The synthesis of angiolam A

• Applicant: Professor Dr. Markus Kalesse
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226515476

Angiolam was discovered at the Helmholtz Center for Infection Research in 1985 by Kohl et al. from the fermentation broth of the myxobacterium Angiococcus disciformis, strain An d30. This isolation was part of the general program at the HZI to search for antibiotics produced by myxobacteria. The configurational assignment was done with the aid of NMR and X-ray spectroscopy and provided the constitution as well as the configuration of angiolam. This natural product contains a 19-membered lacton and a functionalized side chain with overall eight chiral centers. First biological investigation unraveled activities against membrane deficient Escherichia coli mutants, Bacillus subtilis and Candida albicansHere we propose the synthesis of this natural product by taking advantage of a highly convergent and efficient strategy. The ultimate goal is to provide sufficient quantities for detailed biological studies and SAR investigations. In the course of this project we will additionally, investigate and further develop two concepts for rapid and practical natural products synthesis. These two concepts are the vinylogus Mukaiyama aldol reaction of aldehyde derived enol ethers and the conjugate reduction of such unsaturated aldehydes with concomitant asymmetric protonation. Finally, the biological properties of angiolam A will be optimized through derivatization. The biological properties will be performed in collaboration with the HZI in Braunschweig. In synthetic direction we divided angiolam into two equally complex subunits. First, a peptide linkage and second a macro lactonization should be employed in order to join both segments. The macro lactonization should be established between the hydroxyl group at C18 and the corresponding free acid. Removal of all protecting groups should provide angiolam A.We will use a sequence of asymmetric Mukaiyama aldol reaction followed by 1,4-reduction and asymmetric protonation for the rapid assembly of the southern hemisphere. This strategy allows a two-step access to natural products containing an anti-configured 1,4 functional group distance between the hydroxyl and methyl groups. This strategy will be employed twice to establish four chiral centers during this synthesis.

• DFG Programme: Research Grants
• Major Instrumentation: HPLC-Anlage
• Instrumentation Group: 1350 Flüssigkeits-Chromatographen (außer Aminosäureanalysatoren 317), Ionenaustauscher