Towards chemical libraries of annonaceous acetogenins

Many of the Annonaceous acetogenins, particularly those containing a bisTHF moiety, exhibit outstanding cytotoxicity and pesticidal activity. Their remarkable structural diversity suggests that a complete chemical library of these compounds should be prepared and systematically screened. We show here several approaches to meet this synthetic challenge using the naked carbon skeleton strategy as well as a convergent synthesis. The key transformations include the Sharpless asymmetric dihydroxylation reaction, the Mitsunobu inversion of alcohols and ligand-assisted chirality transfer methods based on rhenium and vanadium oxides. These approaches provide an easy access to naturally occurring acetogenins (e.g. asimicin, bullatacin, trilobacin, rolliniastatin and solamin) as well as the non-natural isomers. Jntroduction To date, more than 230 different acetogenins have been isolated from 26 plants of the Annonaceae.[l] Many of these Annonaceous acetogenins have exhibited remarkable cytotoxic, antitumor, antimalarial, immunosuppressive, pesticidal and antifeedant activities.[2] For example, studies with human solid-tumor cell-lines show that some of the bis-THF derivatives, such as compounds 1-4 (Scheme 1), are many orders of magnitude more cytotoxic than adriamycin.[s] Interestingly, these fatty acid derivatives share very similar carbon skeletons, with their striking diversity originating mainly from the relative and absolute configuration of their various stereogenic oxygen functions. '