Total Synthesis of (+)-Geldanamycin and (−)-<i>o</i>-Quinogeldanamycin with Use of Asymmetric <i>Anti- </i>and <i>Syn</i>-Glycolate Aldol Reactions

Abstract

Geldanamycin (GA), an antitumor Hsp90 inhibitor, was made for the first time by using an oxidative demethylation reaction as the final step. A biaryldioxanone auxiliary set the anti C11-12 hydroxy-methoxy functionality and a methylglycolate auxiliary based on norephedrine was used for the syn C6-7 methoxy-urethane. p-Quinone-forming oxidants, CAN and AgO, produced an unusual aza-quinone product. Nitric acid gave GA from a trimethoxy precursor in 55% yield as a 1:10 mixture with nonnatural o-quino-GA. [structure: see text]