Synthetic Studies Towards the Spirolides

Abstract

Spirolides B and D are toxic metabolites of the marine dinoflagellate Alexandrium ostefeldii, which were isolated from the digestive glands of mussels and scallops collected off the coast of Nova Scotia in 1995. This thesis investigates the use of novel iterative oxidative radical cyclisation methodology to assemble the unprecedented 5,5,6-bis-spiroacetal system found in the spirolides, from a precursor containing the required carbon framework with the 6-membered ring already in place. Early work focussed upon an achiral cyclisation precursor model compound (292) which was synthesised from dihydropyran bromide 244 and achiral aldehyde 288 via a Barbier coupling. Despite some initial difficulties, 244 was eventually prepared in good overall yield from 1,3-propanediol. Subsequent successive oxidative radical cyclisations of precursor 292 then proceeded in excellent yield to afford the desired 5,5,6-bis-spiroacetal 309. Diastereomeric bis-spiroacetals (2R,3R)-314-317 containing the required substitution for the spirolides were prepared from precursors 295 and 296, in turn assembled from the Barbier coupling of dihydropyran 244 and aldehyde (3R,4R)-243. Although bis-spiroacetals (2R,3R)-314-317 were initially synthesised as an equimolar mixture, a thermodynamic mixture of 314,316 and 317 (3:1:0.9) was obtained upon exposure to catalytic amounts of acid. The stereochemistry of these compounds was assigned using a combination of 2D NMR spectroscopy and ab initio computer modeling techniques. Bis-spiroacetal alkenes (2R,3R)-314 and 317 were subsequently elaborated to homoallylic alcohols (2R,3R)-346 and 347 using an epoxidation/base-induced rearrangement strategy, with a view to eventual coupling with allyl stannane compounds for assembly of spirolides B and D.