C.V. Stevens

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

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
A1

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.

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

D.D. Claeys, C.V. Stevens, N. Dieltiens
European Journal of Organic Chemistry
(1), 171–179
2008
A1

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)

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

K.G.R. Masschelein, C.V. Stevens, N. Dieltiens, D.D. Claeys
Tetrahedron
63 (22), 4712–4724
2007
A1

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.

Unexpected Four-Membered over Six-Membered Ring Formation during the Synthesis of Azaheterocyclic Phosphonates: Experimental and Theoretical Evaluation

V. Van Speybroeck, K. Moonen, K. Hemelsoet, C.V. Stevens, M. Waroquier
JACS (Journal of the American Chemical Society)
128 (26), 8468-8478
2006
A1

Abstract 

The cyclization of functionalized aminophosphonates is studied on both experimental and theoretical grounds. In a recently described route to phosphono-β-lactams [Stevens C. V.; Vekemans, W.; Moonen, K.; Rammeloo, T. Tetrahedron Lett. 2003, 44, 1619], it was found that starting from an ambident allylic anion only four-membered rings were formed without any trace of six-membered lactams. New anion trapping experiments revealed that the γ-anion is highly reactive in intermolecular reactions. Ab initio calculations predict higher reaction barriers for the γ-anion due to restricted rotation about the C−N bond and due to highly strained transition states during ring closure. The sodium or lithium counterion, explicit dimethyl ether solvent molecules, and bulk solvent effects were properly taken into account at various levels of theory.

The Pyroglutamate Hydantoin Rearrangement

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
A1

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)

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

N. Dieltiens, D.D. Claeys, C.V. Stevens
Journal of Organic Chemistry
71(10), 3863–3868
2006
A1

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.

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

N. Dieltiens, D.D. Claeys, B. Allaert, F. Verpoort, C.V. Stevens
Chemical Communications
(35), 4477
2005
A1

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.

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

C.V. Stevens, N. Dieltiens, D.D. Claeys
Organic Letters
7 (6), 1117–1119
2005
A1

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

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

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
A1

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.

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

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
A1

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.

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