The synthesis of tetrafluorinated heptoses and octoses

Abstract

Luminacin D belongs to a family of bioactive compounds isolated from the fermentation broth of soil bacteria. This molecule was shown to exhibit potent angiogenesis inhibitory activity in several in vitro assays. In addition, in vivo assays performed on another Luminacin member with similar structure showed that this molecule operates by an unusual mechanism of action. Hence, the development of a synthesis giving access to sufficient quantity of luminacin D to enable further research is of interest. Recently, our group developed a highly stereoselective synthesis of luminacin D. This involved the introduction of the epoxide moiety at an early stage of the synthesis, and exploiting its stereochemistry for the construction of an adjacent stereocentre, via a chelation-controlled allylation reaction. However, while excellent selectivity was achieved for this reaction, inversion of the obtained stereocentre was required. The first part of this thesis describes the efforts undertaken in the development of a second generation synthesis that allows direct access to the desired stereochemistry. Lipopolysaccharides (LPS) are the main components of the surface of gram negative bacteria and are involved in their resistance. The inner core of LPS is constituted of a certain number of specific carbohydrates, namely Kdo (3-deoxy-D-manno-oct-2-ulosonic) and heptoses (Lglycero-D-manno-heptose), which play a key role in the bacterial virulence. In this context, we have been interested in the preparation of tetrafluorinated analogues of heptose and Kdo, as potential probes or inhibitors to investigate the LPS biosynthesis pathway. The introduction of hydrophobic perfluoroethylene group into carbohydrate backbone has indeed recently emerged as a strategy to improve the typically low protein-carbohydrate affinity, through the so-called “polar hydrophobicity” effect. The synthesis of tetrafluorinated heptoses and Kdo has been successfully achieved, and will be described in the second part of this thesis.

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ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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