From nucleosides to alkaloids and polyketides

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.