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. 2006 Sep 27;128(38):12562-73.
doi: 10.1021/ja0642616.

Studies on the mechanism of action of prekinamycin, a member of the diazoparaquinone family of natural products: evidence for both sp2 radical and orthoquinonemethide intermediates

Ken S Feldman  1 , Kyle J Eastman
Affiliations

Studies on the mechanism of action of prekinamycin, a member of the diazoparaquinone family of natural products: evidence for both sp2 radical and orthoquinonemethide intermediates

Ken S Feldman et al. J Am Chem Soc. .

Abstract

The putative reductive activation chemistry of the diazoparaquinone antibiotics was modeled with Bu(3)Sn-H and prekinamycin dimethyl ether along with prekinamycin itself. Reaction in various combinations of aromatic solvents, with and without the nucleophile benzylmercaptan present, led to isolation of both radical-trapping arene adducts and nucleophilic capture benzyl thioether products. On the basis of these product distribution studies, the intermediacies of, first, a cyclopentenyl radical and, next, an orthoquinonemethide electrophile are postulated.

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Figures

Figure 1
Figure 1
Diazoparaquinone-containing natural products.
Figure 2
Figure 2
Diazo-containing natural products lacking the paraquinone function.
Figure 3
Figure 3
Hammett study of the reaction between 29 and arene solvents under radical generating conditions.
Figure 4
Figure 4
Yield and ratio of aromatic trapping product 39c/36 upon increasing [Bu3SnH]. All data points result from averaging quadruplicate or pentuplicate measurements.
Figure 5
Figure 5
Yield and ratio of aromatic trapping product 39f/36 upon increasing [Bu3SnH]. All data points result from averaging quadruplicate or pentuplicate measurements.
Scheme 1
Scheme 1
Previous mechanistic thinking on the role of the diazo function in reactions with model biological targets.
Scheme 2
Scheme 2
Proposal for the generation of a C(11) sp2 radical from diazoparaquinones via 1-electron reduction.
Scheme 3
Scheme 3
Speculative pathways by which radical 18 might ultimately lead to DNA damage.
Scheme 4
Scheme 4
Preliminary experiments to probe the formal 1-electron reduction chemistry of prekinamycin and derivatives.
Scheme 5
Scheme 5
A mechanistic proposal for the formation of arene adducts 36/39 from diazoparaquinone 29.
Scheme 6
Scheme 6
Plausible routes to the C(11)-C(11’) dimer 49.
Scheme 7
Scheme 7
Thiol adduct formation in the reductive activation of diazoparaquinone 29.
Scheme 8
Scheme 8
Deuterium labeling experiments with diazoparaquinone 29 and Bu3SnD and/or PhCH2SD.
See this image and copyright information in PMC

References

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