Diplodialides

The telomer 138 is a good building block for the 10-membered skeleton of diplodialide (166) [61]. The terminal double bond in 138 is oxidized with PdCl2/CuCl/02 to the methyl ketone 163 and converted to 164. The phenylthioacetate 165 is prepared and its cyclization gives 9-decanolide (166). 

Based on this method, simple and efficient syntheses of prmtaglandin intomediates, Queen bee substance, zearalenone, dihydtojasmone, jasmone, diplodialide B, lasiodiplodin methyl ether, ... 

Both the Mukaiyama and Bestmann syntheses of the macrocyclic lactone recifeiolide (18), isolated from Cephalosporium recifei, involve sp-carbon alkylation steps (Scheme 36), and Shenvi and Gerlach have synthesi diplodialides A (19) via a route that involved the. rp-carbon alkylation step shown in Scheme 37. 

Simple Monocyclic Macrolides A. Recifeioltide Diplodialides Lasiodiplodin Curvularin Zearalenone Brefeldin A... 

The diplodialides are a family of ten-membered ring macrocyclic lactones isolated from the pathogenic fungus Diplodia pinea. Structural studies by Wada in 1976 had shown these compounds to be quite similar to recifeiolide (1), with an additional oxygen functionality included p to the lactone carbonyl. Diplodialides A, B, C, and D (47-50) are the four most common members of this group. 

Ethyl 5-oxohexanoate (51) was reduced with NaBH4 and the resulting alcohol protected with dihydropyran to give 52. Reduction of the ester moiety to a primary alcohol followed by conversion to the bromide 53 was achieved by conventional means. Alkylation of the dianion of ethyl acetoacetate with 53 afforded a 78% yield the p-keto ester 54, which possesses all the carbons required for the construction of the diplodialides. Protection of the ketone as the dithiane... 

The biosynthetic reduction of the polyketide chain may prevent the formation of aromatic products. Instead, several lactones are formed. For example, a series of bio-active pentaketide metabolites containing a ten-membered ring have been isolated. These include the diplodialides e.g. diplodialide A, 4.73) from Diplodia pinea, the pyrenolides e.g. pyrenolide A, 4.74) from Pyrenophora teres and the cephalosporolides e.g. cephalosporolide B, 4.75) from Cephalosporium aphidi-cola. An unusual dimeric pentaketide, thiobiscephalosporolide A (in which the two lactones are held together by a sulfur), has also been obtained from... 

C. aphidicola. Other metabolites with a ten-membered lactone ring include the decarestrictins (4.76) from PenicUlium species such as P. simplicissimum and putaminoxin (4.77), which is a phytotoxic metabolite of Phoma putamimm. Recifeiolide (4.78) from C. recifei is a hexaketide with a 12-membered ring. Cladospolide A (4.79), also with a 12-membered ring, is a phytotoxic metabolite of Cladosporium fulvum. The decarestrictins affect cholesterol biosynthesis whilst the diplodialides were found to be steroid 11-hydroxylase inhibitors. Biosynthetic experiments with [ C]-labelled acetate established that the decarestrictins were polyketides. 

The foregoing conditions were applied successfully in the synthesis of diplodialide A (175 Scheme 37). Since earlier studies had demonstrated that the sulfide-contraction conditions were not compatible with a,3-unsaturated thioamides, the 3-acetoxy precursor (173) was used instead. The intramolecular sulfide-contraction reaction successfully accomplished the cyclization to generate the P-keto lactone (174) in modest yields. Elimination of the acetoxy group yielded diplodialide A (175). 

The reagent (PPhj + CBr ) used to convert OH to Br is one which takes advantage of the affinity of phosphorus for oxygen. The other product is PhjPO. Reagent (11) has been used in a synthesis of the enzyme inhibitor diplodialide-A. 

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