Abstract

Pestalone (1) is a natural product first isolated by W. Fenical et al. in 2001 from a cofermentation of a marine fungus and antibiotic-resistant marine bacterium. Pestalone was reported to have highly potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MIC = 37 ng/mL) and vancomycin-resistant Enterococcus faecium bacteria (MIC = 78 ng/mL). Consequently, this made pestalone a promising, new antibiotic compound. Due to its challenging chemical structure, total synthesis of 1 has only been achieved by Iijima et al. and Slavov et al. Unfortunately, the latter group reported multiple difficulties during and after total synthesis which include the facile intramolecular cyclization between the C9 aldehyde and bridging ketone forming a lactone, rendering it inactive and discrepancies in the degree of antibacterial activity. This work aims to synthesize C9 pestalone analogs incapable of undergoing the inactivating intramolecular cyclization by replacing the aldehyde with a range of electronic and steric functional groups. To date, eleven analogs were synthesized using a two-step synthesis involving first a Grignard addition of bromobenzene to a substituted phthalic anhydride (30-99% yield), and then modifying the produced carboxylic acid through esterification (47-76% yield) or amidation (7-50% yield). These analogs were then subjected to a broth microdilution minimum inhibitory concentration assay against Staphylococcus aureus, and it was found that only the analogs with the carboxylic acid showed activity. Continuing efforts are being made to access more analogs by synthesizing other substituted phthalic anhydrides.

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