Total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide via target oriented beta-C-glycoside formation.
The total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide via target oriented beta-C-glycoside formation is described. The two key reactions involved a stereoselective reduction of the appropriate oxocarbenium cation and a highly chemo- and diastereoselective ring-closing metathesis protocol for the formation of the macrocyclic core. In addition to the described chemistry, in vitro screening of the antipode of natural dactylolide against the NCI's 60 cancer cell line helped to illuminate the critical importance of the N-acyl hemiaminal side chain of natural zampanolide for its reported potent nanomolar cytotoxicities. Furthermore, by means of the in vitro screen of (-)-dactylolide, a promising cancer therapeutic lead has now emerged for a variety of carcinomas. More specifically, (-)-dactylolide exhibited GI50 values in the nanomolar (25-99 ng/mL) range against the four cell lines HL-60, K-562, HCC-2998, and SF-539, while displaying modest LC50 values.
Ding
Fei
F
Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, USA.
Jennings
Michael P
MP
D000475:Alkenes / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry; D006027:Glycosides / Q000737:chemistry*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry
D000475:Alkenes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003432:Cross-Linking Reagents; D006027:Glycosides; D007783:Lactones; D018942:Macrolides; C451487:dactylolide; C444900:zampanolide; C030011:carbene; D010165:Palladium; D008697:Methane