Chaetomellic acid A anhydride

The second example of synthesis of chaetomellic acids includes the use of a cobaloxime-mediated synthesis reported by Branchaud and Slate [75,76] from the University of Oregon. This synthesis (Scheme 3) made use of photochemical doubly chemoselective cross coupling reactions of myristyl cobaloxime with citraconic anhydride and diphenyldisulfide to give a 64% yield of chaetomellic acid A anhydride in three steps from myristyl bromide. 

Takimoto M, Kawamura M, Mori M, Sato Y (2005) Nickel-catalyzed regio-and stereoselective double carboxylation of trimethylsilylallene under an atmosphere of carbon dioxide and its application to the synthesis of chaetomellic acid A anhydride. Synlett 2005 2019-2022... 

Figure 5 (a) Chaetomellic acid A is a novel dicarboxylate-containing natural product that is thought to mimic farnesyl pyrophosphate and thus to inhibit the enzyme FTPase. This compound can exist in either the dicarboxylate or anhydride form, (b) As peptides that contain aromatic oxamic acids are good inhibitors of tyrosine kinase p56 SH2 domains, it is believed that the oxamic acid moiety may mimic the phosphate group, (c) A symmetric 3,5-disubstituted benzoate analog of S3P (substrate) and EPSP (product) inhibits EPSPS. 

Kates and Schauble from Villanova University reported [77] in 1996 the third synthesis of anhydrides of chaetomellic acids A and B. This five-... 

The last and the seventh synthesis of chaetomellic acid A was reported in 1997 by the Samadi group from CNRS, France [81]. This one step synthesis involves a Barton radical decarboxylation and gave 77% overall yield (Scheme 8). The method requires preparation of a thiohydroxamic ester of the corresponding alkyl acid followed by in-situ irradiation in the presence of citraconic anhydride and silica gel chromatography. The last intermediate in this synthesis is similar to the synthesis reported by Branchaud and Slate [75,76]. 

While chaetomellic acids were isolated in the anhydride form [71] the integrity of the anhydride form in the aqueous assay environment was questionable. This raised questions as to which form, the diacid or the anhydride, was the species that inhibited FPTase enzyme activity. This uncertainty was resolved by demonstrating that the equilibrium between the diacid and the anhydride forms was pH dependent (Figure 12). The UV spectrum of the anhydride in CH3CN exhibited a maximum for a cyclic anhydride at 254 nm. When the anhydride was treated either with O.IN NaOH or HEPES buffer (pH = 7.5) the maximum shifted to X.max 243 nm with a concurrent hypochromic shift. As expected, the process could be reversed by addition of mineral acid indicating that the active species are the open dicarboxylates [71]. 

The rearrangement of a trichloropyrrolidin-2-one, prepared by the CuCl-TMEDA-catalysed atom transfer radical cyclization of A-alkyl-AM3-chloroprop-2-enyl)-2,2-dichloromyristamide, with m-propyl amine or CfbONa-CHsOH, is the key step in a route to chaetomellic anhydride C and ( yerythro -roccellic acid.169... 

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