic anions as key-step in the synthesis of 1,2,3,4- tetrasubstituted 3-chloroazetidines

catak — Fri, 27 Jan 2012 15:03:37 +0000

S. Mangelinckx, B. De Sterck, F. Colpaert, S. Catak, J. Jacobs, S. Rooryck, M. Waroquier, V. Van Speybroeck, N. De Kimpe

Journal of Organic Chemistry

77 (7), 3415–3425

2012

Abstract

Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn alpha-chloro-beta-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn alpha-chloro-beta-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.

Open Access version available at UGent repository

DOI

http://dx.doi.org/10.1021/jo300203t

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12 j.org_.chem 77, 3415 Mangelinckx.pdf

Solvent-controlled selective transformation of 2-Bromomethyl-2-methylaziridines to functionalized aziridines and azetidines

michel — Sun, 18 Dec 2011 20:34:45 +0000

S. Stankovic, H. Goossens, S. Catak, M. Tezcan, M. Waroquier, V. Van Speybroeck, M. D'Hooghe, N. De Kimpe

Journal of Organic Chemistry

77, 3181-3190

2012

Abstract

The reactivity of 2-bromomethyl-2-methylaziridines toward oxygen, sulfur, and carbon nucleophiles in different solvent systems was investigated. Remarkably, the choice of the solvent has a profound influence on the reaction outcome, enabling the selective formation of either functionalized aziridines in dimethylformamide (through direct bromide displacement) or azetidines in acetonitrile (through rearrangement via a bicyclic aziridinium intermediate). In addition, the experimentally observed solvent-dependent behavior of 2-bromomethyl-2-methylaziridines was further supported by means of DFT calculations.

Open Access version available at UGent repository

DOI

http://dx.doi.org/10.1021/jo202637a

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12 j.org_.chem 77, 3181 Stankovic.pdf

A theoretical study on the solvated structural properties of various metalated 3-halo-1-azaallylic anions

wim — Mon, 03 Oct 2011 11:54:56 +0000

B. De Sterck, V. Van Speybroeck, S. Mangelinckx, G. Verniest, N. De Kimpe, M. Waroquier

Journal of Physical Chemistry A

113 (22), 6375-6380

2009

Abstract

Metalated 3-halo-1-azaallylic anions are important building blocks for the preparation of a wide variety of heterocyclic and highly functionalized compounds. A theoretical description of the structural properties of halogenated 1-azaallylic anions in vacuo and in tetrahydrofuran (THF) solution is presented to gain insight into their reactivity behavior. The configurational flexibility of fluorinated and chlorinated 1-azaallylic anions is examined, and it is shown that these anions have far less configurational flexibility as compared with nonhalogenated analogues, with a strong preference to occur as Z/anti isomers. In addition, the driving force for transmetalation, that is, the replacement of the lithium cations with K+, Cu+, ZnCl+, CuCl+, or MgBr+ is studied. To obtain reliable results, the structures were modeled in THF using the combined implicit/explicit solvent approach resulting in different coordination numbers for lithium in the Z/anti and E/anti isomers. Calculations on dimerization energies show that coordination with THF is energetically preferred over aggregation.

DOI

http://dx.doi.org/10.1021/jp811317y

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09 j. phys. chem. A 113(22)6375 de sterck.pdf

Nucleophile-dependent regioselective ring opening of 2-substituted N,N-dibenzylaziridinium ions: bromideversushydride

wim — Mon, 03 Oct 2011 10:22:31 +0000

S. Young Yun, S. Catak, W. Koo Lee, M. D'Hooghe, N. De Kimpe, V. Van Speybroeck, M. Waroquier, Y. Kim, H-J. Ha

Chemical Communications

(18), 2508-2510

2009

Abstract

The ring opening of 2-substituted N,N-dibenzylaziridinium ions by bromide exclusively occurs at the substituted aziridine carbon atom in a stereospecific way, whereas the opposite regioselectivity was observed for hydride-induced ring opening at the unsubstituted position; furthermore, this unprecedented hydride-promoted reactivity was validated by means of Density Functional Theory (DFT) calculations.

