Tethered libraries: solid-phase synthesis of substituted urea-linked bicyclic guanidines.
The general concept of tethered combinatorial libraries of compounds in which two pharmacophores are found is described. In particular, an improved method for the solid-phase synthesis of bicyclic guanidines from reduced N-acylated dipeptides, and its use in the synthesis of urea-linked bicyclic guanidines, is described. The exhaustive reduction of glutamine-containing resin-bound N-acylated dipeptides, using borane-THF, generated compounds containing three secondary amines and one primary amine. Following selective trityl protection of the primary amine, treatment of the three secondary amines with thiocarbonyldiimidazole (CSIm2) and mercuric acetate (Hg(OAc)2) generated the resin-bound bicyclic guanidines. Following trityl deprotection, an Fmoc-amino acid was coupled. Upon removal of the Fmoc protecting group, the resulting primary amine was treated with hexyl isocyanate to generate the urea-linked bicyclic guanidines. The desired products were cleaved from the resin using hydrogen fluoride. The selection of building blocks and characterization of controls for the synthesis of a combinatorial library is discussed.
Acharya
A N
AN
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, California 92121, USA.
Nefzi
A
A
Ostresh
J M
JM
Houghten
R A
RA
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D020650:Combinatorial Chemistry Techniques; D006146:Guanidines / Q000138:chemical synthesis*; D014508:Urea / Q000737:chemistry*
D001643:Bridged Bicyclo Compounds; D006146:Guanidines; D014508:Urea