Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Herzon, Seth

Abstract

(–)-Lomaiviticin A (1) is a complex C2-symmetric bacterial metabolite which was isolated from a fermentation broth of Salinispora DPJ-19 by He and co-workers in 2001. The structure of 1 was proposed through detailed analysis of NMR spectral data (Figure 1). Due to the presence of a diazotetrahydrobenzo[b]fluorene substructure, 1 belongs to a family of natural products often referred to as “diazofluorenes” among which the kinamycins (A, C, and F seen in Figure 1) are the earliest known members. (–)-Lomaiviticin A (1) is the most cytotoxic member of the diazofluorene family known with half maximal inhibitory potencies (IC50S) in the nanomolar to picomolar range. In addition to the interesting biological activity of 1, 1 possesses a variety of synthetically challenging structural features including two diazotetrahydrobenzo[b]fluorene (diazofluorene) residues, four dideoxyglycosides, and a highly functionalized D-ring with the dimeric bond on the more hindered face of the monomeric unit. Thus, this intriguing structure has garnered significant attention from the synthetic community. However, as a result of the difficult synthetic challenges no synthetic intermediate has yet been linked to a semisynthetic compound or related natural product. More recently, the proposed structure of 1 has been called into question by emerging data obtained from microcrystal electron diffraction (MicroED) which has resulted in an alternative proposed structure for (–)-Lomaiviticin C (2) (linked to 1 via semisynthesis). This thesis descibes a continuation of synthetic studies towards 1, the structural revision of (–)-lomaiviticin A, and the development of a new synthetic strategy towards the revised structure.

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