A Novel Approach for the Solid-Phase Synthesis of Substituted Cyclic Guanidines, Their Respective Bis Analogues, and N-acylated Guanidines From N-acylated Amino Acid Amides

J Comb Chem. Nov-Dec 2001;3(6):578-89. doi: 10.1021/cc0100262.

Abstract

An efficient method for the solid-phase synthesis of cyclic guanidines from N-acylated amino acid amides, bis cyclic guanidines from N-acylated dipeptides derived from orthogonally protected diamino acids, and N-acylated guanidines from disubstituted cyclic guanidines is described. The exhaustive reduction of N-acylated amino acid amides yields diamines that on treatment with cyanogen bromide lead to the formation of cyclic guanidines. Resin-bound orthogonally protected diamino acids (i.e., N(alpha)-Fmoc-N(x)-(Boc)-diamino acid, x = beta, gamma, delta, epsilon) were N-acylated following removal of the Fmoc group. Removal of the Boc functionality from the side chain then generated a primary amine. Subsequent coupling of Boc amino acids, followed by removal of the Boc group, generated dipeptides that were N-acylated. Exhaustive reduction of amide bonds of the N-acylated dipeptides generated tetraamines having four secondary amines, which upon cyclization with cyanogen bromide afforded the resin-bound trisubstituted bis cyclic guanidines. Treatment of the resin-bound disubstituted cyclic guanidines with carboxylic acids gave N-acylated guanidines. On the basis of their high yield and purity, bis cyclic guanidines derived from N(alpha)-Fmoc-N(epsilon)-Boc-lysine and N-acylated guanidines were chosen for preparation of mixture-based combinatorial libraries. Details of the preparation of these positional scanning libraries using the "libraries from libraries" concept are presented.

Publication types

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

MeSH terms

  • Amides / chemistry
  • Amino Acids / chemistry
  • Combinatorial Chemistry Techniques*
  • Guanidines / chemical synthesis*
  • Heterocyclic Compounds / chemical synthesis

Substances

  • Amides
  • Amino Acids
  • Guanidines
  • Heterocyclic Compounds