Concise asymmetric syntheses of radicicol and monocillin I.
Radicicol (1) exhibits potent anticancer properties in vitro, which are likely to be mediated through its high affinity (20 nM) for the molecular chaperone Hsp90. Recently, we reported the results of a synthetic program targeting radicicol (1) and monocillin I (2), highlighted by the application of ring-closing metathesis to macrolide formation. These efforts resulted in a highly convergent synthesis of radicicol dimethyl ether but failed in the removal of the two aryl methyl ethers. Simple exchange of these methyl ethers with more labile functionalities disabled a key esterification in the initial route. Through extended experimentation, a successful route to both natural products was secured, along with some intriguing results that emphasize the implications of this design on a broad range of fused benzoaliphatic targets, including analogues of these natural products.
Garbaccio
R M
RM
The Laboratory for Bioorganic Chemistry, The Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA.
Stachel
S J
SJ
Baeschlin
D K
DK
Danishefsky
S J
SJ
D000935:Antifungal Agents / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis*; D018942:Macrolides; D013237:Stereoisomerism
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D007783:Lactones; D018942:Macrolides; C444505:monocillin I; C035359:monorden