A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

Abstract

Ladder polyether natural products are a class of natural products denoted by their high functional group density and large number of well-defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogues with interesting biological activity. 1,3-Dioxan-5-ol substrates display remarkable ‘enhanced template effects’ in water-promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases they provide near complete endo to exo selectivity in the cyclization of epoxy alcohols, thereby strongly favouring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP-based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template.

Total Synthesis of the Marine Ladder Polyether Gymnocin B

“…However, whereas the polyTHP product shown in Scheme 1C features a non-functionalized THP template, 13 required a scaffold bearing functional group handles. Based on our experience with a 1,3-dioxane template, 16 the dimethyl acetonide was chosen due to its similar conformational and electronic properties and ease of removal for further elaboration.…”

Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

“…4 Additionally, Murai has demonstrated that a methoxymethyl group can direct endo -cyclization through Lewis acid chelation. 5 Templating 6 allows for highly-selective THP formation without the need for directing groups, and we have reported the use of a preformed THP 7 or 1,3 dioxane 8 in water-promoted cyclizations. This approach has enabled the synthesis of THPs bearing methyl substituents at the ring junctions 9 as well as marine ladder polyether fragments via polyepoxide cascades.…”

“…Initial studies investigated the monocyclization of bicycle 9 , which was synthesized from known 1,3-diol 2 8 in 11 steps (Scheme 1). We hypothesized that the introduction of an electron-withdrawing hydroxyl group would favor endo -cyclization, as it would destabilize partial positive charge buildup at the exo -site during cyclization.…”

“…Lewis acidic conditions promote epoxy alcohol cyclizations, but these reactions typically form mixtures of THFs and THPs. 8 The presence of the neighboring hydroxyl group is proposed to enable epoxide activation and concomitant chelation to direct endo -selectivity. Sharpless has demonstrated that the addition of a chelating Lewis acid increases regioselectivity for epoxide opening distal to the alcohol in both inter- 17 and intramolecular 18 cases.…”

“…This ratio is consistent with previous findings for templated epoxy-alcohol cyclizations under Lewis acidic conditions. 8 However, because templated water-promoted cyclizations are known to proceed with excellent endo -selectvity, we decided to decouple the two cyclizations to capitalize on the individual needs of each cyclization event. Thus, the epoxidation/cyclization methodology was performed at a shorter reaction time to form tricycle 17 (Scheme 5b).…”