Total Asymmetric Synthesis of the Putative Structure of the Cytotoxic Diterpenoid (-)-Sclerophytin A and of the Authentic Natural Sclerophytins A and B
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- 作者：Patrick Bernardelli ; Oscar M. Moradei ; Dirk Friedrich ; Jiong Yang ; Fabrice Gallou ; Brian P. Dyck ; Raymond W. Doskotch ; Tim Lange ; and Leo A. Paquette
- 刊名：Journal of the American Chemical Society
- 出版年：2001
- 出版时间：September 19, 2001
- 年：2001
- 卷：123
- 期：37
- 页码：9021 - 9032
- 全文大小：225K
- 年卷期：v.123,no.37(September 19, 2001)
- ISSN：1520-5126
文摘
An enantioselective synthetic route to the thermodynamically most stable diastereomer of the structureassigned to sclerophytin A (5) has been realized. The required tricyclic ketone 33 was prepared by sequentialTebbe-Claisen rearrangement of lactones 29 and 30, which originated from the Diels-Alder cycloaddition ofDanishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furanone (14). An allyl and a cyano group were introducedinto the resulting adduct by means of stereocontrolled allylindation under aqueous Barbier-like conditions andby way of cyanotrimethylsilane, respectively. Following stereocontrolled nucleophilic addition of a methylgroup to 33, ring A was elaborated by formation of the silyl enol ether, ytterbium triflate-catalyzed condensationwith formaldehyde, O-silylation, and Cu(I)-promoted 1,4-addition of isopropylmagnesium chloride. Thesuperfluous ketone carbonyl was subsequently removed and the second ether bridge introduced by means ofoxymercuration chemistry. Only then was the exocyclic methylene group unmasked via elimination. Analternative approach to the 
-carbinol diastereomer proceeds by initial -oxygenation of 37 and ensuing 1,2-carbonyl transposition. Neither this series of steps nor the Wittig olefination to follow induced epimerizationat 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 O2 in the presenceof 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 
-direction to deliver (-)-60. Comparisonof the high-field 1H and 13C NMR properties and polarity of synthetic 5 with natural material required thatstructural revision be made. Following a complete spectral reassessment of the structural assignments to manysclerophytin diterpenes, a general approach to sclerophytin A, three diastereomers thereof, and of sclerophytinB was devised. The presence of two oxygen bridges as originally formulated was thereby ruled out, and absoluteconfigurations 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 exocyclicmethylene group at C-11, and stereocontrolled 1,2-reduction of the -hydroxy ketone functionality madeavailable earlier.
-carbinol diastereomer proceeds by initial -oxygenation of 37 and ensuing 1,2-carbonyl transposition. Neither this series of steps nor the Wittig olefination to follow induced epimerizationat 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 O2 in the presenceof 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 -direction to deliver (-)-60. Comparisonof the high-field 1H and 13C NMR properties and polarity of synthetic 5 with natural material required thatstructural revision be made. Following a complete spectral reassessment of the structural assignments to manysclerophytin diterpenes, a general approach to sclerophytin A, three diastereomers thereof, and of sclerophytinB was devised. The presence of two oxygen bridges as originally formulated was thereby ruled out, and absoluteconfigurations 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 exocyclicmethylene group at C-11, and stereocontrolled 1,2-reduction of the -hydroxy ketone functionality madeavailable earlier.