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.
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.
Acharya
A N
AN
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
Ostresh
J M
JM
Houghten
R A
RA
D000577:Amides / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D006146:Guanidines / Q000138:chemical synthesis*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis
D000577:Amides; D000596:Amino Acids; D006146:Guanidines; D006571:Heterocyclic Compounds