The unifying theme this proposal is polyether synthesis via epoxide-opening cascades. 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 and Nicolaou. 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 development of new methods of synthesis and the study of the reaction mechanisms involved in these processes are critical for the achievement of these goals and thus are under intense investigation.
The unifying theme this proposal is polyether synthesis via epoxide-opening cascades. The methods constitute a new strategy for the synthesis of polyethers of the ladder structural class and emulate the biogenesis proposed by Nakanishi and Nicolaou. The utility of these efficient epoxide-opening cascades is demonstrated in the syntheses of several ladder polyether natural products and derivatives, whose biomedical and therapeutic applications will be investigated by several collaborators.
|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|
|Mousseau, James J; Morten, Christopher J; Jamison, Timothy F (2013) A dioxane template for highly selective epoxy alcohol cyclizations. Chemistry 19:10004-16|
|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|
|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|
|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|
|Morten, Christopher J; Jamison, Timothy F (2009) New synthetic strategies for the stereocontrolled synthesis of substituted "skipped" diepoxides. Tetrahedron 65:6648-6655|
|Sparling, Brian A; Simpson, Graham L; Jamison, Timothy F (2009) Strategic use of nickel(0)-catalyzed enyne-epoxide reductive coupling towards the synthesis of (-)-cyatha-3,12-diene. Tetrahedron 65:3270-3280|
|Van Dyke, Aaron R; Jamison, Timothy F (2009) Functionalized templates for the convergent assembly of polyethers: synthesis of the HIJK rings of gymnocin A. Angew Chem Int Ed Engl 48:4430-2|
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