Research in the Jamison Group

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Epoxide-Opening Cascades

   The discovery and development of epoxide-opening cascades in the Jamison group is directly tied to our interest in the ladder polyether family of natural products, which has attracted a great deal of interest in the synthetic organic chemistry community. In 1984, Nakanishi proposed that these natural products arise from a single epoxide-opening cascade which must proceed in an all-endo fashion to produce the repeating fused cyclic ethers containing a continuous C–C–O connectivity and a trans-syn-trans ring junction geometry.

   A drawback of this biosynthetic hypothesis is that when treated with either acid or base, simple disubstituted epoxy alcohols cyclize to favor the undesired exo products. A breakthrough occurred when our group discovered that if a tetrahydropyran (THP) ring template was formed prior to the epoxide cyclization, the desired endo product was obtained in a 10:1 endo/exo ratio simply by heating the substrate in neutral water. This effect could be carried directly into multi-epoxide cascades – the first time that an endo-selective nucleophilic cascade of unbiased epoxides had ever been observed.

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   The influence of the THP template on regioselectivity was examined further in a series of mechanistic studies. Other templates, such as a cyclohexane or oxepane were unsuccessful in overcoming the inherent exo preference of epoxide opening. The combination of both the water and the THP template was necessary to produce endo product. We believe water to play critical roles both in charge stabilization and in exerting conformational changes to the template, e.g. stabilization of a twist boat conformer.
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   Detailed kinetic studies demonstrated that these epoxide-opening cascades are stepwise and proceed from the template alcohol through each epoxide (i.e., nucleophilic cascade). Additionally, each epoxide-opening event becomes faster and more selective as each fused THP is formed. With this understanding of the nature and capabilities of THP-templated epoxy alcohol cyclizations, efforts to apply epoxide-opening cascades to the total synthesis of ladder polyether natural products are ongoing.

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Representative Publications:
  • Byers, J. A.; Jamison, T. F. “Entropic Factors Provide Unusual Reactivity and Selectivity in Water-Promoted Epoxide-Opening Reactions,”Proc. Natl. Acad. Sci. 2013, 110, 16724. Download PDF
  • Mousseau, J. J.; Morten, C. J.; Jamison, T. F. “A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations,” Chem. Eur. J. 2013, 19, 10004-10016. Download PDF
  • Underwood, B. S.; Tanuwidjaja, J.; Jamison, T. F. “Total Syntheses of the Squalene-Derived Halogenated Polyethers ent-Dioxepandehydrothyrsiferol and Armatol A via Bromonium- and Lewis Acid-Initiated Epoxide-Opening Cascades,” Tetrahedron 2013, 69, 5205-5220. Download PDF
  • Morten, C. J.; Byers, J. A.; Jamison, T. F. “Evidence that Epoxide-Opening Cascades Promoted by Water are Stepwise and Become Faster and More Selective After the First Cyclization” J. Am. Chem. Soc. 2011, 133, 1902-1908. Download PDF
  • Morten, C. J.; Byers, J.A.; Van Dyke, A.R.; Vilotijevic, I.; Jamison, T. F. "The Development of Endo-Selective Epoxide-Opening Cascades in Water" Chem. Soc. Rev. 2009, 38, 3175-3192. Download PDF
  • Morten, C. J.; Jamison, T. F. "Water Overcomes Methyl Group Directing Effects in Epoxide-Opening Cascades" J. Am. Chem. Soc. 2009, 131, 6678-6679. Download PDF
  • Byers, J. A.; Jamison, T. F. " On the Synergism Between H2O and a Tetrahydropyran Template in the Regioselective Cyclization of an Epoxy Alcohol" J. Am. Chem. Soc. 2009, 131, 6383-6385. Download PDF
  • Vilotijevic, I.; Jamison, T. F. "Epoxide-Opening Cascades Promoted by Water" Science 2007, 317,1189-1192. Download PDF
  • Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F. "Ladder Polyether Synthesis via Epoxide-Opening Cascades Using a Disappearing Directing Group" J. Am. Chem. Soc. 2006, 128, 1056-1057. Download PDF