Abstract:
Portimine A was first isolated in 2013 from the marine benthic dinoflagellate, Vulcanodinium rugosm off the coast of Northland, New Zealand. To date, portimine A has been isolated four times with a worldwide geological distribution: New Zealand (2013), Qatar (2016), USA (2019) and J apan (2019). Initial biological testing of portimine A has exhibited a potent in vitro cytotoxicity against leukemic T cell lymphoblasts (P388, EC50 = 2.7 nM), yet a very low in vivo toxicity. Added to this, portimine A has recently demonstrated promising anti-fouling and anti-viral activity, showcasing a distinctive bioactivity profile in stark contrast to other CI toxins of its class. It is believed that the bioactivity of portimine is caused by caspase activation, inducing cell-apoptotic pathway. Portimine A, along with recently discovered portimine B, contains a unique 5,6-spirocyclic imine functionality appended within a 14-membered macrocycle, and make up a small family of cyclic imine (CI) toxins. Whilst the spiroimine motif is commonly observed in CI toxins, the 5,6-spiroimine system present in the portimine family is the smallest spirocyclic imine functionality found thus far, with a synthetically challenging contiguous tertiary and all carbon quaternary stereocentres. To date, the Fujiwara group has reported the only body of work to access a precursor to the 5,6-spiroimine fragment found in portimine, with the requisite anti stereochemistry at the contiguous tertiary and quaternary stereocentres. With the spiroimine unit of CI toxins established as the putative pharmacophore of this class of marine biotoxins, synthesis of the 5,6-spiroimine fragment represents a synthetic challenge of great interest. This study provides a convergent Diels-Alder approach to access the 5,6-spiroimine fragment found in portimine A and derivatives thereof. During these studies, it was realised that the diastereoselectivity of the Diels-Alder adduct was heavily influenced by the nature of the dienophile. This strategy has allowed the development of a viable pathway for the synthesis of the 5,6-spiroimine fragment found in the portimine family with both the requisite anti and the undesired syn stereochemistry at the contiguous tertiary and quaternary stereocentres. Furthermore, a novel approach towards the direct synthesis of N-vinylamides and acrylamides were discovered.