Ansamycin lactams

Chemistry of / -Lactam Antibiotics and Ansamycins D. Zivanov-Stakic, Arh. Farm., 1979, 29, 311-328. 

Ansamycins are a class of macrocyclic compounds in which non-adjacent positions on an aromatic ring system are spanned by the long aliphatic bridge (Latin ansa = handle). The aromatic portion may be a substituted naphthalene or naphthaquinone, or alternatively a substituted benzene ring. The macrocycle in the ansamycins is closed by an amide rather than an ester linkage, i.e. ansamycins are lactams. The only ansamycins currently used therapeutically are semi-synthetic naphthalene-based macrocycles produced from rifamycin B. 

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. 

In specific antibiotic research areas, development of improved e-lactams (see Chapter li) and work on aminocyclitol antibiotics represented a significant portion of the effort. Advances were also made in areas of interest on other antibiotics of importance in medicine or agriculture, such as the macrolides, tetracyclines, lincomycins, ansamycins, novobiocins, polyethers, and peptides. 

These ansamycins are characterized by a 19-membered ring lactam, in which the ansa tether bridges the meta positions on a substituted benzoquinone moiety. The ansa chain contains seven stereocenters, one isolated double bond and a (Z, )-dienamide. 

Rifamycin B, produced by Amycolatopsis mediterranei, is one of the most notable members of the ansamycin family [36, 37, 64, 65] (Fig. 14). It has been used clinically in a synthetically modified form called rifampicin and it is still one of the first-line therapies effective in the treatment of tuberculosis and other mycobacterial infections. The starter unit for rifamycin polyketide assembly is part of the chromophore and is derived from 3-amino-5-hydroxybenzoic acid. Five polyketide synthases are involved in the formation of rifamycin chromophore and the first polyketide synthase contains at the N terminus the loading domain for 3-amino-5-hydroxybenzoic acid, which consists of an acyl-CoA ligase linked to ACP, and module 1-3. The rifamycin polyketide synthase lacks a TE domain at the C terminus. The release of polyketide chain from polyketide synthase and the formation of amide to generate the macrocyclic lactam will be catalyzed by RifF, which is very similar to arylamine A-acetyltransferase. 

Macrocyclic lactam antibiotics consist of the ansamycin antibiotics and a number of other compounds which are classified as non-ansamycin macrocyclic lactams (Scheme 1). 

As examples of the non-ansamycin macrocyclic lactams, stubomycin (hitachimycin) was first isolated as an antitumor antibiotic [4-8]. Ikarugamycin [9], capsimycin [10], rapamycin and demethoxy-rapamycin [11-13] are other examples. Through the investigation of the biosynthesis of stubomycin (hitachimycin), it was found that the benzene ring of the P-phenylalanine moiety was involved as a chromophore outside of the macrocyclic moiety [5,14]. 

As described in the introduction, macrocyclic lactams can be classified as ansamycins and other compounds, and the ansamycins consist of an ansa-chain and a chromophore-containing moiety. The ansamycins are typically divided into two groups, i.e., the naphthalenoid ansamycins and the benzenoid ansamycins, according to their chromophores. 

The lactam functional group is encountered in numerous macrocychc lactams like, for example, the inacrocy-clic polyamine alkaloids and the ansamycin antibiotics. Lactam formation can be achieved by intramolecular reaction between acyl chloride and amine functional... 

A new class of ansamycin compounds bearing a ( , , )-triene within a 21-membered ring lactam were recently described. In particular, cytotrienins A-D (175) that were isolated from Streptomyces sp. RK95-74 and are important antitumoral compounds. Their synthesis was disclosed by Panek etal and the cmcial RCM step was performed on polyenic substrate 173. Surprisingly, when using [Ru]-II, the insertion of the ruthenium took place on one of the disubstituted double bonds thus affording the 19-membered ring. On the other... 

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