Macrolactamization versus macrolactonization: total synthesis of FK228, the depsipeptide histone deacetylase inhibitor.
The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.
Wen
Shijun
S
School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
Packham
Graham
G
Ganesan
A
A
D000438:Alcohols / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D002625:Chemistry, Organic / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007783:Lactones / Q000737:chemistry*; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry
D000438:Alcohols; D000903:Antibiotics, Antineoplastic; D002264:Carboxylic Acids; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007783:Lactones; D010455:Peptides; C087123:romidepsin