Synthetic Studies Towards The Marine Toxin Portimine

Abstract

This thesis describes synthetic endeavours towards portimine (1), a polycyclic marine toxin recently isolated from the dinoflagellate Vulcanodinium rugosum collected off the coast of Northland, New Zealand. Portimine (1) contains an unprecedented bridged spiroketal ring system and spirocyclic imine functionality. Whilst the spiroimine motif is commonly observed in a number of algae-derived toxins the 5,6-ring system is unique to portimine. Initial biological testing has indicated that it exhibits potent inhibition of leukaemia cells in vitro (P388 cells, EC50 = 2.7 nM) despite demonstrating low in vivo toxicity, in stark contrast to other related natural products. A convergent and flexible synthetic strategy for the preparation of portimine (1) was proposed, in which the molecular framework of 1 may be constructed by union of either polyketide fragment 238 or 239 with glyoxal 468 by C5–C6 aldol coupling. Subsequent Nozaki-Hiyama- Kishi mediated macrocyclisation to forge the C14–C15 bond would prepare the tricyclic core 481 or 482. Finally, spiroketalisation and stereoselective oxidation—to furnish the unusual α,α'-dihydroxyketone moiety—would complete the synthesis of portimine. It was unknown how the olefin geometry of 481 or 482 would affect stereochemistry of the α,α-dihydroxyketone after oxidation so both vinyl halide isomers 238 and 239 were prepared for investigation. Considerable synthetic effort was devoted to the development of a scalable, robust preparation of a series of viable polyketide coupling fragments such as 238 and 239 from common aldehyde 204, for application in the total synthesis. In turn, aldehyde 204 was prepared using a modified, stereocontrolled Leighton crotylation as the key step, allowing for efficient, enantioselective access to this key building block. With the successful preparation of polyketide coupling fragments 238 and 239 established, attention then focused on examination of the proposed fragment coupling strategies. Notably, the unprecedented coupling of silyl enol ether 359 and model glyoxal electrophile 310 was shown to be a viable disconnection for the C5–C6 coupling of the polyketide and spirocyclic fragments of portimine. Preliminary model studies for the proposed C14–C15 Nozaki-Hiyama- Kishi macrocyclisation step resulted in the development of optimised conditions for the chromium(II)-mediated reaction of bromides 237, 238 and 239 with aldehyde 381. Together with the successful preparation of polyketide fragments 238 and 239, the model fragment coupling strategies developed herein provide a strong basis from which a convergent total synthesis of portimine (1) may now be framed. Furthermore, these efforts may allow synthetic access to structural analogues of portimine (1) in order to probe its biological mode of action.