Efforts towards the biomimetic total synthesis of cladosins E and G are detailed. These compounds were isolated by Li and coworkers from the deep-sea fungus Cladosporium sphaerospermum in 2014 and 2015 respectively. Their congener, cladosin C, was found to be active against Influenza A H1N1 (IC50 = 276 μM). However, only minute quantities of these compounds could be extracted from their natural source, making them excellent targets for chemical synthesis. Key transformations in this route include a fragment-uniting aldol reaction with 2,2,6-trimethyl-4H-1,3-dioxin-4-one, followed by thermolysis and nucleophilic capture of the resultant acyl ketene to generate a divergent intermediate which can be carried on to both natural products. To produce cladosin G, a Lacey–Dieckmann condensation is used to prepare the tetramic acid motif, whereas the aromatic ring of cladosin E will be prepared via an acid-catalysed cyclization/dehydration process. In order to complete the synthesis of cladosin G, it was necessary to develop a method for the oxidation of tetramic acids to introduce the final degree of unsaturation in the natural product. Using a test substrate, this was accomplished by treating the precursor with hypervalent iodine to generate the N-acylimine, which then tautomerized to the desired enamide on silica. Cladosins E and G, along with several unnatural analogs, will be submitted to Eli Lily’s Open Innovation Drug Discovery Program (OIDD) for more extensive biological testing.

Towards a total synthesis of cladosins E and G

253rd National Meeting (2017)

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