Total asymmetric synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin A and of the authentic natural sclerophytins A andB

An enantioselective synthetic route to the thermodynamically most stable di astereomer of the structure assigned to sclerophytin A (5) has been realize d. The required tricyclic ketone 33 was prepared by sequential Tebbe-Claise n rearrangement of lactones 29 and 30, which originated from the Diels-Alde r cycloaddition of Danishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furan one (14). An allyl and a cyano, group were introduced into the resulting ad duct by means of stereocontrolled allylindation under aqueous Barbier-like conditions and by way of cyanotrimethylsilane, respectively. Following ster eocontrolled nucleophilic addition of a methyl group to 33, ring A was elab orated by formation of the silyl enol ether, ytterbium triflate-catalyzed c ondensation with formaldehyde, O-silylation, and Cu(I)-promoted 1,4-additio n of isopropylmagnesium chloride. The superfluous ketone carbonyl was subse quently removed and the second ether bridge introduced by means of oxymercu ration chemistry. Only then was the exocyclic methylene group unmasked via elimination. An alternative approach to the alpha -carbinol diastereomer pr oceeds by initial alpha -oxygenation of 37 and ensuing 1,2-carbonyl transpo sition. Neither this series of steps nor the Wittig olefination to follow i nduced 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 separate d from its isomer 73 after oxidation to 61. Hydride attack on this ketone p roceeded with high selectivity from the beta -direction to deliver (-)-60. Comparison of the high-field H-1 and C-13 NMR properties and polarity of sy nthetic 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 abso lute configurations were properly determined. Key elements of the strategy include dihydroxylation of a medium-ring double bond, oxidation of the seco ndary hydroxyl in the two resulting diols, unmasking of an exocyclic methyl ene group at C-11, and stereocontrolled 1,2-reduction of the alpha -hydroxy ketone functionality made available earlier.