Ansamycin antibiotic group

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

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. 

Naphthalenoid ansamycins with C i ansa chains can be further classified into three groups, namely, the rifamycin group, the proto-streptovaricin group and the streptovarlcin group, based on the difference of their chromophores. Awamycin [34,35] is an example of the naphthalenoid ansamycin antibiotics and belongs to the protostrepto-varicin group with a sulphur atom in the molecule. 

As a member of the rifamycin group of ansamycin antibiotics, tolypomycin Y (6) was isolated from the culture broth of Streptomyces tolypophorus and its structure was determined. Compound 6 consists of tolypomycinone and tolyposamine [48, 49]. 

In the biosynthesis of compound 72 (Fig. 9) and other ansamycin antibiotics, 3-amino-5-hydroxyl-coenzyme A might act as a starter-molecule. To this seven-carbon amino unit the first propionate unit (via methylmalonyl-CoA), then an acetate unit via malonyl-CoA) and finally another propionate unit are added by condensation and decarboxylation. In the case of 72, the resulting aromatic triketide is then converted into the product P8/1-OG (72) by hydrogenation of the keto group at C-7 and enolization of the keto groups at C-3 and C-5. The CoA is then split off, possibly during the excretion of the product [118]. 

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... 

Rifamycin B (136), a macrocyclic antibiotic of the ansamycin class, associates enan-tioselectively with amino alcohols. As 136 bears a carboxyl group, it can be used as a host molecule to resolve enantiomeric mixtures by CE. This was applied to analyze a variety of drugs, including terbutalin (137), bamethan (138), norphenylephrine (139),... 

Macrocyclic antibiotics The multiple chiral atoms and several functional groups allow multiple interactions with the analytes to enable chiral recognition. The primary interaction is ionic secondary interactions include hydrogen bonding, dipole-dipole, n-n, hydrophobic interactions, and steric repulsion. Rifamycin B, rifamycin SV, ristocetin A, teicoplanin, fradiomycin, kanamycin, ansamycins, avoparcin, and vancomycin. Amephoterin, a-aminoadipic acid, flurbiprofen, fenoprofen, methionine, methotrexate, ketoprofen, and suprofen, etc. 

Maytansine (73) was the first example of a benzenoid ansamycin with a Ci5 ansa chain. Maytansine was isolated originally from the higher plant Maytenus ovatus (Celastraceae). Subsequently, antibiotics related to maytansine were isolated from the fermentation broth of Nocardia sp. as well as other higher plants. Compounds belonging to the maytansinoid group possess a 1,3,5-trisubstituted benzene moiety as a chromophore. 

The w-CyN unit described was shown to be incorporated in the biosynthesis of both the ansamycins and also other related antibiotics, such as pactamycin and other compounds [188-190]. With respect to other naturally occurring compounds which contain a partial structure derived from the m-CyN unit in the molecule, asukamycin [191] is a possible shunt metabolite from 3-dehydroquinic acid in the shikimate pathway. Incorporation of [l - 3C]-AHBA (118) into the C-6 methyl group of porfiromycin (120) (a mitomycin group antibiotic) was reported (Fig. 6) [192], and the participation of a m-CyN unit in this biosynthetic pathway and the antibiotics containing a m-CyN unit were reviewed [178,188,190]. 

Streptovaricin and rifamycin belong to the ansamycin group of antibiotics, which also includes maytansine 3. The ansa chains (shown in bold in 1, 2, and 3)... 

The very largest of the polyketides are the macrolide antibiotics, e.g. nystatin 3.106). Further examples are the ansamycins which derive by a mixed acetate-propionate pathway (Section 7.6.1). Intermediate in size are the cytochalasins which derive by an acetate (malo-nate) pathway (Section 7.6.2). Where propionate units account for C3 fragments in the ansamycins, methionine and acetate serve in the cytochalasins. The macrolide antibiotics discussed below all follow the former way of generating C3 units. It is clear that, if methyl groups are introduced by two different pathways, this is not adventitious. The methyl groups must have a function possibly like the double bonds in dictating the conformation of the macrocycle. 

The ansamycin group of antibiotics are formed by elongation of a C N starter unit by acetate and propionate. The exact nature of the C. N unit was unknown but two independent studies... 

The streptovaricins were the first ansamycins reported 100, 130, 158) and they also provide the most numerous group of antibiotics within the naphthoquinonoid ansamycins. Structures have been assigned to nine members of the family (Fig. 1) - streptovaricins A-G (107), plus J (103), and K (47). Streptovaricins H and I were reported early as chromatographic entities, but have not been described again until recently, when atropisostreptovaricin F was shown to have the same chromatographic... 

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