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 Article

Acharya, AN, Ostresh, JM, Houghten, RA. (2001). 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 . 3(6), 578-589. 10.1021/cc0100262

cited authors

  • Acharya, AN; Ostresh, JM; Houghten, RA

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., Nα-Fmoc-Nx-(Boc)-diamino acid, x = β, γ, δ, ε) 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 resinbound disubstituted cyclic guanidines with carboxylic acids gave N-acylated guanidines. On the basis of their high yield and purity, bis cyclic guanidines derived from Nα-Fmoc-Nε-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 date

  • November 1, 2001

Digital Object Identifier (DOI)

start page

  • 578

end page

  • 589

volume

  • 3

issue

  • 6