Total Synthesis and Biological Evaluation of Pacidamycin D and Its 3′-Hydroxy Analogue

Abstract

Full details of the total synthesis of pacidamycin D (<b>4</b>) and its 3′-hydroxy analogue <b>32</b> are described. The chemically labile <i>Z</i>-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of <b>4</b> include the efficient and stereocontrolled construction of the <i>Z</i>-oxyvinyl halides <b>6</b> and <b>7</b> and their copper-catalyzed cross-coupling with the tetrapeptide carboxamide <b>5</b>, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3′-hydroxy analogue <b>32</b>. The assemblage by cross-coupling of the <i>Z</i>-oxyvinyl halide <b>6</b> and the carboxamide <b>5</b> at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety