Synthese der AB-Ring-Substruktur von Granaticin A und Totalsynthese von Fulicinerosid

Synthesis of the AB-ring substructure of Granaticin A An efficient synthesis of the AB-ring pyranolactone substructure of the tetracyclic natural product Granaticin A was developed. Key steps in the construction of the pyranolactone scaffold are featured by a Tsuji carbonylation, a tandem Sharpless bishydroxylation-lactonization and a thermodynamically controlled oxa-Pictet-Spengler cyclization. The preparation of the final anhydride coupling fragment was achieved via an unprecedented ozonolytic degradation. The addition of an aryl Grignard reagent to the anhydride coupling fragment proceeded regioselectively. As an alternative strategy for the construction of the B-ring, a benzyne-furan cycloaddition could be established. Total synthesis of Fulicineroside The total synthesis of the proposed structures of Fulicineroside and its aglycone Fulicinerine was accomplished. The construction of the dibenzofuran core was achieved via an Ullmann biphenylether synthesis followed by a directed double C-H activation. A pyridine and a carbamate were determined as the most potent directing groups. The installation of the C2 side chain was achieved by an anionic Fries rearrangement. The C6 side chain was attached via a Stille cross coupling and a Julia-Kocienski olefination. The synthesis of the corresponding sulfone proceeded via a regioselective thiol Mitsunobu reaction and a Julia-Kocienski olefination. A Sharpless asymmetric epoxidation was applied to synthesize both the erythro- and the threo-epoxy alcohol. The air sensitive aglycone Fulicinerine was obtained in a sequence of 18 steps (total steps: 29). The completion of Fulicineroside was achieved by a late stage glycosylation (linear sequence: 22 steps, total steps: 63). NMR data analysis revealed a misassignment of the natural product’s structure.