Rapid cleavage of cyclic tertiary amides of Kemp's triacid: effects of ring structure

Bioorg Med Chem Lett. 2004 Aug 16;14(16):4153-6. doi: 10.1016/j.bmcl.2004.06.024.

Abstract

The piperidyl and prolyl amides of Kemp's triacid (7 and 8, respectively) have been prepared and their rates of intramolecular acylolysis measured as a function of pD. The piperidyl derivative 7 reacts approximately four-times faster (e.g., t(1/2)=3 min at 20 degrees C and pD7.7) than the previously reported pyrrolidyl and methylphenethyl amide derivatives, while the prolyl derivative 8 reacts two-times more slowly (e.g., e.g., t(1/2)=30 min at 20 degrees C and pD7.8). Molecular-mechanics calculations indicate that the nonbonded interactions in the piperidyl derivative 7 are distinct from those in the prolyl, pyrrolidyl, and methylphenethyl amide derivatives, a result that supports the suggestion that ground-state pseudoallylic strain contributes to the enormous reactivity of Kemp's triacid tertiary amides. In sum, the results reported indicate that the Kemp's triacid scaffolding provides a general means of activating tertiary amide derivatives.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acids / chemistry*
  • Amides / chemistry*
  • Kinetics
  • Molecular Structure

Substances

  • Acids
  • Amides