Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche - And anti -3-fluoro- and 3-hydroxypyrrolidines

Grant R. Krow, Ram Edupuganti, Deepa Gandla, Fang Yu, Matthew Sender, Philip E. Sonnet, Michael J. Zdilla, Charles Debrosse, Kevin C. Cannon, Charles W. Ross, Amit Choudhary, Matthew D. Shoulders, Ronald T. Raines

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Abstract

N-Acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized Cβ-gauche and Cβ-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the KT/C values of N-acetylamide conformers in both CDCl3 (43-54% trans) and D 2O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl3 (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D2O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The KT/C results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

Original languageEnglish (US)
Pages (from-to)3626-3634
Number of pages9
JournalJournal of Organic Chemistry
Volume76
Issue number10
DOIs
StatePublished - May 20 2011

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    Krow, G. R., Edupuganti, R., Gandla, D., Yu, F., Sender, M., Sonnet, P. E., Zdilla, M. J., Debrosse, C., Cannon, K. C., Ross, C. W., Choudhary, A., Shoulders, M. D., & Raines, R. T. (2011). Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche - And anti -3-fluoro- and 3-hydroxypyrrolidines. Journal of Organic Chemistry, 76(10), 3626-3634. https://doi.org/10.1021/jo200117p