title: Total asymmetric synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin a and of the authentic natural sclerophytins A and B.
abstract: An enantioselective synthetic route to the thermodynamically most stable diastereomer of the structure assigned to sclerophytin A (5) has been realized. The required tricyclic ketone 33 was prepared by sequential Tebbe-Claisen rearrangement of lactones 29 and 30, which originated from the Diels-Alder cycloaddition of Danishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furanone (14). An allyl and a cyano group were introduced into the resulting adduct by means of stereocontrolled allylindation under aqueous Barbier-like conditions and by way of cyanotrimethylsilane, respectively. Following stereocontrolled nucleophilic addition of a methyl group to 33, ring A was elaborated by formation of the silyl enol ether, ytterbium triflate-catalyzed condensation with formaldehyde, O-silylation, and Cu(I)-promoted 1,4-addition of isopropylmagnesium chloride. The superfluous ketone carbonyl was subsequently removed and the second ether bridge introduced by means of oxymercuration chemistry. Only then was the exocyclic methylene group unmasked via elimination. An alternative approach to the alpha-carbinol diastereomer proceeds by initial alpha-oxygenation of 37 and ensuing 1,2-carbonyl transposition. Neither this series of steps nor the Wittig olefination to follow induced epimerization at C10. Through deployment of oxymercuration chemistry, it was again possible to elaborate the dual oxygen-bridge network of the target ring system. Oxidation of the organomercurial products with O(2) in the presence of sodium borohydride furnished 72, which was readily separated from its isomer 73 after oxidation to 61. Hydride attack on this ketone proceeded with high selectivity from the beta-direction to deliver (-)-60. Comparison of the high-field (1)H and (13)C NMR properties and polarity of synthetic 5 with natural material required that structural revision be made. Following a complete spectral reassessment of the structural assignments to many sclerophytin diterpenes, a general approach to sclerophytin A, three diastereomers thereof, and of sclerophytin B was devised. The presence of two oxygen bridges as originally formulated was thereby ruled out, and absolute configurations were properly determined. Key elements of the strategy include dihydroxylation of a medium-ring double bond, oxidation of the secondary hydroxyl in the two resulting diols, unmasking of an exocyclic methylene group at C-11, and stereocontrolled 1,2-reduction of the alpha-hydroxy ketone functionality made available earlier.
authors.affiliation: Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bernardelli
authors.forename: O M
authors.initials: OM
authors.lastname: Moradei
authors.forename: D
authors.initials: D
authors.lastname: Friedrich
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: F
authors.initials: F
authors.lastname: Gallou
authors.forename: B P
authors.initials: BP
authors.lastname: Dyck
authors.forename: R W
authors.initials: RW
authors.lastname: Doskotch
authors.forename: T
authors.initials: T
authors.lastname: Lange
authors.forename: L A
authors.initials: LA
authors.lastname: Paquette
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000633:toxicity; D005663:Furans / Q000138:chemical synthesis* / Q000633:toxicity; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D005663:Furans; C412667:sclerophytin A; C412668:sclerophytin B