The unifying theme this proposal is polyether synthesis via epoxide-opening cascades conducted in aqueous environments. The methods constitute a new strategy for the synthesis of polyethers of the "ladder" structural class (similar to brevetoxin and other "Red Tide" toxins) and emulate the epoxide cascade biogenesis proposed by Nakanishi more than two decades ago. The utility of these efficient epoxide-opening cascades is demonstrated in the syntheses of ladder polyether natural products and derivatives of biomedical relevance. The methods are developed with generality in mind and the syntheses are designed for flexibility. Thus, an important component of this proposal is the preparation of specific compounds suitable for testing. The diseases targeted include cystic fibrosis (brevenal and structural variants), and the necessary collaborations for these activities have already been established.
The unifying theme this proposal is polyether synthesis via epoxide-opening cascades conducted in aqueous environments. The methods constitute a new strategy for the synthesis of polyethers of the ladder structural class (similar to brevetoxin and other Red Tide toxins), and will be used to prepare compounds of this type that are of biomedical relevance (including gambierol and gymnocin B) or have therapeutic potential (including brevenal). The diseases targeted include cystic fibrosis.
|Armbrust, Kurt W; Beaver, Matthew G; Jamison, Timothy F (2015) Rhodium-catalyzed endo-selective epoxide-opening cascades: formal synthesis of (-)-brevisin. J Am Chem Soc 137:6941-6|
|Czabaniuk, Lara C; Jamison, Timothy F (2015) Hydroxyl-substituted ladder polyethers via selective tandem epoxidation/cyclization sequence. Org Lett 17:774-7|
|Byers, Jeffery A; Jamison, Timothy F (2013) Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water. Proc Natl Acad Sci U S A 110:16724-9|
|Underwood, Brian S; Tanuwidjaja, Jessica; Ng, Sze-Sze et al. (2013) Total syntheses of the squalene-derived halogenated polyethers ent-dioxepandehydrothyrsiferol and armatol A via bromonium- and Lewis acid-initiated epoxide-opening cascades. Tetrahedron 69:5205-5220|
|Mousseau, James J; Morten, Christopher J; Jamison, Timothy F (2013) A dioxane template for highly selective epoxy alcohol cyclizations. Chemistry 19:10004-16|
|Matsubara, Ryosuke; Gutierrez, Alicia C; Jamison, Timothy F (2011) Nickel-catalyzed Heck-type reactions of benzyl chlorides and simple olefins. J Am Chem Soc 133:19020-3|
|Morten, Christopher J; Byers, Jeffery A; Jamison, Timothy F (2011) Evidence that epoxide-opening cascades promoted by water are stepwise and become faster and more selective after the first cyclization. J Am Chem Soc 133:1902-8|
|Beaver, Matthew G; Jamison, Timothy F (2011) Ni(II) salts and 2-propanol effect catalytic reductive coupling of epoxides and alkynes. Org Lett 13:4140-3|
|Heffron, Timothy P; Simpson, Graham L; Merino, Estibaliz et al. (2010) Ladder polyether synthesis via epoxide-opening cascades directed by a disappearing trimethylsilyl group. J Org Chem 75:2681-701|
|Morten, Christopher J; Byers, Jeffery A; Van Dyke, Aaron R et al. (2009) The development of endo-selective epoxide-opening cascades in water. Chem Soc Rev 38:3175-92|
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