Studies towards the total synthesis of anthracimycin

Anthracimycin (1) was first isolated from a culture of the marine microorganism of Streptomyces sp. CNH365 by the Fenical group in 2013. The isolated natural product displayed significant activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA) and pathogen B. Anthracis. In 2020, Brimble and co-workers reported the first total synthesis of 1 in which the key step involved a bioinspired intramolecular Diels–Alder (IMDA) reaction to furnish the decalin core as a partially separable mixture of three diastereomers with a ratio of 7:1:7 (trans:trans:cis). In our work towards the core structure of 1 in 14 steps, the key reactions include an enantioselective enolisation to form the key enantioenriched enone 3, a stereo- and regioselective Diels–Alder cycloaddition, followed by epimerisation to afford the decalin core 4. The synthesis of malonate 6 was achieved in five steps from trans-decalin 4. The unprecedented intramolecular Michael addition of malonate 6 using the combination of La(O-i-Pr)3 and Hunig’s base constructed tricyclic lactone 7 as a single diastereomer. Methylation of 7, followed by triflation and Pd-catalysed reduction sequence, and decarboxylation generated the core structure of anthracimycin.