Water is an effective promoter of the endo-selective opening of trisubstituted epoxides, enabling related cascades leading to a variety of substituted ladder polyether structures. When used in conjunction with a tetrahydropyran-templated nucleophile, water can overcome the powerful electronic directing effect of a methyl substituent at either site of the epoxide, making water a uniquely versatile medium and promoter for epoxide opening.In 1985 Nakanishi advanced a concise and appealing proposal for the biosynthesis of the ladder polyether family of natural products, a synthesis that culminates in a cascade of regio-and stereoselective epoxide openings (Scheme 1). 1 Our group recently reported an emulation of the Nakanishi hypothesis, wherein water serves as the superior promoter of endo-selective epoxide-opening cascades. 2 This earlier account was limited to cascades of trans-disubstituted epoxides, and we herein report that water (as solvent) is also a simple and general solution for cascades involving trisubstituted epoxides. Overcome by this method is the well documented, strong directing effect that methyl (Me) groups have on epoxide ring-opening reactions, 3 and thus enabled is the rapid assembly of multiple patterns of substituted ladder polyether subunits. An angular Me group is the only substituent other than hydrogen (H) observed at ladder polyether ring junctions, and every structure in this large family of natural products possesses at least one Me group. Nature has conceived two variations of this substitution, requiring two chemically quite different kinds of (E)-trisubstituted epoxides in the corresponding polyepoxide precursors. For example, in the hypothesized precursor (1) to brevetoxin B (Scheme 1), Me groups are observed both and 4 to the internal nucleophile; the putative cascade must tolerate both possibilities. In fact, nearly all ladders bearing more than one Me group, including the brevetoxins, maitotoxin, gambierol, and gymnocin B, are proposed to arise from similar polyepoxides bearing an "out-of-register" mixture of both distally and proximally substituted epoxides.The crux of the problem is that the Me group is generally a strong director of epoxide-opening regioselectivity, particularly under acid catalysis. Valuable methods for endo-selective opening, epitomized by those developed by the McDonald group,3a-c take advantage of this directing effect, 3 but these necessarily accommodate only Me substitution. Moreover, distal Me substitution at every epoxide is generally vital for high regioselectivity and yield. 5 The endo-selective opening of epoxides with a Me or other simple alkyl group 6 to the pendent nucleophile has not been documented except under enzyme catalysis7 or when a stronger directing group at the distal site of the epoxide was used. 8 We conjectured that tetrahydropyran (THP)-templated, water-promoted cascades might prove relatively insensitive to the electronic effects and afford a general solution to the problem of Me substitution, particularly for the challe...

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A detailed kinetic study of the endo-selective epoxide-opening cascade reaction of a diepoxy alcohol in neutral water was undertaken using 1H NMR spectroscopy. The observation of monoepoxide intermediates resulting from initial endo and exo cyclization indicated that the cascade proceeds via a stepwise mechanism rather than through a concerted one. Independent synthesis and cyclization of these monoepoxide intermediates demonstrated that they are chemically and kinetically competent intermediates in the cascade. Analysis of each step of the reaction revealed that both the rate and regioselectivity of cyclization improve as the cascade reaction proceeds. In the second step, cyclization of an epoxy alcohol substrate templated by a fused diad of two tetrahydropyran rings, proceeds with exceptionally high regioselectivity (endo:exo = 19:1), the highest we have measured in the opening of a simple trans-disubstituted epoxide. The origins of these observations are discussed.

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.

When the US Food and Drug Administration (FDA) approves a new drug, federal law requires public disclosure of the review documents prepared by scientific disciplines (eg, clinical, toxicology, statistical) during the review. 1 These scientific reviews are published on the FDA Drugs@FDA website (https://www.accessdata.fda. gov/scripts/cder/daf/index.cfm). In many cases, the data and analyses contained in those reviews have proved useful to public health. A well-known example involves the Celecoxib Long-term Arthritis Safety Study (CLASS), which was published in 2000. 2 The article reported that after long-term follow-up (6 months), treatment with celecoxib (Celebrex) "was associated with a lower incidence of symptomatic ulcers and ulcer complications combined" 2(p1247) compared with ibuprofen and diclofenac, thus offering support for the claim that celecoxib was a safer alternative to other nonsteroidal antiinflammatory agents. The CLASS trial was funded by celecoxib's manufacturer and authored by its employees and academic researchers who were also consultants to the manufacturer. 2 However, independent researchers used the FDA's publicly available scientific reviews to question the safety claim for celocoxib. 3 They found that: the published CLASS trial differs from the original protocol in primary outcomes, statistical analysis, trial duration, and conclusions. In particular, the unpublished data [in an FDA scientific review] show that by week 65, celecoxib was associated with a similar number of ulcer complications as diclofenac and ibuprofen. 3(p2398)