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The total synthesis of the glycosylated antibiotic fidaxomicin and methionine-derived iminium lactones

Kaufmann, Elias. The total synthesis of the glycosylated antibiotic fidaxomicin and methionine-derived iminium lactones. 2016, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12126

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Abstract

This thesis is divided into two chapters, describing two organic chemistry projects, both born from fundamentally different motivations. The main part of this work was application-driven research, in which a specific “real-world”-problem was approached, targeting a goal with a direct impact on our society. In the contrary, the second chapter describes a curiosity-driven project, based on a simple idea not having a direct application for society that is obvious.
In Chapter 1 the stereoselective total synthesis of the antibiotic, fidaxomicin, is described. The chapter starts with an introduction about the history and origin of antibiotics, and the increasing threat of multidrug-resistant pathogens. The promising bioactivity of fidaxomicin against many pathogens and the shortcomings of the natural product as therapeutic make the natural product an interesting synthetic target. The goal of this project was the development of a new antibiotic, based on the fidaxomicin lead structure, with improved pharmacological profile. Synthetically, six main fragments were prepared and assembled in the end-game, leading to a highly convergent and flexible route, required for prospective structure-activity relationship studies. The key features of the total synthesis were the first ever β-selective noviosylation, a Suzuki cross-coupling of sterically demanding substrates, a ring-closing metathesis and a challenging, β-selective rhamnosylation. Furthermore, semisynthetic studies were performed, intercepting a late-stage intermediate of the total synthesis. The synthetic route is currently used to produce diverse analogues of fidaxomicin for biological evaluation in our group.
The genesis of the project in Chapter 2 was created from the idea, to apply methionine derivatives as precursors for 1,3-oxazines, making use of the thioether as triggerable leaving group. In the course of the studies, the focus of the project changed as we discovered a novel methodology for the preparation of isolable iminium lactones from methionine. The synthetic utility of the methionine-derived iminium lactones as electrophiles was explored. Despite the interesting features of the transformation that may find its use in the synthesis of unnatural amino acids and peptidomimetics, the method has a major drawback that the cyclisation leads to racemic products. To make synthetic use of the methionine-derived iminium lactones, future studies will have to address this issue.
Advisors:Gademann, Karl and Altmann, Karl-Heinz
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Organische Chemie (Gademann)
UniBasel Contributors:Kaufmann, Elias and Gademann, Karl
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12126
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (VIII, 200 Seiten)
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:52
Deposited On:15 May 2017 10:51

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