Synthesis of functionalized furopyrazines as restricted dipeptidomimetics

Abstract

Herein, an efficient synthetic approach to a furopyrazine scaffold with four points of diversity, starting from 2(1H)-pyrazinones, with dipeptomimetic properties, is presented. R-groups corresponding to amino acid side chains were introduced during the 2(1H)-pyrazinone and subsequent furopyrazine formation. The furopyrazine scaffold was further functionalized with an amino- and a carboxy-terminus resulting in a conformationally restricted dipeptidomimetic scaffold. The carboxy-terminus was introduced via a chemoselective vinylation of the 7-position followed by oxidative cleavage, while the amino-terminus was obtained via Buchwald–Hartwig amidation of the 2-position of the scaffold. The versatility of the synthetic method was demonstrated by the synthesis of a small library of diversely substituted furopyrazines having various amino acid side chains on the four points of diversity. Evaluation with an X-ray structure of the scaffold and computational analysis supports the exploitation of the furopyrazine scaffold as a restricted dipeptide mimic, which can mimic the two central residues of a β-turn.