title: Synthesis of (±)-spongiolactone enabling discovery of a more potent derivative.
abstract: An eleven-step synthesis of (±)-spongiolactone from 1,3-cyclohexanedione is reported that relies on a diastereoselective, nucleophile-catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β-lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure-activity studies that revealed a regio- and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.
authors.affiliation: Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, TX 77842 (USA) http://www.chem.tamu.edu/rgroup/romo/index.html.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Harvey
authors.forename: Joanna
authors.initials: J
authors.lastname: Krysiak
authors.forename: Supakarn
authors.initials: S
authors.lastname: Chamni
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Cho
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
authors.forename: Daniel
authors.initials: D
authors.lastname: Romo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones
keywords: allyl zinc reagent; beta-lactone; cytotoxicity; spongiane diterpenoid; total synthesis