Formation of the pyridazine natural product azamerone by biosynthetic rearrangement of an aryl diazoketone

Abstract

A variety of feeding experiments with ¹³C and ¹⁵N-labeled molecules established the phthalazinone core of azamerone is derived from the diazo chlorinated meroterpenoid SF2415A3 (see scheme). We propose that an oxidative rearrangement of the aryl diazoketone followed by rearomatization with the dinitrogen group occurs during the biotransformation. This unique biochemistry extends our limited knowledge of the biosynthesis of natural products containing N–N bonds.

Figure 1

Selected natural products containing a N–N bond.

Figure 2

¹³C-labeling of azamerone (3) derived from [1,2-¹³C₂]acetate and L-[methyl-¹³C]methionine. Two equally independent labeling patterns 3a and 3b were evident from the incorporation of [1,2-¹³C₂]acetate (bold lines and dots signify double and single enrichments, respectively). The enrichment from L-[methyl-¹³C]methionine is shown as a dashed line. The numbering scheme for azamerone has been adopted from Ref. and .

Scheme 1

Proposed biosynthetic pathway for the diazo chlorinated meroterpenoids 6–8^[8] and their relation to the chlorinated dihydroquinones such as 4 and 5. A summation of the two [1,2-¹³C₂]acetate labeling patterns are shown in black (bold lines and dots signify double and single enrichments, respectively). Enrichment from L-[methyl-¹³C]methionine is shown as a dashed line, and enrichment from [¹⁵N]nitrite or [¹⁵N]nitrate is shown in bold font.

Scheme 2

Proposed oxidative rearrangement of the aryl diazoketone SF2415A3 (6) via A80915D (7) to azamerone (3) in S. sp. CNQ-766. Isotopically labeled C and N atoms from [2-¹⁵N, 9-¹³C]6 are shown in bold font.