Organocatalytic Domino Michael-Aldol Reactions for the Construction of Heterocyclic Natural Products

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A large number of natural products contain heterocycie motifs. Although many approaches have been used, there are only few organo-catalytic domino reactions known in the literature. In this project, aldol/vinylogous aldol and Michael reactions will be combined with organo catalysis to give chiral complex heterocycie scaffolds. In particular, the natural products yaequinolone, lachnone C and marmycin A will be synthesized for the very first time. Yaequinolones are polycyclic chiral chromenes. They were isolated from the culture broth of the fungal strain Penicillium sp. FKI-2140 and showed growth inhibitory activity against brine shrimp {Artemia salina). Lachnone C is a recently isolated chromone, isolated from the filamentous fungus Lachnum sp. BCC 2424. Lachnones mildly inhibited the growth of Mycobacterium tuberculosis. Using the reaction sequence outlined above, we will synthesize the heterocyclic part of the marmycins. They are new cytotoxic quinones of the angucycline class and were isolated from the culture broth of a marine sediment-derived actinomycete related to the genus Streptomyces. The gross structures and absolute configurations of both compounds were determined by spectroscopic and crystallographic methods. Marmycin A displayed significant cytotoxicity against several cancer cell lines, some at nanomolar concentrations. For marmycin A, tumor cell cytotoxicity appeared to coincide with induction of modest apoptosis and arrest in the GI phase of the cell cycle.