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Theses Doctoral

Halonium-Induced Reactions for the Synthesis of Diverse Molecular Scaffolds

Brucks, Alexandria

A vast number of halogenated natural products have been isolated to date that contain unique structural and electronic characteristics due to the installed halogen. These properties not only aid in their bioactivity, but also put into question nature's biosynthesis of these complex molecules. Nature's ability to install halogens in a direct and concise manner has inspired our group to seek out chemical transformations that accomplish the same efficiency in the context of synthesizing complex natural products. Specifically, our group has targeted challenges in the areas of halonium-induced polyene cyclization, asymmetric halonium addition to alkenes, and medium-sized bromoether formation, as having access to such transformations would further facilitate total syntheses of these halogenated isolates. Only a few electrophilic iodonium reagents have proven capable of inducing polyene cyclization of linear terpene precursors, though, to date, these only include substrates with electron rich functional groups. Due to this, we targeted development of a new iodonium reagent, IDSI. This easily synthesized, isolable solid has promoted cyclization of both electron rich and poor linear polyene precursors in good yields and diastereoselectivities. The produced iodinated cores allow for further diversification as demonstrated in the formal synthesis of loliolide, stemodin, and K-76. In general, the use of IDSI in previous routes decreases step count, increases overall yields, and avoids the use of stoichiometric amounts of toxic metals. In addition, the chloronium variant, CDSC, completed the first polyene cyclization ever to be initiated by a chloronium electrophile. With the development of our halonium reagents, BDSB (the bromonium variant), IDSI, and CDSC, we next varied the synthesis of each reagent to include an asymmetric component. While their use in polyene cyclization only produced racemic materials, the iodohydroxylation of simple alkenes provided up to 63% ee with only a select substrate. Yet, this chiral IDSI reagent is one of only a handful of strategies capable of transferring an iodonium electrophile with moderate enantioselectivity (above 50% ee). By analyzing the hypothesized biosynthesis of the Laurencia natural isolates, we realized the proposed direct 8-membered bromoetherification from a linear precursor was most likely an unfavorable event, leading us to investigate an alternative idea. Discovery of a unique bromonium-induced ring expansion method generated 8-membered bromoethers diastereoselectively in a single step in good yields. From easily prepared tetrahydrofuran precursors, a variety of diastereomers of 8-endo and 8-exo bromoethers were generated selectively, modeling the cores of over half of the medium-sized isolates. This method was then expanded to include diastereoselective synthesis of 9-membered bromoethers, also found in the Laurencia family. The BDSB-induced ring expansion strategy was then used as the key step in the completed formal total synthesis of laurefucin, an 8-endo bromoether in the Laurencia natural products. By utilizing this method, we have developed the shortest synthesis of any 8-membered bromoether isolate in the family to date. Due to the breadth of products this transformation has generated, we believe this bromonium-induced ring expansion may have biosynthetic relevance. Our proposed biosynthesis could account for generation of not only the 8-membered bromoethers, but also additional 5-, 7- and 9-membered ethers found in the family. Additional experiments were completed to support this pathway, including mimicking enzymatic conditions as well as intercepting the proposed intermediates.


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More About This Work

Academic Units
Thesis Advisors
Snyder, Scott A.
Ph.D., Columbia University
Published Here
March 7, 2014