Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin with use of asymmetric anti- and syn-glycolate aldol reactions

Org Lett. 2002 Oct 3;4(20):3549-52. doi: 10.1021/ol0267432.

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]

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibiotics, Antineoplastic / chemical synthesis*
  • Antibiotics, Antineoplastic / chemistry
  • Benzoquinones
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Lactams, Macrocyclic
  • Molecular Structure
  • Quinones / chemical synthesis*
  • Quinones / chemistry

Substances

  • Antibiotics, Antineoplastic
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Quinones
  • quinogeldanamycin
  • geldanamycin