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Diastereoselective Transformations of Macrocyclic 1,4-Diketones for the Synthesis of Cyclobutane-containing Natural Products




Johnson, Kara

Type of Degree

PhD Dissertation


Chemistry and Biochemistry


Macrocyclic conformation has been investigated since the 1950s. The understanding of this phenomenon has been applied to predict and explain diastereoselective reactions to macrocyclic systems since this time, and correlation is observed between the low-energy conformation of a macrocycle and the diastereoselectivity of reactions to that system. High levels of diastereoselectivity have been observed for Grignard reactions of macrocyclic 1,4-diketones. In all of the macrocycles investigated, ring size proved to be the greatest contributor to diastereoselectivity. As the size of the macrocyclic 1,4-diketone system employed decreases, the observed diastereoselectivity of the 1,2-addition increases. For vinyl Grignard additions other factors affecting the observed diastereoselectivity include Grignard halide, solvent, and bridging motif. Based on the results obtained from the studies of the Grignard reaction to macrocyclic 1,4-diketones, an investigation of enolate alkylations to these same macrocyclic diketones as a means to alkylate the α and α' positions diastereoselectively was undertaken. High levels of diastereoselectivity where obtained in these vicinal alkylation reactions, and the resulting macrocyclic 1,4-diketones were subsequently subjected to a five step sequence, featuring a transannular McMurry reaction, to afford di-O-methylendiandrin A as well as other lignan-type cyclobutane-containing compounds.