Structural and Biosynthetic Investigations of the Rubromycins

Abstract

The structure of the known secondary metabolite β‐rubromycin was corrected, based on spectroscopic and chemical investigations, from o‐quinone 1 to p‐quinone 6. By feeding [U‐13C3]malonic acid to the rubromycin‐producing strain, Streptomyces sp. A1, the polyketide origin of the skeleton was verified, but the identity of the starter unit and the folding mechanism of the polyketide chain are still unclear. From the culture broth of the strain A1, in addition to 6, the co‐metabolites γ‐rubromycin (3), δ‐rubromycin (4) and 3′‐hydroxy‐β‐rubromycin (7) were isolated. Their structures were determined or confirmed by detailed spectroscopic analysis. The rubromycins inhibit HIV‐1 reverse transcriptase (RT) and are cytostatically active against different tumor cell lines.

Determination of the Absolute Configurations of γ-Rubromycin and Related Spiro Compounds by Quantum Chemical CD Calculations

“…On the basis of this result, the absolute configuration of β-rubromycin (3), which can be converted into 2 [3] and the CD spectrum of which (see Figure 4) is very similar to that of γ-rubromycin (2), can likewise be assigned as (S).…”

“…Accordingly, it has emerged that diverse actinomycetes can generate different acetal configurations. (1), and the constitution of γ-rubromycin (2) and β-rubromycin (3) of the other naturally occurring spiro acetals have yet been assigned stereochemically. In this paper, we describe the elucidation of the absolute configuration of 2 (and thus also of 3) as (S), i.e.…”

“…The rubromycins [1,2] are antibacterially and cytostatically active microbial secondary metabolites [3] containing a hydroxynaphthoquinone chromophore and an isocoumarin moiety connected through a spiro acetal system. Structurally related to the rubromycins are purpuromycin, [4] the griseorhodins, [5Ϫ9] the DK-7814 compounds, [10] and heliquinomycin (1, see Figure 1), [11] all of which are isolated from actinomycetes.…”

“…Structurally related to the rubromycins are purpuromycin, [4] the griseorhodins, [5Ϫ9] the DK-7814 compounds, [10] and heliquinomycin (1, see Figure 1), [11] all of which are isolated from actinomycetes. The numerous structural investigations on these dyes were followed by detailed work on the mode of action, [12Ϫ14] the chemical reactivity, [15] the biosynthesis, [3,16] and the total synthesis [17] of selected representatives of this so-called rubromycin group of antibiotics. However, until now, the absolute configuration has been established only for one single representative, heliquinomycin (1), which was accomplished by X-ray crystallographic analysis coupled with the fortuitous presence of a sugar moiety of which the absolute configuration could be established through degradation experiments.…”

“…[11] This was, however, not possible for γ-rubromycin (2), nor for another naturally occurring derivative β-rubromycin (3, see Figure 1), which may be converted into the stereochemically identical 2 by acid-catalyzed transformation without loss of optical purity. [3] Moreover, attempts to crystallize brominated rubromycin derivatives failed, [18] so that neither 2 nor 3, nor any signed. By further quantum chemical CD calculations, we were likewise able to confirm the absolute stereostructure of heliquinomycin (1), previously assigned by X-ray structural and degradative studies, thus providing independent corroboration of our results for γ-and β-rubromycin (2 and 3).…”