From nucleosides to alkaloids and polyketides

Hager, Dominik (2012): From nucleosides to alkaloids and polyketides: total synthesis of herbicidin C and studies toward stephadiamine and divergolides. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

This dissertation describes the synthetic work on several natural products including nucleosides, alkaloids, and polyketides. The first and main part of this thesis focuses on the total synthesis of the nucleoside antibiotics herbicidin C and its hydrolysis product aureonuclemycin. Due to their diverse biological activity, the herbicidins are considered as promising herbicides for agricultural application. In cooperation with Bayer CropScience AG, a flexible and efficient access to the herbicidins was developed and the challenges and successes of this synthesis are described in detail. More specifically, the route to the undecose moiety integrates a stereoselective C-glycosylation with several reagent-controlled stereoselective transformations. The nucleobase was introduced by a surprisingly facile and highly diastereoselective late-stage N-glycosylation. In addition to that, natural herbicidin A was transformed into promising derivatives and all compounds, including the intermediates of the total synthesis, were provided to Bayer CropScience AG for a structure activity relationship study (SAR). A list of all provided derivatives is given at the end of the thesis. The progress toward the synthesis of stephadiamine is described in the second chapter of this thesis. The natural product is the first example of a C-norhasubanan alkaloid natural product and despite its structural beauty, no total synthesis of stephadiamine has been reported to date. The proposed racemic retrosynthetic analysis of stephadiamine makes use of a Curtius rearrangement and a late lactonization. The propellane skeleton of this alkaloid was envisioned to be made by means of a homoconjugated addition/Mannich cascade of the key enamine in an extremely efficient manner. An alternative strategy is proposed for future work, which includes a Tsuji-Trost allylation arising the potential for an enantioselective synthesis of stephadiamine. In chapter III, the progress toward the divergolides C and D is presented. Attention was focused on the large scale preparation of the volatile side chain, and its unusual isolation method is pointed out in detail. In addition, the assembly of the three main building blocks is discussed. The preparation of Legionella autoinducer 1 (LAI-1) is described in chapter IV. The bacterial signaling molecule LAI-1 belongs to the class of alpha-hydroxyketones (AHKs). Given the effects of LAI-1 on virulence and motility of the bacteria L. pneumophila, this signaling molecule has the potential for clinical or technical applications. For a deeper understanding of the signaling circuit in L. pneumophila and in order to gain more insight in the mechanism of cell-cell communication, synthetic LAI-1 was prepared and provided to the research group of H. Hilbi, who investigates the gene regulation by AHK-mediated signaling. Chapter V includes the experimental procedures for the preparation of all compounds, backed up by full analytical characterization. In addition, 1H- and 13C-NMR spectra as well as crystallographic details are given.

Abstract

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 17. Dezember 2012
• 1. Bericht­erstatter:in: Trauner, Dirk