Synthesis of Proteasome Inhibitor Omuralide Featuring Stereocontrolled Ugi Reaction and Novel Convertible Isocyanide

Abstract

Stereocontrolled formal total synthesis of proteasome inhibitor omuralide is described. This is featured by the application of Ugi 4–center 3–component condensation reaction to prepare a highly functionalized pyroglutamic acid. To this end, a novel convertible isocyanide was developed, which is readily available by preparative synthesis from nitrotoluene. The hydrolysis of the sterically hindered C–terminal amide derived from the isocyanide was facilitated by the conversion to N–acylindole. By careful design of the γ–ketoacid precursor, a substrate–controlled diastereoselective Ugi reaction was successfully accomplished. Also, several highly functionalized pyroglutamic acid amides were prepared with high diastereoselectivity.