title: Synthesis of antifungal glucan synthase inhibitors from enfumafungin.
abstract: An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.
authors.affiliation: Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. yongli_zhong@merck.com
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Zhong
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gauthier
authors.forename: Yao-Jun
authors.initials: YJ
authors.lastname: Shi
authors.forename: Mark
authors.initials: M
authors.lastname: McLaughlin
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chung
authors.forename: Philippe
authors.initials: P
authors.lastname: Dagneau
authors.forename: Benjamin
authors.initials: B
authors.lastname: Marcune
authors.forename: Shane W
authors.initials: SW
authors.lastname: Krska
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reamer
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Yasuda
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D002911:Chrysenes / Q000138:chemical synthesis* / Q000737:chemistry*; D054714:Echinocandins / Q000737:chemistry*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006027:Glycosides / Q000737:chemistry*; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism; D014315:Triterpenes / Q000737:chemistry*
chemical_list: D000438:Alcohols; D000935:Antifungal Agents; D002911:Chrysenes; D054714:Echinocandins; D006027:Glycosides; D014315:Triterpenes; C421868:enfumafungin; D010165:Palladium; D005964:Glucosyltransferases; C040232:glucan synthase