K. Moonen

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


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.

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


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.

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