The Chemical Synthesis Program supports the research of Prof. Frank E. McDonald at Emory University, in a project exploring the stereo- and regioselective exo-mode cyclizations of acyclic polyene precursors bearing allylic oxygen substituents as stereoinduction elements. This project is the basis for a novel cascade polycyclization approach to brevenal, a non-toxic inhibitor of brevetoxin binding. Major objectives for the granting period include uncovering the diastereoselectivities of metal-catalyzed cycloisomerization and halonium-ion mediated cyclization processes, and demonstrating the feasibility and generality of bicyclization and multiple ring-forming polycyclization processes. In addressing the broader impact of meaningful inclusion of less-experienced researchers such as undergraduate researchers and K-12 science teachers, the McDonald laboratory also develops new synthetic routes for the acyclic precursors required for cascade cyclization processes, based on efficient and scalable preparations of multiply-functionalized building blocks of general interest to the synthetic community.
This research focuses on discovering new strategies for the chemical synthesis of structurally complex compounds of marine origin. A critical barrier to progress in this field has been the dozens of steps required for preparing compounds of potential medicinal and commercial importance. The McDonald laboratory is addressing this challenge by developing a novel synthetic strategy, to form structurally complex compounds in a single operation, from relatively simple and easily prepared linear precursors. The potential impact of this research includes the efficient preparation of relatively complex compounds such as brevenal, which is a non-toxic inhibitor of airborne toxins naturally produced by red tide events in tropical and subtropical marine regions, including the Gulf of Mexico. Broader impacts of this research feature inclusion of undergraduate students and K-12 science teachers through several summer research programs at Emory.
Our research focuses on new methods for preparing structurally complicated compounds, generally with applications to new pharmaceutical compounds or materials. With the support of NSF grant CHE-1151304, we have developed several new chemical methods for carbon-oxygen (C-O) bond formation, which will be applied in our ongoing work toward preparing the cyclic ethers in brevenal (image 1), a rare but naturally occurring compound that blocks the harmful activity of red tide neurotoxins. The intellectual merit of our research approach primarily lies in shifting the research paradigm in the field of cyclic ether synthesis, from working on a longstanding but difficult approach with narrow applicability, to a more straightforward approach with broader applicability. The desired cyclic ether is represented by structure 2 (see image 2), which recurs throughout the structure of brevenal. The old paradigm from epoxide 1 to form desired product 2 by C-O bond formation requires precisely defined conditions, primarily because the reaction pathway leading to undesired product 3 generally occurs quite easily, in some cases even spontaneously. In general, the formation of undesired product 3 arises from the simple principle that tethered reactive functional groups of opposite polarity (reactive atoms colored "blue" and "red" in image 2) are more likely to react at the atoms that are closer together on the tether, rather than at atoms that are further apart. Thus the oxygen atom (O, in blue) is more likely to react with the nearer carbon atom (C, in red), rather than the more distant carbon atom, which would be required to get to product 2. Many researchers have been fixated on the old paradigm for more than a decade, inspired by a provocative but as yet unproven idea that product 2 might be formed from epoxide 1 in nature. Although there have been a few simple demonstrations forming product 2 from epoxide 1, all attempts to extend the old paradigm to the more complicated systems required for practical applications have failed, giving instead the undesired product 3 from epoxide 1. In contrast, our new paradigm from alkene 4 is more broadly general and tolerant of variations in the experimental protocols, even suggesting potential for general applications beyond the work of our own laboratory. Specifically, we have shifted the position of the two reactive "red" atoms by one position, so that C-O bond formation to the desired product 2 occurs from the tethered reactive atoms of "blue" and "red" polarity that are closer together, instead of forming the larger ring represented by structure 5. Our research to explore this new approach has been enabled by recent advances from other laboratories developing new methods for carbon-carbon bond formation utilized in our preparation of alkene 4, which would have been more difficult to achieve a decade ago. From the alkene 4, we have now established a conceptually simple yet novel route that may be applied to preparing brevenal, as well as non-naturally occurring structural analogs that will be available only by chemical preparations. Broader impacts of this project have included summer research experiences for visiting undergraduate students from other institutions, who have gained experience in laboratory chemistry in the context of developing scalable, safe, and reproducible methods for preparing building blocks used in our principal research project.
