Total synthesis of (±)-naphthacemycin A 9, possessing both antibacterial activity against methicillin-resistant Staphylococcus aureus and circumventing effect of β-lactam resistance

Abstract

The total synthesis of KB-3346-5A9, named naphthacemycin A9, has been accomplished by combining the Dötz reaction and Suzuki-Miyaura cross coupling as well as employing Friedel-Crafts reaction with dienone-phenol rearrangement as key steps. We also describe the preparation of the simplified tetarimycin A and naphthacemycin A analogs as a model study, which coincidentally reveal unique properties of naturally occurring naphthacene-5,6,11(12H)-trione framework. The synthesized compounds were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE) to elucidate their structure-activity relationships (SARs), the results of which agreed with a previously reported preliminary SAR study of tetarimycin A.