Synthesis of various 3-substituted 1,2,4-oxadiazole-containing chiral beta 3- and alpha-amino acids from Fmoc-protected aspartic acid.
Various 3-substituted chiral 1,2,4-oxadiazole-containing Fmoc-beta(3)- and -alpha-amino acids were synthesized from Fmoc-(l or d)-Asp(OtBu)-OH and Fmoc-l-Asp-OtBu, respectively, in three steps (i.e., condensation of an aspartyl derivative with differentially substituted amidoximes, formation of the 1,2,4-oxadiazole, and cleavage of the tert-butyl ester). These compounds represent new series of nonnatural amino acids, which could be used in combinatorial synthesis. A simple protocol has been developed to generate the 1,2,4-oxadiazole ring. Indeed, common methods resulted in cleavage of the Fmoc group or required long reaction times. We found that sodium acetate in refluxing ethanol/water (86 degrees C) was a convenient and efficient catalyst to promote conversion of Fmoc-amino acyl amidoximes to 1,2,4-oxadiazoles, and this procedure proved to be compatible with Fmoc protection. It is shown that these compounds can be prepared without significant loss of enantiomerical purity. Furthermore, the alkaline conditions used to cleave the Fmoc protecting group from these compounds did not induce epimerization of their chiral center.
Hamzé
Abdallah
A
Laboratoire des Aminoacides Peptides et Protéines, CNRS UMR 5810, Universités Montpellier I et II, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093 Montpellier cédex 5, France.
Hernandez
Jean-François
JF
Fulcrand
Pierre
P
Martinez
Jean
J
D000596:Amino Acids / Q000138:chemical synthesis*; D001224:Aspartic Acid / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D010069:Oxadiazoles / Q000138:chemical synthesis*
D000596:Amino Acids; D010069:Oxadiazoles; D001224:Aspartic Acid