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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072566-08
Application #
8208139
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2005-01-17
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$303,051
Indirect Cost
$89,879
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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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