THE TOTAL SYNTHESIS OF THE ANTITUMOR MACR OLIDE, RHIZOXIN

The first total synthesis of the antitumor macrolide rhizoxin in a hig hly stereocontrolled manner has been achieved. The efficient construct ion of optically pure key building fragments designed based on rationa l retrosynthetic analysis was accomplished in a concise manner. Synthe sis of the Right-Wing started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig live r esterase. The remaining chiral centers of the fragment were construc ted by cyclic hydroboration. Synthesis of the Left-Wing was accomplish ed starting from methyl (S)-3-hydroxy-2-methylpropionate which in turn had been prepared again by enzyme mediated transformation. Coupling o f Right-Wing and Left-Wing was carried out by Julia condensation, and the macrocyclic lactone was constructed by intramolecular Horner-Emmon s reaction. Finally, the stereoselective epoxidation was achieved clea nly after formation of unsaturated 16-membered macrocyclic lactone. Ch romophore-side-chain moiety was constructed at final stage by reaction of the phosphineoxide in 80% yield with high selectivity (E/Z = >20/1 ). The present methodology will be useful for the synthesis of the hom ologues or man-made rhizoxins.