Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 04/06 Archiv

Synthetic studies towards the total synthesis of the natural polyketide portentol. Synthetic studies to thiocarbonyl ylide based 1,3-dipoles. An efficient formal synthesis of dimethylglutamine via [3+2] cycloaddition of a thiocarbonyl ylide and subsequent Raney nickel reduction. Synthetic studies towards vinyl-quinone-Diels-Alder reactions. The first X-ray crystal structure of the Dess-Martin Periodinane

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.

The rare alkali ion caesium (Cs+) is assimilated by eukaryotes, even though it is not an essential nutrient. It poses an environmental concern through the anthropogenic release of its radioisotopes, 134Cs and 137Cs. Bioavailability and long half-lives favour its uptake and accumulation in plants, via which radiocaesium can be introduced to the food chain. Cs+ ions are taken up via potassium-(K+)-related pathways due to the biophysical similarity of these cations. This makes it difficult to solely manipulate Cs+ accumulation in plants without disturbing the homeostasis of essential ions at the same time. This work shows that the soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) Sec22p, previously described as a member of the protein sorting machinery, specifically affects Cs+ accumulation in yeast by regulating the selectivity of vacuolar deposition. A similar phenotype became apparent for a homologous plant protein, SEC22. The loss of Saccharomyces cerevisiae Sec22p reduces Cs+ uptake by more than half, while at the same time leaving essential cations undisturbed. Mathematical modelling of wild-type and mutant Cs+ uptake kinetics proposes that sec22Δ is defective in vacuolar compartmentalisation of Cs+, which is proven by biochemical fractionation. Morphological alterations were not produced by the loss of Sec22p, only a Cs+-dependent vacuolar fragmentation can be observed. These results indicate a so far undescribed function of Sec22p in assuring a non-selective ion deposition to the vacuole, which is necessary in ion detoxification, while its loss induces discrimination against vacuolar Cs+ deposition. A developmentally controlled loss-of-function mutant of the orthologous gene SEC22 (At1g11890) in A. thaliana displays a similar phenotype, having specifically reduced Cs+ enrichment without detrimental growth defects, thereby translating the yeast findings to a multicellular context. Furthermore, a functional complementation of the yeast mutant Cs+ phenotype by the plant gene transcript was possible. Selective reduction of Cs+ accumulation in plants by loss of a single gene product represents a new route to limit radiocaesium input to the food chain without disturbing basic plant nutrition and growth.