Synthesis of (purin-6-yl)amino acids

Abstract

Purines bearing carbon substituents attached to carbon atoms of purine ring (positions 2, 6 and/or 8) are of great interest due to potential applications in medicinal chemistry and chemical biology. Transition metal-catalyzed cross-coupling reactions are a powerful tool [1] for the synthesis of these compounds but, in most cases, were only used for an introduction of simple unfunctionalized alkyl, alkenyl, alkynyl, aryl and hetaryl substituents. An extension of this methodology to introduction of functionalized C-substituents, is a very challenging target. One of the prominent functionalized substituents of high biological relevance is an amino acid residue. Our goal is to develop approaches towards the synthesis of a novel class of compounds: carbon-carbon linked conjugates of amino acids and purines. We have developed a facile and efficient synthesis of two classes of purines with amino acid attached in position 6 of purine scaffold, (purin-6-yl)alanines [2] and (purin-6yl)phenylalanines.[3] These derivatives were prepared by palladium catalyzed cross-coupling reactions of 6-halopurines with organometallic reagents based on protected amino acid residue. Conditions of cross-coupling reactions were optimized to avoid racemization in cases when enantiopure amino acid reagents were used. Final complete deprotection of the products was performed under mild conditions in order to prevent racemization or cleavage of acidolabile nucleosidic bonds. We obtained free purine bases, purine nucleosides and 9alkylated purines bearing free amino acid in position 6.