Synthesis of 2,5-dioxygenated pyrazine 4-oxides: total synthesis of a new inhibitor of superoxide anion generation, OPC-15161

Abstract

The total synthesis of OPC-15161 1, a new inhibitor of superoxide anion generation, is described in full. Three approaches, routes A–C, have been investigated focusing on the pivotal structure 2,5-dioxygenated pyrazine 4-oxide. Among them, route A led to the total synthesis of 1. That is, the key precursor, 5-hydroxypyrazin-2(1H)-one-4-oxide 7 has been prepared from tryptophan methyl ester 2 in three steps, and direct methylation of the 5-hydroxy group of 7 or three-step methylation via the 2-O-Boc derivative 10 afforded 1 in 9.9–10.6% overall yields.