Total synthesis and biological evaluation of (+)- and (-)-bisanthraquinone antibiotic BE-43472B and related compounds.
The bisanthraquinone antibiotic BE-43472B [(+)-1] was isolated by Rowley and co-workers from a streptomycete strain found in a blue-green algae associated with the ascidian Ecteinascidia turbinata and has shown promising antibacterial activity against clinically derived isolates of methicillin-susceptible, methicillin-resistant, and tetracyclin-resistant Staphylococcus aureus (MSSA, MRSA, and TRSA, respectively) and vancomycin-resistant Enterococcus faecalis (VRE). Described herein is the first total synthesis of both enantiomers of this bisanthraquinone antibiotic, the determination of its absolute configuration, and the biological evaluation of these and related compounds. The developed synthesis relies on a highly efficient cascade sequence involving an intermolecular Diels-Alder reaction between diene (R)-61 and dienophile 55, followed by an intramolecular nucleophilic aromatic ipso substitution. Late-stage transformations included a remarkable photochemical alpha,beta-epoxyketone rearrangement [80 --> (+)-1]. Interestingly, the unnatural enantiomer [(-)-1] of antibiotic BE-43472B exhibited antibacterial properties comparable to those of the natural enantiomer [(+)-1].
Nicolaou
K C
KC
Department of Chemistry and The Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA. kcn@scripps.edu
Becker
Jochen
J
Lim
Yee Hwee
YH
Lemire
Alexandre
A
Neubauer
Thomas
T
Montero
Ana
A
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002244:Carbon / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; C540975:BE-43472B; D002244:Carbon