Center for Molecular Modeling - GOA06

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

Accurate prediction of 1H-chemical shifts in interstrand cross-linked DNA

michel — Thu, 12 Jul 2012 06:53:36 +0000

E. Pauwels, D.D. Claeys, J. Martins, M. Waroquier, G. Bifulco, V. Van Speybroeck, A. Madder

RSC Advances

2013 (3), 3925-3938

2013

Abstract

Structural analysis of modified DNA with NMR is becoming ever more difficult with increasingly complex compounds under scrutiny for use in medical diagnosis, therapeutics, material science and chemical synthesis. To facilitate this process, we develop a molecular modeling approach to predict proton chemical shifts in sufficient agreement with experimental NMR measurements to guide structure elucidation. It relies on a QM/MM partitioning scheme and first principle calculations to predict the spatial structure and calculate corresponding proton chemical shifts. It is shown that molecular dynamics simulations that take into account solvent and temperature effects properly are of utmost importance to sample the conformational space sufficiently. The proposed computational procedure is universally applicable to modified oligonucleotides and DNA, attaining a mean error for the proton chemical shifts of less than 0.2 ppm. Here, it is applied on the Drew-Dickerson d(CGCGAATTCGCG)2 dodecamer as a benchmark system and the mispair-aligned N3T-ethyl-N3T cross-linked d(CGAAAT*TTTCG)2 undecamer, illustrating its universal use as computational tool to assist in structure elucidation. For the proton chemical shifts in the cross-linked system our methodology yields a strikingly superior description, surpassing the predictive power of (semi-)empirical methods. In addition, our methodology is the only one available to make an accurate prediction for the protons in the actual cross-link. To the best of our knowledge, this is the first computational study that attempts to determine the chemical shifts of oligonucleotides of this size and at this level of complexity.

DOI

http://dx.doi.org/10.1039/C3RA22408B

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13_rsc_advances_3_3925_Pauwels.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

Intramolecular π−π Stacking Interactions in 2-Substituted N,N-Dibenzylaziridinium Ions and Their Regioselectivity in Nucleophilic Ring-Opening Reactions

wim — Tue, 13 Sep 2011 13:00:01 +0000

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

Journal of Organic Chemistry

75 (3), 885–896

2010

Abstract

The ring opening of 2-substituted N,N-dibenzylaziridinium ions by bromide is known to occur exclusively at the substituted aziridine carbon atom via an SN2 mechanism, whereas the opposite regioselectivity has been observed as the main pathway for ring opening by fluoride. Similarly, the hydride-induced ring opening of 2-substituted N,N-dibenzylaziridinium ions has been shown to take place solely at the less hindered position. To gain insight into the main factors causing this difference in regioselectivity, a thorough and detailed computational analysis was performed on the hydride- and halide-induced ring openings of 1-benzyl-1-(α-(R)-methylbenzyl)-2(S)-(phenoxymethyl)aziridinium bromide. Intramolecular π−π stacking interactions in the aziridinium system were investigated at a range of levels that enable a proper description of dispersive interactions; a T-stacking conformer was found to be the most stable. Ring-opening mechanisms were investigated with a variety of DFT and high level ab initio methods to test the robustness of the energetics along the pathway in terms of the electronic level of theory. The necessity to utilize explicit solvent molecules to solvate halide ions was clearly shown; the potential energy surfaces for nonsolvated and solvated cases differed dramatically. It was shown that in the presence of a kinetically viable route, product distribution will be dictated by the energetically preferred pathway; this was observed in the case of hard nucleophiles (both hydride donors and fluoride). However, for the highly polarizable soft nucleophile (bromide), it was shown that in the absence of a large energy difference between transition states leading to competing pathways, the formation of the thermodynamic product is likely to be the driving force. Distortion/interaction analysis on the transition states has shown a considerable difference in interaction energies for the solvated fluoride case, pointing to the fact that sterics plays a major role in the outcome, whereas for the bromide this difference was insignificant, suggesting bromide is less influenced by the difference in sterics.

