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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM072566-09A1
Application #
8629964
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2005-01-17
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$272,703
Indirect Cost
$72,703
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
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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