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J Am Chem Soc. 2012 Oct 17;134(41):17262-73. doi: 10.1021/ja307497h. Epub 2012 Oct 3.

Development of enantioselective synthetic routes to (-)-kinamycin F and (-)-lomaiviticin aglycon.

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Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.


The development of enantioselective synthetic routes to (-)-kinamycin F (9) and (-)-lomaiviticin aglycon (6) are described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a β-trimethylsilylmethyl-α,β-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39→37), and diazo transfer (37→53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the β-trimethylsilylmethyl-α,β-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer provided the advanced diazofluorene 63, which was elaborated to (-)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C(2)-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome in the coupling is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid-dichloromethane) to form mixtures of the chain isomer of lomaiviticin aglycon 98 and the ring isomer 6. These mixtures converged on purification or standing to the ring isomer 6 (39-41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%). We establish that dimeric diazofluorenes undergo hydrodediazotization 2-fold faster than related monomeric diazofluorenes. This enhanced reactivity may underlie the cytotoxic effects of (-)-lomaiviticin A (1). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC(50) = 500 nM).

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