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

• Published in: Organic letters Vol. 4; no. 20; pp. 3549 - 3552
• Main Authors: Andrus, Merritt B, Meredith, Erik L, Simmons, Bryon L, Soma Sekhar, B. B. V, Hicken, Erik J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03-10-2002
• Subjects: Antibiotics, Antineoplastic - chemical synthesis; Antibiotics, Antineoplastic - chemistry; Benzoquinones; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Lactams, Macrocyclic; Molecular Structure; Quinones - chemical synthesis; Quinones - chemistry
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol0267432

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.