Synthesis of Methyl-Branched lipids from mycobacterium tuberculosis.

PhD Ceremony: dhr. B. ter Horst, 14.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Synthesis of Methyl-Branched lipids from mycobacterium tuberculosis.

Promotor(s): prof.dr. B.L. Feringa, prof.dr.ir. A.J. Minnaard

Faculty: Mathematics and Natural Sciences

Contact: Bjorn ter Horst, tel. 06 1449 5743, e-mail: bjornter.horst@gmail.com

For physiological and, especially, immunological studies, access to pure cell wall lipidic compounds is of paramount importance. However, next to being severely restricted, culturing of Mycobacterium tuberculosis (M. tuberculosis) is difficult and purification of components from the lipid fraction is very complicated. An effective synthetic route to these lipids is therefore highly desirable.

This thesis describes to synthesis of the following methyl-branched fatty acids from M. tuberculosis; mycocerosic, phthioceranic, hydroxyphthioceranic, mycolipenic, mycolipanolic and tuberculostearic acid. Moreover, the absolute configuration of the until now unknown C-17 hydroxy stereocenter is elucidated in the synthesis of hydroxyphthioceranic acid. Direct comparison between the two possible (synthetic) diastereomers and the natural product isolated from M. tuberculosis allowed us to unambiguously determine the absolute configuration of the C-17 stereocenter. The configuration was established as R. The first total synthesis of PDIM A and a newly isolated phospholipid (collaboration with Prof. Moody, Harvard Medical School, VS) from M. tuberculosis are also described. The structure of this newly isolated phospholipid was elucidated by asymmetric synthesis and MS/MS analysis.

The enantioselective copper-catalyzed 1,4-addition reaction with MeMgBr to unsaturated thioesters was used as a key synthetic strategy for the synthesis of the methyl-branched fatty acids. The efficiency and selectivity of this methodology in combination with newly developed synthetic methodologies allowed us to isolate and fully characterize these components from M. tuberculosis for the very first time.