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A combined experimental and theoretical investigation of the stereoselectivity in the synthesis of azahetrocyclic phosphonates

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Abstract
Since the discovery of the biological activity of aminoalkylphosphonates, e.g. as enzyme inhibitors, many researchers have focused their attention on conformationally constrained azaheterocyclic phosphonates. Stereocontrol is of major interest during the synthesis of these products. Therefore our research group has developed a new route towards tricyclic phosphono pyrrolidines using an intramolecular Diels-Alder reaction with furans (IMDAF), as given in the scheme. We wanted to reveal the stereoselectivity of these IMDAF-reactions experimentally and computationally. This would enable us to direct the reaction to one isomer and gives an idea of the influence of the position of the carbonyl group on the stereoselectivity. 2OP(OMe)2N1ONP(OMe)2OOROOROP(OMe)2NR3O4RNP(OMe)2OOOO Difference NOE, 2-dimensional NMR-data and an X-ray analysis of adducts 2 revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo- or endo-orientation. A thermodynamic preference for the minor isomer with an endo-substituent was observed experimentally. DFT calculations confirmed this and linked it with a larger steric hindrance of the bulky tether substituents in the exo-isomer. The same computational methods predicted that the single isomer formed starting from aminophosphonate 3 was the endo-isomer. A relation with the JHP coupling constant was found. Furthermore, a computational study at the post Hartree-Fock level could reproduce the kinetic preference for the exo-isomer of adduct 2, while the presence of the carbonyl function in the tether results in the endo-isomer only.

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MLA
Claeys, Diederica, Kristof Moonen, Bart Roman, et al. “A Combined Experimental and Theoretical Investigation of the Stereoselectivity in the Synthesis of Azahetrocyclic Phosphonates.” Book of Abstracts : 12th Sigma-Aldrich Organic Synthesis Meeting. 2008. Print.
APA
Claeys, Diederica, Moonen, K., Roman, B., Van Speybroeck, V., Waroquier, M., & Stevens, C. (2008). A combined experimental and theoretical investigation of the stereoselectivity in the synthesis of azahetrocyclic phosphonates. Book of abstracts : 12th Sigma-Aldrich organic synthesis meeting. Presented at the 12th Sigma-Aldrich Organic Synthesis Meeting.
Chicago author-date
Claeys, Diederica, Kristof Moonen, Bart Roman, Veronique Van Speybroeck, Michel Waroquier, and Christian Stevens. 2008. “A Combined Experimental and Theoretical Investigation of the Stereoselectivity in the Synthesis of Azahetrocyclic Phosphonates.” In Book of Abstracts : 12th Sigma-Aldrich Organic Synthesis Meeting.
Chicago author-date (all authors)
Claeys, Diederica, Kristof Moonen, Bart Roman, Veronique Van Speybroeck, Michel Waroquier, and Christian Stevens. 2008. “A Combined Experimental and Theoretical Investigation of the Stereoselectivity in the Synthesis of Azahetrocyclic Phosphonates.” In Book of Abstracts : 12th Sigma-Aldrich Organic Synthesis Meeting.
Vancouver
1.
Claeys D, Moonen K, Roman B, Van Speybroeck V, Waroquier M, Stevens C. A combined experimental and theoretical investigation of the stereoselectivity in the synthesis of azahetrocyclic phosphonates. Book of abstracts : 12th Sigma-Aldrich organic synthesis meeting. 2008.
IEEE
[1]
D. Claeys, K. Moonen, B. Roman, V. Van Speybroeck, M. Waroquier, and C. Stevens, “A combined experimental and theoretical investigation of the stereoselectivity in the synthesis of azahetrocyclic phosphonates,” in Book of abstracts : 12th Sigma-Aldrich organic synthesis meeting, Spa, Belgium, 2008.
@inproceedings{526118,
  abstract     = {Since the discovery of the biological activity of aminoalkylphosphonates, e.g. as enzyme inhibitors, many researchers have focused their attention on conformationally constrained azaheterocyclic phosphonates. Stereocontrol is of major interest during the synthesis of these products. Therefore our research group has developed a new route towards tricyclic phosphono pyrrolidines using an intramolecular Diels-Alder reaction with furans (IMDAF), as given in the scheme. We wanted to reveal the stereoselectivity of these IMDAF-reactions experimentally and computationally. This would enable us to direct the reaction to one isomer and gives an idea of the influence of the position of the carbonyl group on the stereoselectivity. 2OP(OMe)2N1ONP(OMe)2OOROOROP(OMe)2NR3O4RNP(OMe)2OOOO Difference NOE, 2-dimensional NMR-data and an X-ray analysis of adducts 2 revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo- or endo-orientation. A thermodynamic preference for the minor isomer with an endo-substituent was observed experimentally. DFT calculations confirmed this and linked it with a larger steric hindrance of the bulky tether substituents in the exo-isomer. The same computational methods predicted that the single isomer formed starting from aminophosphonate 3 was the endo-isomer. A relation with the JHP coupling constant was found. Furthermore, a computational study at the post Hartree-Fock level could reproduce the kinetic preference for the exo-isomer of adduct 2, while the presence of the carbonyl function in the tether results in the endo-isomer only.},
  author       = {Claeys, Diederica and Moonen, Kristof and Roman, Bart and Van Speybroeck, Veronique and Waroquier, Michel and Stevens, Christian},
  booktitle    = {Book of abstracts : 12th Sigma-Aldrich organic synthesis meeting},
  language     = {eng},
  location     = {Spa, Belgium},
  title        = {A combined experimental and theoretical investigation of the stereoselectivity in the synthesis of azahetrocyclic phosphonates},
  year         = {2008},
}