Triple Diels-Alder Cascades: Development and Application to Daphnezomine Synthesis

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We have recently shown that 1,2,4-triazines and ketones can be employed in a tandem cascade sequence producing complex polycyclic diamines. This remarkable transformation proceeds via initial enamine formation and then a triple Diels-Alder cascade (inverse electron demand, retro and intramolecular) transforming flat starting materials into complex polycyclic products with the formation of 2 new rings. 4 new bonds and 5 new stereogenic centres! Based on these encouraging preliminary results, we now seek funds to appoint a postdoctoral researcher who will optimise, extend and apply this new technology as follows:(i) To optimise the triple Diels-Alder cascade sequence and fully establish its scope,(ii) To investigate the use of alternative aza-dienes and dienophiles in these triple Diels-Alder sequences leading to a range of novel polycyclic amines,(iii) To develop enantioselective variants of the above processes using enantiopure Lewis acids, enantiopure enamines or chiral auxiliaries,(iv) To apply the triple Diels-Alder methodology to prepare the anti-cancer natural products, the Daphnezomines, along with novel aza-analogues for biological screening..