Center for Molecular Modeling - D.D. Claeys

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

Private attachment

13_rsc_advances_3_3925_Pauwels.pdf

Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

wim — Mon, 03 Oct 2011 09:36:36 +0000

D.D. Claeys, K. Moonen, B.I. Roman, V.N. Nemykin, V.V. Zhdankin, M. Waroquier, V. Van Speybroeck, C.V. Stevens

Journal of Organic Chemistry

73 (20), 7921-7927

2008

Abstract

During the synthesis of tricyclic phosphonopyrrolidines via intramolecular Diels−Alder reactions of 1-acylamino(furan-2-yl)methyl phosphonates, two isomers are formed in most cases. The presence of a short three-atom tether together with spectroscopic data, including difference NOE, revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo or endo orientation. This was confirmed via X-ray analysis. A thermodynamic preference for the product with the phosphonate function in the endo position was observed experimentally and was confirmed theoretically. Density functional theory methods and several high-level post Hartree−Fock procedures were used to rationalize the observed isomer ratio of the IMDAF-reactions. This was done for two different types of reagents: with the activating carbonyl group in the tether or as a substituent on the tether. For the first type of molecules there is a large steric hindrance of the bulky tether substituents that disfavors the exo-isomer. In the latter case, there was a very small energy difference between the transition states causing a mixture of epimers being formed.

DOI

http://dx.doi.org/10.1021/jo801138s

Private attachment

08 j. org. chem. 73(20)7921 claeys.pdf

The Formation of trans-Fused Macrocycles from N3,N3′-Polymethylenebis(hydantoins) by Ring-Closing Metathesis

wim — Mon, 03 Oct 2011 08:31:01 +0000

D.D. Claeys, C.V. Stevens, N. Dieltiens

European Journal of Organic Chemistry

(1), 171–179

2008

Abstract

A straightforward ring transformation giving polymethylenebis(hydantoins) was extended, as these are HMBA analogues. Firstly, ethyl or allyl pyroglutamate was carbamoylated with a diisocyanate. Upon treatment with KOtBu in allyl alcohol the bis(carbamoyllactam) rearranged to give the hydantoin, which was followed by the ring-opening of the pyrrolidinone with formation of the allyl ester. These compounds were subsequently ring-closed in the presence of second-generation Grubbs' catalyst to form macrocycles containing the ester functionality in the ring. It was established by HSQC experiments with inverse detection that only the E isomers were formed in the cases of the 24- and 26-membered heterocycles. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

DOI

http://dx.doi.org/10.1002/ejoc.200700836

Private attachment

08 eur. j. org. chem 1 171 claeys.pdf

Exploiting the regioselectivity of pyroglutamate alkylations for the synthesis of 6-azabicyclo[3.2.1]octanes and 4-azabicyclo[3.3.0]octanes

wim — Mon, 03 Oct 2011 07:20:21 +0000

K.G.R. Masschelein, C.V. Stevens, N. Dieltiens, D.D. Claeys

Tetrahedron

63 (22), 4712–4724

2007

Abstract

Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.

DOI

http://dx.doi.org/10.1016/j.tet.2007.03.084

Private attachment

07 tetrahadron 22 7412 masschelein.pdf

The Pyroglutamate Hydantoin Rearrangement

wim — Fri, 30 Sep 2011 13:49:24 +0000

N. Dieltiens, D.D. Claeys, V.V. Zhdankin, V.N. Nemykin, B. Allaert, F. Verpoort, C.V. Stevens

European Journal of Organic Chemistry

2006 (11), 2649–2660

2006

Abstract

When a mixture of a pyroglutamate and an isocyanate in THF is treated with NaH, a ring transformation occurs leading to functionalised hydantoins. The novel reaction involves a ring-closing ring-opening sequence providing a new and straightforward access to an interesting class of heterocyclic compounds. Furthermore, starting from pyroglutamates allows the synthesis of highly substituted hydantoins under very mild conditions. This ring transformation in combination with ring-closing metathesis is used in a four-step reaction sequence for the synthesis of multi-functionalised bicyclic hydantoin derivatives.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

DOI

http://dx.doi.org/10.1002/ejoc.200600051

Private attachment

06 eur. j. org. chem. 11 2649 dieltiens.pdf

Synthesis of N(3),N‘(3)-Polymethylene-bis-hydantoins and Their Macrocyclic Derivatives

wim — Fri, 30 Sep 2011 13:46:21 +0000

N. Dieltiens, D.D. Claeys, C.V. Stevens

Journal of Organic Chemistry

71(10), 3863–3868

2006

Abstract

An efficient and straightforward two-step approach toward N(3),N‘(3)-polymethylene-bis-hydantoins was developed. As a first step, a pyroglutamate is reacted with a diisocyanate to produce a bis-carbamoyllactam. The second step is a double-ring transformation by treatment of this bis-carbamoyllactam with KOtBu in ethanol. In this fashion N(3),N‘(3)-polymethylene-bis-hydantoins are produced in two quantitative steps and under very mild conditions. When properly derivatized, these compounds can be converted to their macrocyclic derivatives upon treatment with 5 mol % of second-generation Grubbs' catalyst. These macrocyclic derivatives are so far not described in the literature. It was proven that exclusively (E)-isomers are formed.

