Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin: asymmetric glycolate aldol reactions and biological evaluation

J Org Chem. 2003 Oct 17;68(21):8162-9. doi: 10.1021/jo034870l.

Abstract

The total synthesis of (+)-geldanamycin (GA), following a linear route, has been completed using a demethylative quinone-forming reaction as the last step. Key steps include the use of two new asymmetric boron glycolate aldol reactions. To set the anti-C11,12 hydroxymethoxy functionality, (S,S)-5,6-bis-4-methoxyphenyldioxanone 8 was used. Methylglycolate derived from norephedrine 5 set the C6,7 methoxyurethane stereochemistry. The quinone formation step using nitric acid gave the non-natural o-quino-GA product 55 10:1 over geldanamycin. Other known oxidants gave an unusual azaquinone product 49. o-Quino-GA 55 binds Hsp90 with good affinity but is less cytotoxic compared to GA.

Publication types

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

MeSH terms

  • Aldehydes / chemistry*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzoquinones
  • Cell Survival / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Lactams, Macrocyclic
  • Molecular Structure
  • Quinones / chemical synthesis*
  • Quinones / chemistry
  • Quinones / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Aldehydes
  • Antineoplastic Agents
  • Benzoquinones
  • Lactams, Macrocyclic
  • Quinones
  • quinogeldanamycin
  • 3-hydroxybutanal
  • geldanamycin