Progress toward the Total Synthesis of Lomaiviticins
Lee, Hong Geun
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CitationLee, Hong Geun. 2012. Progress toward the Total Synthesis of Lomaiviticins. Doctoral dissertation, Harvard University.
AbstractA synthetic plan for the dimeric diazobenzofluorene natural product lomaiviticin A and lomaiviticin B is presented. The route features a late-stage oxidative enolate dimerization of a monomeric oxanorbornanone, as well as a cyanophthalide-based anionic annulation. In chapter 2, a synthetic route to enone 2.42 is described. Starting from the readily prepared intermediate 1.101, enone 2.42 was prepared in seven steps. A key cyanophthalide annulation utilizing enone 2.42, where the C1 and C5 ketones are differentiated, was successfully applied. Chapter 3 describes an optimization study of the oxanorbornanone enolate dimerization. By using simple ketone 3.3 as a model, reaction conditions minimizing undesired side reactions were identified. These conditions were effectively applied to the dimerization of the fully elaborated tetracyclic precursor. A synthesis of the full carbon skeleton of the lomaiviticin aglycone is illustrated in chapter 4. A tetracyclic intermediate 4.13, prepared from enone 2.42, underwent stereoselective dimerization under the optimized conditions to provide \(C_2\)-symmetric dimer 4.12. During the dimerization study, a critical remote steric effect of C11 substituent was observed. A crystal structure of a dimeric intermediate helps lend support to our hypothesis regarding the remote steric effect. Finally, synthetic efforts to accomplish a synthesis of the lomaiviticin aglycone ent-1.3 is described in chapter 5. Although the C4 sulfone of dimer 4.12 was efficiently substituted with an oxygen atom, the key \(C11_b-O\) bond cleavage was not realized under a variety of strategies.
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