DOI

http://dx.doi.org/10.1021/jo060370r

Private attachment

06 j. org. chem. 71(10)3863 dieltiens.pdf

Synthesis of 1,3-dioxo-hexahydropyrido[1,2-c][1,3]diazepine carboxylates, a new bicyclic skeleton formed by ring expansion–RCM methodology

wim — Fri, 30 Sep 2011 13:02:42 +0000

N. Dieltiens, D.D. Claeys, B. Allaert, F. Verpoort, C.V. Stevens

Chemical Communications

(35), 4477

2005

Abstract

A short and elegant synthetic pathway was developed for the synthesis of 1,3-dioxo-hexahydropyrido[1,2-c][1,3]diazepine carboxylates, a new 1,3-diazepan-2,4-dione containing bicyclic moiety, starting from pyroglutamate esters.

DOI

http://dx.doi.org/10.1039/B508663A

Private attachment

05 chem. comm. 35 4477 dieltiens.pdf

Straightforward Ring Expansion of Pyroglutamates to Perhydro-1,3-diazepine-2,4-diones

wim — Fri, 30 Sep 2011 12:58:12 +0000

C.V. Stevens, N. Dieltiens, D.D. Claeys

Organic Letters

7 (6), 1117–1119

2005

Abstract

Perhydro-1,3-diazepine-2,4-diones are rare and can only be prepared, up to now, by special methods. A new one-step protocol was developed, comprising N-carbamoylation using an isocyanate followed by intramolecular ring expansion. This new methodology provides a straightforward access to this interesting seven-membered skeleton.

(Additions and corrections: Org. Lett., 2005, 7, 5347), 2005

DOI

http://dx.doi.org/

Private attachment

05 org. lett. 7(6)1117 stevens.pdf

Conformational Sampling of Macrocyclic Alkenes Using a Kennard−Stone-Based Algorithm

wim — Tue, 13 Sep 2011 12:08:55 +0000

D.D. Claeys, T. Verstraelen, E. Pauwels, C.V. Stevens, M. Waroquier, V. Van Speybroeck

Journal of Physical Chemistry A

114 (25), 6879–6887

2010

Abstract

The properties and functions of (bio)molecules are closely related to their molecular conformations. A variety of methods are available to sample the conformational space at a relatively low level of theory. If a higher level of theory is required, the computational cost can be reduced by selecting a uniformly distributed set of conformations from the ensemble of conformations generated at a low level of theory and by optimizing this selected set at a higher level. The generation of conformers is performed using molecular dynamics runs which are analyzed using the MD-Tracks code [ J. Chem. Inf. Model. 2008, 48, 2414]. This article presents a Kennard−Stone-based algorithm, with a distance measure based on the distance matrix, for the selection of the most diverse set of conformations. The method has been successfully applied to macrocyclic alkenes. The correct thermodynamic stability of the double-bond isomers of a flexible macrocyclic alkene containing two chiral centers is reproduced. The double-bond configuration has a limited effect on the conformation of the whole macrocycle. The chirality of the stereocenters has a larger effect on the molecular conformations.

DOI

http://dx.doi.org/10.1021/jp1022778

Private attachment

10 j. phys. chem. A 114(25)6879 claeys.pdf

Experimental and computational study of the ring opening of tricyclic oxanorbornenes to polyhydro isoindole phosphonates

wim — Tue, 13 Sep 2011 11:48:06 +0000

D.D. Claeys, C.V. Stevens, B.I. Roman, P. Van De Caveye, M. Waroquier, V. Van Speybroeck

Organic & Biomolecular Chemistry

8, 3644-3654

2010

Abstract

Phosphonylated azaheterocycles are an important class of compounds with high biological potential as conformationally restricted bioisosteres of amino acids. Therefore, it is of interest to synthesize conformationally constrained amino phosphonates. We wanted to investigate possible routes via ring opening of α-amino phosphonates with an oxanorbornene skeleton, as these can be synthesized with high stereoselectivity. This was achieved using different Lewis acids, leading to a range of products. The reaction with TiCl4 and FeCl3 was modelled at a DFT level of theory to get insight in the pathways towards the corresponding products. To ease the work up, the Fe(III) catalyst was coated on montmorillonite clay, but this accelerated aromatization after ring opening. Quenching the FeCl3 catalyzed reaction mixture on celite caused complete aromatization.

DOI

http://dx.doi.org/10.1039/C002926B

Private attachment

10 org. & biomolecular chem 8, 3644 claeys.pdf