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Formal syntheses of eribulin and synthesis of biologically-active small molecules

Resource type
Thesis type
(Thesis) Ph.D.
Date created
2022-01-27
Authors/Contributors
Abstract
Natural products have been used as medicines since the dawn of recorded history and, today, continue to be an integral part of the drug discovery process. Yet, their impact has decreased significantly over the past two decades following the advent of high-throughput screening (HTS) and the post-genomic era. In this regard, total synthesis has served as a powerful tool to address some of the challenges associated with natural product drug discovery. A noticeable example is the discovery and development of the natural product analogue, eribulin mesylate, the most complex, fully synthetic drug on the market. Albeit impressive, the commercial process of eribulin involves a total of 67 steps from which, 45 are used to construct the C14-C35 fragment of the macrocyclic lactone. To improve upon this process, we exploited methodology developed in the Britton group for tetrahydrofuran synthesis. Most notably, we anticipated that the application of our expertise in the stereoselective synthesis of hydroxytetrahydrofurans would allow us to considerably reduce the overall length of the synthesis and consequently the cost of producing eribulin. Following this strategy, we have developed concise and stereoselective syntheses of two C14-C35 key fragments and also, a scalable synthesis of the C14-C26 building block. Nucleoside analogues have largely been used as anticancer drugs or for the treatment of infectious diseases. Among them, immucillin H was approved in Japan in 2017 to treat peripheral T-cell lymphoma and immucillin A was found active against a broad range of viruses. Driven by the concept of "step economy", we have developed a concise and stereoselective formal synthesis of these two nucleoside analogues. Moreover, a collaboration between the Britton group, the Structural Genomics Consortium, and Bayer has led to the design and synthesis of inhibitors selective against PRMT4, an enzyme overexpressed in several cancers.
Document
Extent
229 pages.
Identifier
etd21784
Copyright statement
Copyright is held by the author(s).
Permissions
This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Supervisor or Senior Supervisor
Thesis advisor: Britton, Robert
Language
English
Member of collection
Download file Size
etd21784.pdf 6.32 MB

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