Total synthesis of shishijimicin A, design, synthesis and biological evaluation of analogues thereof, and total synthesis and full structural elucidation of namenamicin
| dc.contributor.advisor | Nicolaou, Kyriacos C. | |
| dc.contributor.committeeMember | Kurti, Laszlo | |
| dc.contributor.committeeMember | Farach-Carson, Mary C. | |
| dc.creator | Li, Ruofan | |
| dc.date.accessioned | 2019-05-17T16:04:56Z | |
| dc.date.available | 2019-08-01T05:01:08Z | |
| dc.date.created | 2018-08 | |
| dc.date.issued | 2018-08-31 | |
| dc.date.submitted | August 2018 | |
| dc.date.updated | 2019-05-17T16:04:56Z | |
| dc.description.abstract | Enediyne natural products possessing both sophisticated chemical structures and outstanding bioactivities have received intensive attentions from chemical and biological communities since their first discovery made in 1960s. The isolations of these unusual naturally occurring substances have provoked tremendous efforts from interdisciplinary areas, culminating in comprehensive understandings and implementations on fermentative production, cytotoxicity, structural elucidation, mechanism of action, biosynthesis and total synthesis. Shishijimicins A–C and namenamicin are recently discovered marine-originated 10-membered ring enediyne natural products that render subnanomolar to picomolar levels of antibacterial and antitumor potencies. While these properties are highly desired in the targeted cancer therapies, such pharmaceutical applications are largely hampered by their scarce natural sources, which led to hitherto very limited understandings on these enediyne siblings. As a counterpart to the natural producer, chemical synthesis has long been valued for its potential of providing not only naturally existing materials, but also structurally modified analogues thereof, the latter being essential for the structure–activity relationship (SAR) studies. Therefore, in Chapter 1, we disclosed our first total synthesis of shishijimicin A, featuring a practical and scalable construction of its disaccharide domain by employing glycal glycosidation, β-carboline C–H functionalization, and lithio-β-carboline–aldehyde coupling reactions. The established synthetic methods and strategies have enabled the generation of an array of shishijimicin A analogues with various degree of chemical modifications as described in Chapter 2. The biological evaluations of the latter revealed several tolerable and intolerable structural changes with regards to the cytotoxic potencies, resulting in a graphic SAR on shishijimicin A. An intermediate en route to the total synthesis of shishijimicin A was diverted to the trisaccharide domain of namenamicin by utilizing modern glycosidation methods, which also gained its success in the final coupling with the enediyne warhead and led to, as presented in Chapter 3, the first syntheses of both 7′-epimers of namenamicin. The mysterious stereogenic center at 7′ position of natural namenamicin was unequivocally assigned by 1H NMR analysis on the rigidified polycyclic compounds. Additionally, the implemented semi-pinacol rearrangement within the synthesis of the methylthio sugar fragment has validated the use of 2-deoxy-ribofuranoside as a precursor of 2-deoxy-hexose through a ring expansion strategy, expanding our knowledge and synthetic toolbox in the carbohydrate synthesis. | |
| dc.embargo.terms | 2019-08-01 | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.citation | Li, Ruofan. "Total synthesis of shishijimicin A, design, synthesis and biological evaluation of analogues thereof, and total synthesis and full structural elucidation of namenamicin." (2018) Diss., Rice University. <a href="https://hdl.handle.net/1911/105836">https://hdl.handle.net/1911/105836</a>. | |
| dc.identifier.uri | https://hdl.handle.net/1911/105836 | |
| dc.language.iso | eng | |
| dc.rights | Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder. | |
| dc.subject | total synthesis | |
| dc.subject | enediyne natural products | |
| dc.subject | shishijimicin A | |
| dc.subject | namenamicin | |
| dc.title | Total synthesis of shishijimicin A, design, synthesis and biological evaluation of analogues thereof, and total synthesis and full structural elucidation of namenamicin | |
| dc.type | Thesis | |
| dc.type.material | Text | |
| thesis.degree.department | Chemistry | |
| thesis.degree.discipline | Natural Sciences | |
| thesis.degree.grantor | Rice University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |
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