DOI

http://dx.doi.org/10.1039/B822763B

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09 chemcomm (18) 2508 yun.pdf

Experimental and Computational Study of the Conrotatory Ring Opening of Various 3-Chloro-2-azetines

wim — Mon, 03 Oct 2011 09:27:40 +0000

S. Mangelinckx, V. Van Speybroeck, P. Vansteenkiste, M. Waroquier, N. De Kimpe

Journal of Organic Chemistry

73 (14) 5481-5488

2008

Abstract

A combined experimental and theoretical study is presented on 2-azetines, a class of azaheterocyclic compounds, which are difficult to access but have shown a unique reactivity as strained cyclic enamines. New highly substituted 2-azetines bearing aryl substituents at the 2- and 4-position were synthesized from 3,3-dichloroazetidines. Whereas 2-aryl-3,3-dichloroazetidines gave stable 2-aryl-3-chloro-2-azetines upon treatment with sodium hydride in DMSO, 2,4-diaryl-3,3-dichloroazetidines showed a remarkably different reactivity in that they afforded benzimidoyl-substituted alkynes under similar mild treatment with base. The formation of the alkynes involves electrocyclic ring opening of intermediate 2,4-diaryl-3-chloro-2-azetines and elimination of hydrogen chloride. Ab initio theoretical calculations confirmed the experimental findings and demonstrated that the 4-aryl substituent is responsible for this remarkably enhanced reactivity of 2-azetines toward electrocyclic conrotatory ring opening by a significant decrease in reaction barrier of about 30 kJ/mol. This activation effect by an aryl group in the allylic position toward electrocyclic ring opening of unsaturated four-membered rings is of general importance since a similar increased reactivity of 4-aryloxetes, 4-arylthiete-1,1-dioxides, and 3-arylcyclobutenes has been reported in literature as well.

DOI

http://dx.doi.org/10.1021/jo800522b

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08 j. org. chem. 73(14)5481 mangelinckx.pdf

Novel Synthesis of 3,4-Diaminobutanenitriles and 4-Amino-2-butenenitriles from 2-(Cyanomethyl)aziridines through Intermediate Aziridinium Salts: An Experimental and Theoretical Approach

wim — Mon, 03 Oct 2011 07:37:36 +0000

M. D'Hooghe, V. Van Speybroeck, A. Van Nieuwenhove, M. Waroquier, N. De Kimpe

Journal of Organic Chemistry

72 (13), 4733-4740

2007

Abstract

1-Arylmethyl-2-(cyanomethyl)aziridines were transformed into 4-(N,N-bis(arylmethyl)amino)-3-(pyrrolidin-1-yl)butanenitriles and 4-(N,N-bis(arylmethyl)amino)-2-butenenitriles via 4-(N,N-bis(arylmethyl)amino)-3-bromobutanenitriles in high yields and purity. The key steps involve the unprecedented regiospecific ring opening of intermediate 2-(cyanomethyl)aziridinium salts by bromide and pyrrolidine in acetonitrile, exclusively at the substituted aziridine carbon atom. The results were rationalized on the basis of ab initio calculations.

DOI

http://dx.doi.org/10.1021/jo0704210

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07 j. org. chem 72(13)4733 d'hooghe.pdf

Four-Membered Heterocycles with a Carbon−Heteroatom Exocyclic Double Bond at the 3-Position: Puckering Potential and Thermodynamic Properties

wim — Mon, 03 Oct 2011 07:22:08 +0000

P. Vansteenkiste, V. Van Speybroeck, G. Verniest, N. De Kimpe, M. Waroquier

Journal of Physical Chemistry A

111 (14), 2797-2803

2007

Abstract

Despite the specific importance of four-membered heterocycles with a carbon−heteroatom double bond at the 3-position in organic and medicinal chemistry, little attention has been given up to now to theoretical computational studies on these molecules. However, the overall geometry, and degree of ring puckering especially, could significantly influence the reactivity and biological properties of these four-membered ring compounds. In this paper, focus is made on the influence of different substituents on the equilibrium geometry, ring puckering potential, and thermodynamic quantities. It was found that these properties are mainly affected by the heteroatom (oxygen, nitrogen, sulfur, phosphorus) contained in the ring skeleton. Moreover, the correct description of the puckering potential with the hindered rotor treatment leads to substantial corrections on the thermodynamic properties in the harmonic oscillator approximation.

DOI

http://dx.doi.org/10.1021/jp068454r

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07 j. phys. chem. A 111(14)2797 vansteenkiste.pdf

Regio- and stereospecific ring opening of 1,1-dialkyl-2- (aryloxymethyl)aziridinium salts by bromide

wim — Fri, 30 Sep 2011 14:34:03 +0000

M. D'Hooghe, V. Van Speybroeck, M. Waroquier, N. De Kimpe

Chemical Communications

14, 1554 -1556

2006

Abstract

Enantiomerically pure 2-(aryloxymethyl)aziridines are efficiently transformed into chiral N-(2-bromo-3-aryloxypropyl)amines via a regio- and stereospecific ring opening of the intermediate aziridinium salts, and the experimental results are rationalized on the basis of some high level ab initio calculations

DOI

http://dx.doi.org/10.1039/B518298K

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06 chem. comm (14) 1554 d'hooghe.pdf