C.V. Stevens

Beyond the diketopiperazine family with alternatively bridged brevianamide F analogues

I. Wauters, H. Goossens, E. Delbeke, K. Muylaert, B.I. Roman, K. Van Hecke, V. Van Speybroeck, C.V. Stevens
Chemistry - A European Journal
80 (16), 8046-8054
2015
A1

Abstract 

A method for the preparation of 3,5-bridged piperazin-2-ones from a tryptophan–proline-based diketopiperazine is described using diphosgene to induce the ring closure. Density functional theory calculations were conducted to study the mechanism of this C–C bond formation. Several derivatives of the thus obtained α-chloroamine were synthesized by substitution of the chlorine atom using a range of O-, N-, S-, and C-nucleophiles. This novel class of brevianamide F analogues possess interesting breast cancer resistance protein inhibitory activity.

DOI 

http://dx.doi.org/10.1021/acs.joc.5b01161

Elucidating the Structural Isomerism of Fluorescent Strigolactone Analogue CISA-1

H. Goossens, T.S.A Heugebaert, B. Dereli, M. Van Overtveldt, O. Karahan, I. Doğan, M. Waroquier, V. Van Speybroeck, V. Aviyente, S. Catak, C.V. Stevens
European Journal of Organic Chemistry
2015 (6), 1211–1217
2015
A1

Abstract 

The synthesis of a new potent strigolactone analogue (CISA-1), resulting in the formation of two interconverting structural isomers, which could not be identified, was recently reported by Rasmussen et al [Molecular Plant, 2013, 6, 100]. In the present study, a combined computational and experimental approach is used to identify the exact nature of these structural isomers. While standard experimental techniques were not able to determine the identity of the isomers, chromatographic methods excluded E/Z isomerisation. Computational 1H NMR chemical shift values and DFT calculations on interconversion barriers strongly suggest that the CISA-1 isomers were interconverting (Z)-configured atropisomers.

DOI 

http://dx.doi.org/10.1002/ejoc.201403457

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.

DOI 

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

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)

DOI 

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

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.

DOI 

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

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.

DOI 

http://dx.doi.org/10.1021/ja0584119

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)

DOI 

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

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.

DOI 

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

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.

DOI 

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

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

DOI 

http://dx.doi.org/

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