title: Exploiting the facile release of trifluoroacetate for the α-methylenation of the sterically hindered carbonyl groups on (+)-sclareolide and (-)-eburnamonine.
abstract: An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of (19)F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC(50) = 14.12 μM) in drug-resistant MDA-MB-231 breast cancer cells.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Riofski
authors.forename: Jinu P
authors.initials: JP
authors.lastname: John
authors.forename: Mary M
authors.initials: MM
authors.lastname: Zheng
authors.forename: Julia
authors.initials: J
authors.lastname: Kirshner
authors.forename: David A
authors.initials: DA
authors.lastname: Colby
mesh_terms: D045744:Cell Line, Tumor; D004224:Diterpenes / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry*; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D014269:Trifluoroacetic Acid / Q000737:chemistry*; D014748:Vinca Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004224:Diterpenes; D007659:Ketones; D014748:Vinca Alkaloids; C030011:carbene; C109395:sclareolide; D014269:Trifluoroacetic Acid; C016422:eburnamonine; D008697:Methane