Stereoselective total synthesis and enantioselective formal synthesis of the antineoplastic sesquiterpene quinone metachromin A

The first total synthesis of the antineoplastic marine natural product meta chromin-A (1) was accomplished through a convergent synthetic approach amen able to the preparation of analogues for biological studies. The synthesis involved twelve steps in its longest sequence and sixteen steps overall. Th e total synthesis of the racemic metachromin-A features: (I) an efficient s ynthesis of the quinone intermediate 11; (2) efficient protocols for the pr eparation of the key fragments 5 and 6; (3) a highly regioselective Thiele- Winter acetoxylation step; and (4) a stereoselective Horner-Wadsworth-Emmon s coupling reaction employing fragment 6 as a non-stabilized phosphonate as an effective partner. The metachromin-A synthesis was made formally enanti oselective by the asymmetric synthesis of fragment 5 employing the methodol ogies developed by Simpkins (asymmetric deprotonation with a chiral nitroge nated base) and d'Angelo (enantioselective deracemization). This latter pro tocol furnished fragment 5 with an enantiomeric excess of similar to 85%, a s determined by H-1-NMR spectroscopy.