Palladium-mediated tandem carbon-carbon bond forming methodology and approaches to the synthesis of magellanane alkaloids

Methodology has been developed for the consecutive formation of two carbon-carbon bonds by the palladium-mediated alkylation of carbon nucleophiles with {dollar}pi{dollar}-allylpalladium complexes produced as intermediates in the Heck reaction. This three component condensation of a vinyl halide, an olefin, and a carbon nucleophile can be performed both inter- and intramolecularly. Completely intermolecular examples react regioselectivity to produce compounds which result from the addition of the vinyl halide to the less substituted carbon of the acceptor olefin, with the major product arising from attack of the malonate nucleophile at the less substituted terminus of the intermediate {dollar}pi{dollar}-allylpalladium complex. Bifunctional vinyl halide olefin compounds undergo the palladium-catalyzed reaction with dimethyl malonate to afford functionalized carbocyclic products. The completely intramolecular variation of this reaction results in fused and bridged carbobicyclic products. Linear compounds which contain a vinyl halide, internal olefin, and nucleophilic moiety did not undergo the bis-cyclization to afford spirobicyclic products.; Attempts were made to apply this methodology to the synthesis of members of the magellanane group of Lycopodium alkaloids. However, none of the model systems examined cyclized to the desired hydrindenone compounds. Instead, bicyclic alkylidenetetrahydrofurans were formed by the O-alkylation of the {dollar}beta{dollar}-keto ester or sulfone enolate with the intermediate {dollar}pi{dollar}-allylpalladium complex. Another attempt to form the skeleton of these alkaloids involved a conjugate addition of {dollar}beta{dollar}-picoline to a bicyclic enone. The cuprate reagent derived from {dollar}beta{dollar}-picoline did not add to the bicyclic enone, derivatives of {dollar}beta{dollar}-picoline could not be deprotonated at the methyl group, and a cuprate reagent could not be prepared from picolyl bromide.