The overall goal of this project is the development of several general strategies of complex molecule synthesis, using natural products that have the potential to improve human health to illustrate the features of each of these approaches. A recently discovered catalytic epoxide-alkyne reductive coupling is used in each of the three strategies for a different purpose: as a fragment coupling for rapid assembly of a family of natural products from common building blocks (Specific Aim 1), as a macrocyclization (Specific Aim 2), and for the synthesis of stereodefined 1,3-dienes used in transannular Diels-Alder reactions that assemble the tricyclic core of several diterpenoids (Specific Aim 3).
In Specific Aim 1, two complementary approaches are presented for the synthesis of four natural products, amphidinolides T2-T5 and three molecules structurally related to them. In the first, amphidinolides T1 and """"""""pseudo-T1"""""""" are assembled from four simple building blocks and converted to the other six targets in this study by way of three reactions that may be involved in the biogenesis of these natural products. An alternative strategy uses the same building blocks and prepares four of the targets directly. The goal of Specific Aim 2 is the demonstration of a strategy in which a catalytic macrocyclization also installs a critical functional group array found in many families of organic molecules.
Specific Aim 3 describes the development of a flexible synthetic strategy for the cyatane-type diterpenes, including the erinacines, which induce the synthesis of nerve growth factor, and the cyathins, allocyathins, and cyathatriols, which possess antibacterial and antifungal activity. The strategy is first established for two cyathadiene natural products and then extended to several highly oxygenated erinacines, cyathins, allocyathins, and cyathatriols.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Katcher, Matthew; Jamison, Timothy F (2018) Studies toward brevisulcenal F via convergent strategies for marine ladder polyether synthesis. Tetrahedron 74:1111-1122
Czabaniuk, Lara C; Jamison, Timothy F (2015) Hydroxyl-substituted ladder polyethers via selective tandem epoxidation/cyclization sequence. Org Lett 17:774-7
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
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

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