Total Synthesis - Partly Including the 3D-Assignments of Hitherto Unknown Stereocenters - of 3-(Polyenoyl)tetramic Acid and 3 (Polyenoyl)hydroxypyridone Natural Products: Militarinones, Farinosone B, Fumosorinone, and two Anomeric Aurantosides

• Applicant: Professor Dr. Reinhard Brückner
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392556093

Tetramic acids are 5-membered ketolactams, active methylene-compounds, and weak acids (pKa 6.4). 3-(Polyenoyl)tetramic acids are active methine-compounds and stronger acids (pKa 3.4). Four natural compounds of the latter type belong to our synthetic goals. Moreover, we plan to synthesize analogous 6-membered ketolactam natural products (five targets) and model compounds (two targets), each with a 3-polyenoyl group. These compounds shall be aromatic or non-aromatic and display an N-H or N-OH motif. They can be binned as 3-(polyenoyl)hydroxypyridones.3-(Polyenoyl) tetramic acids are antibiotics, antivirals, cytotoxics and/or fungicides. This makes them relevant for pharmacy and crop protection. 3-(Polyenoyl)hydroxypyridones affect signal transduction in the nervous system. Therefore, they represent leads for the chemotherapy of diseases destroying nerve cells (Alzheimer's, Parkinson's, injuries of th spinal cord).A main objective of ours is (continuing) the development of efficient synthetic methodology. Firstly, bromoolefin-containing ß-ketothioesters shall be the central trifunctional building block both of 3-(polyenoyl)tetramic acids and hydroxypyridones. We feel encouraged in this regard by the first-time use of such a building block in our structure-elucidating total synthesis of the 3-(polyenoyl)tetramic acids a- and ß-lipomycin. Secondly, the heterocycle of both target molecule groups shall result from Dieckmann condensations. Reaching 5-membered acylketolactames thereby from ß-ketoacylated a-amino acid esters is well-known. In contrast, reaching 6-membered acylketolactames thereby from ß-ketoacylated ß-amino- or ß-(hydroxyamino)acid esters is much less studied. Moreover, certain ß-(hydroxyamino)acid esters shall be prepared from isoxazolidinones. Containing the motif C(= O)-O-N, the latter are no cyclic Weinreb amides. Virtually nothing is known about their enolate chemistry. Just it might serve our objectives well, though.Another main objective is establishing or completing the 3D structure of the seven target molecules, whose configurations are not (fully) known. For elucidating them, we intend to synthesize enantiomerically pure diastereomers of each such compound in such numbers that the absolute value of the specific rotation of one diastereomer must equal the published value. Comparing signs of rotation will then yield the configuration.The militarinones A-C and D-E suggest to have the configuration of their methylated stereocenters clarified by degrading hteir trienoyl side-chain under Lemieux-Johnson conditions. This should deliver alcohols with a syn-oriented pair of methyl groups. Their stereostructure should yield to GC comparisons with pairs of enantiomorphic reference samples (which, in turn, shall stem from synthetis). We acquired expertise in the underlying techniques when cultivating Streptomyces, isolating a-lipomycin, degrading it oxidatively, and GC-ing the resulting alcohols after (trifluoroacetyl)ation.

• DFG Programme: Research Grants