Ansamycins hydroquinone

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

Among the naphthalenoid and benzenoid ansamycin antibiotics, some ansamycins possess a 1,4-naphthoquinone or a 1,4-quinone unit as a chromophore, and others possess a 1,4-hydroxynaphthalene or a 1,4-hydroquinone units (or their derivatives) as a chromophore. Since these two types of chromphore are in most cases reversible, it is not appropriate to classify by the difference of the oxidation stage of the chromophore. In this review, benzenoid and naphthalenoid ansamycins are further divided according to the difference of the length of their ansa chains. Thus, naphthalenoid ansamycins are divided into 3 groups, i.e., naphthalenoid ansamycins with C17 ansa chains, naphthalenoid ansamycins with C23 ansa chains, and naphthalenoid ansamycins with C9 ansa chains. The benzenoid ansamycins are divided into 2 groups, i.e., benzenoid ansamycins with C15 ansa chains and benzenoid ansamycins with Ci7 ansa chains. The relationships between, and the antibiotics within these groups are indicated in Scheme 2. 

Among other benzenoid ansamycins with C15 ansa chains, geldanamycin, the macbecins and the herbimycins are classified in this category. These compounds possess a 1,4-quinone or a 1,4-hydroquinone moiety as a chromophore. 

It was reported that some compounds which contained the chromophoric units of the ansamycins were cytotoxic. For example, hydroquinone isolated from Polemoniaceae plant Ipomopsis aggregata [224] and the naphthoquinone derivative, tricrozarin B (X3,6-trimettioxynaphthazarin) isolated from the Iridaceae plant Tritonia crocosmaejlora [225] showed cytotoxic activity. 

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