Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Herzon, Seth
Abstract
The thesis herein describes a series of synthetic endeavors encompassing different natural product scaffolds and chemical space. In chapter one, I outline the first total synthesis of nenestatin A (10), an isolate featuring the benzo[b]fluorene core found in other atypical angucyclines such as the lomaiviticins and kinamycins. The route development was highly inspired by the synthetic groundwork laid by our laboratory for the lomaiviticin A monomeric unit, utilizing key fragments cyclohexenone (19) and masked quinone (20). Additionally, an adopted radical mediated cyclization furnished the fused ring system following a stereocontrolled aldol addition (59→61). The oxidation state of target nenestatin A (10) revealed additional challenges regarding stability and naphthoquinone access not seen with the prior lomaiviticin work. This led to a strategy incorporating diazo-containing intermediates via unique installation to the benzoindene using 4-acetamidobenzenesulfonyl azide. With this, I ultimately passed through diazonenestatin A 72, exposing a further topic of study regarding the abundance of diazo-containing species in nature. In alignment with previous bioinformatic findings, I found that diazonenestatin A 72 transformed to nenestatin A (10) when treated with conditions mimicking that of the natural product isolation (N4 media). This serves as experimental evidence confirming hypotheses that bacterial media have the capacity to reduce the diazo moiety leading to isolates lacking the functionality. This discovery, paired with the first synthetic preparation of nenestatin A (10), sets the stage for further atypical angucycline biosynthetic pathway investigations. In chapter two, I present synthetic studies towards the first total synthesis of microansamycin A (93), a parent compound demonstrating rare, post-PKS modifications. A key bond construction joining the elaborated ansa chain 146b to an aniline species via a silver-mediated amidation afforded the β-ketoanilide moiety. Additional studies providing flexibility in synthetic approach were pursued to append the difficult, macrocyclic sp2/sp3 linkage. Two lead strategies were highlighted: a copper-catalyzed Suzuki-type cross coupling and conjugate addition into a quinone monoketal. With advanced intermediate 152 in hand, and experimental data to support completion of microansamycin A (93), this work provides a foundation for continued pursuit of synthetic access to the series of microansamycins. Chapter three discusses the preparation and attempted use of vancosamine-originated glycosyl donors in our laboratory’s anionic glycosylation methodology. First, I demonstrated an abbreviated, robust route to fully synthetic L-4-epi-vancosamines by modifying a previously employed intramolecular conjugate amination to now give a single diastereomer 195. Next, I prepared a small library of donor and acceptor species varying in electronics to probe the capability of the method on more complex glycosides than the original report. The glycosyl residues chosen mapped onto a saccharomicins A and B fragment (167) to provide a relevant application in ongoing synthetic efforts. I delineate the major challenges observed with the glycosylation screening and reveal the remaining work to be done in the field regarding linkages containing 2,6-dideoxy aminoglycosides.
Recommended Citation
Frischling, Madeline Chellel, "The Total Synthesis of Nenestatin A, Studies Towards the Total Synthesis of Microansamycin A, and Exploration of Aminoglycoside Anionic Glycosylation Applicability Using 4-Epi-Vancosamines" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1155.
https://elischolar.library.yale.edu/gsas_dissertations/1155