Open Access version available at UGent repository

DOI

http://dx.doi.org/10.1021/jo902493w

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10 j. org. chem. 75(3)885 catak.pdf

Systematic Study of Halide-Induced Ring Opening of 2-Substituted Aziridinium Salts and Theoretical Rationalization of the Reaction Pathways

wim — Tue, 13 Sep 2011 12:11:31 +0000

M. D'Hooghe, S. Catak, S. Stankovic, M. Waroquier, Y. Kim, H-J. Ha, V. Van Speybroeck, N. De Kimpe

European Journal of Organic Chemistry

25, 4920-4931

2010

Abstract

The ring-opening reactions of 2-alkyl-substituted 1,1-bis(arylmethyl)- and 1-methyl-1-(1-phenylethyl)aziridinium salts with fluoride, chloride, bromide and iodide in acetonitrile have been evaluated for the first time in a systematic way. The reactions with fluoride afforded regioisomeric mixtures of primary and secondary fluorides, whereas secondary β-chloro, β-bromo and β-iodo amines were obtained as the sole reaction products from the corresponding halides by regiospecific ring opening at the substituted position. Both experimental and computational results revealed that the reaction outcomes in the cases of chloride, bromide and iodide were dictated by product stability through thermodynamic control involving rearrangement of the initially formed primary halides to the more stable secondary halides. The ring opening of the same aziridinium salts with fluoride, however, was shown to be mediated by steric interactions (kinetic control), with the corresponding primary β-fluoro amines being obtained as the main reaction products. Only for 2-acylaziridinium ions was the reaction outcome shown to be under full substrate control, affording secondary β-fluoro, β-chloro, β-bromo and β-iodo amines through exclusive attack at the activated α-carbonyl carbon atom.

Open Access version available at UGent repository

DOI

http://dx.doi.org/10.1002/ejoc.201000486

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10 Eur. J. of Org. Chem. 4920-4931 dhooghe.pdf

Synthesis of 3-Methoxyazetidines via an Aziridine to Azetidine Rearrangement and Theoretical Rationalization of the Reaction Mechanism

wim — Mon, 22 Aug 2011 14:38:15 +0000

S. Stankovic, S. Catak, M. D'Hooghe, H. Goossens, K. Abbaspour Tehrani, P. Bogaert, M. Waroquier, V. Van Speybroeck, N. De Kimpe

Journal of Organic Chemistry

76 (7), 2157-2167

2011

Abstract

The synthetic utility of N-alkylidene-(2,3-dibromo-2-methylpropyl)amines and N-(2,3-dibromo-2-methylpropylidene)benzylamines was demonstrated by the unexpected synthesis of 3-methoxy-3-methylazetidines upon treatment with sodium borohydride in methanol under reflux through a rare aziridine to azetidine rearrangement. These findings stand in contrast to the known reactivity of the closely related N-alkylidene-(2,3-dibromopropyl)amines, which are easily converted into 2-(bromomethyl)aziridines under the same reaction conditions. A thorough insight into the reaction mechanism was provided by both experimental study and theoretical rationalization.

DOI

http://dx.doi.org/10.1021/jo102555r

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11 j. org. chem. 76,2157 stankovic.pdf

Regioselectivity in the ring opening of non-activated aziridines

wim — Mon, 22 Aug 2011 14:00:39 +0000

S. Stankovic, M. D'Hooghe, S. Catak, M. Waroquier, V. Van Speybroeck, N. De Kimpe, H-J. Ha

Chemical Society Reviews

41, 643-665

2012

Abstract

In this critical review, the ring opening of non-activated 2-substituted aziridines via intermediate aziridinium salts will be dealt with. Emphasis will be put on the relationship between the observed regioselectivity and inherent structural features such as the nature of the C2 aziridine substituent and the nature of the electrophile and the nucleophile. This overview should allow chemists to gain insight into the factors governing the regioselectivity in aziridinium ring openings (81 references).

DOI

http://dx.doi.org/10.1039/C1CS15140A

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12 Chem. Soc. Rev.41 643 Stancovic.pdf.pdf

Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines

wim — Mon, 22 Aug 2011 13:32:06 +0000

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

Journal of Organic Chemistry

76 (20), 8364–8375

2011

Abstract

The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding β-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an SN2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.

DOI

http://dx.doi.org/10.1021/jo201556t

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11 j. org. chem. 76(20)8364 mollet.pdf