The mystery of the angular tricyclic chromone derviatives of a marine Aspergillus Versicolor. Total synthesis of a structure attributed to aspergillitine and its relationship with TMC-120B.

SEBASTIÁN O. SIMONETTI; ENRIQUE L. LARGHI; TEODORO S. KAUFMAN

Araraquara

Congreso; Sao Paulo Advanced School on Biorganic Chemistry; 2013

FAPESP

In the search of new bioactive natural products, bacteria and fungi of marine origin have captured a big attention. Particularly, marine sponges live in symbiosis with many microorganisms representing local diversity, reflecting complex and specialized interactions. In this context, fungi associated with sponges are an interesting source of natural products. In 2003, Proksch et al. isolated a family of heterocycles with unique structure of a strain of Aspergillus versicolor from the sea sponge Xestospongia exigua. These were called Aspergillitine and Aspergiones a-f (assigned by NMR analysis). Such compounds presented a 2,3-dimethylchromone structure motif. In addition, Aspergillitine was embodied with a pyridine ring, unusual in fungal polyketides, while Aspergiones showed a pyran ring. On the other hand, Pseudodeflectusine, Ustusorane C and the alkaloid TMC-120B were isolated from terrestrial fungi. Recently, by chemical synthesis was shown that Aspergiones A and B, should be reallocated as Pseudoflectusine and Ustusorane C, respectively. Therefore, with the dual aim of synthesize an unprecedented structure and unveil a possible link between our interest compound and TMC-120B, we proposed to carry out the first total synthesis of Aspergillitine by two complimentary retrosynthetic paths. Strategy A: build up a 2,3-dimethylchromone core from an appropriately substituted propiophenone, to finally prepare (by cyclization of 1,3,5-azatriene) the pyridine ring. Strategy B, the synthesis would have the intermediacy of an isoquinoline core from the suitable salicylaldehyde, and the final step would be the assembly of chromone ring. Mainly due to the availability of the starting materials, we decided to explore the strategy A. The propionylation of the 3-bromophenol followed by a Kostanecki-Robinson approach (aimed to obtain the chromone ring) gave unsatisfactory yields. In view of these results, we decided to modify the propiophenone reactivity, changing the substituents on aromatic ring. Applying the same sequence, chromone was obtained with 56% yield. This was followed by a Duff formylation in order to install a formyl group in the molecular achitecture. Triflation of phenol group, protection of the aldehyde as dimethylacetal, Stille cross-coupling, double bond migration and deprotection of the acetal furnished a key intermediate. This compound was subjected to an oximation reaction, and after a microwave-assisted 6-ð-electrocyclization, Aspergillitine was obtained with a 15% overall yield (11 steps from propiophenone). An NMR analysis of synthetic compound showed several discrepancies with the reported natural aspergillitine. Quite surprising was the observation that 1H and 13C NMR spectra were similar to TMC-120B. Consequently, we suggest that the compound isolated by the Proksch?s group is actually TMC-120B, and the structure of Aspergillitine still remain unknown as a natural product.