Aglycone of the antibiotic

Dilute solutions in aqueous buffers exposed to diffused or direct sunlight gave dimethylamine and 5-diazoimidazole-4-carboxamide (215). At pH 1.0 or pH 7.4 and above, this cyclized to 2-azahypoxanthine (216). In the intermediate pH range, a different product was obtained (217) which happens to be the aglycone of the antibiotic bredinin. Compound (217) was not formed by irradiation of (216). It was suggested that the betaine arose from a carbene (218) which had been quenched by water. However, (217) is colourless. Formulated injection solutions which had been found to lose activity contained 10 mg/ml... 

Let us consider Woodward s synthesis of erythronolide A -the aglycone of the antibiotic erythromycin A- which was published posthumously [2]. 

Ammonia reacts with the methoxyimine (94) to give directly the pyrrolopyrimidine (95), valuable for the preparation of the aglycone of the antibiotic toyocamycin (96 Scheme 32)... 

A similar methodology has been used for synthesis of the methyl ether of kidamycinone (13), the aglycone of the antibiotic kidamydn. This substance contains a 4H-anthra[l,2ft]pyrane nucleus. The anthracene unit was constructed by Michael addition of 7 with methyl crotonate followed by methylation to give 8. This... 

Roush, Nicolaou, and Evans have also demonstrated the efficiency of thallium hydroxide in tlie synthesis of an aglycone of the antibiotic kijanimicin [84], chlorothricolide [85], (5Z, 8Z, lOE", 12R, 14Z)-12-hydroxy-5,8,10,14-icosatetraenoic acid [(IZR)-HETE] [86], and a macrolide antibiotic, rutamycin B [87] (Scheme 2-30). 

The synthesis of the aglycone of the antibiotic giivocarcin-M was accompiished by T.C. McKenzie et ai. by a sequentiai Meerwein arylation-Diels-Alder cycloaddition.The anthraniiic methyi ester substrate was first subjected to diazotization and then the resuiting diazonium chioride was coupied to 2,6-dichiorobenzoquinone in water to afford the quinone product in moderate yieid. it is important to mention that the Meerwein arylation was conducted in water at 80 C in the absence of a cataiyst. 

Tylonolide hemiacetal (33), the aglycone of the antibiotic tylosin, possesses an anti 14-hydroxymethyl-15-acyloxy stereochemistry conveniently contained in 26, which may be viewed as the western half of 33. In order to prepare the eastern half of 33, an aldol reaction leading to the desired syn stereochemistry at C-3 and C-4 is exploited. The reaction of achiral aldehyde 27 with the S-boron enolate 28 proceeds with the expected diastereofacial selectivity to provide, in a combined yield of 80% after O-silylation, a separable mixture of 29 (derived from the / -enantiomer of 27) and 30 (from the S-enantiomer of 27). Subsequent functional group transformation of 30 ultimately leads to the a-(TMS)methylketone 31. The anion of 31, generated with lithium hexamethylsilazide in THF at — 78 °C, undergoes a Peterson condensation with 26 to afford in 60% yield the seco-diC d 32. Treatment of 32 with 70% acetic acid at 85 °C for one hour affords 33 in 60% yield. The attractive feature of this... 

A further publication has appeared on synthetic approaches to chlorothricolide (153), the aglycone of the antibiotic chlorothricin. The "7-epi-bottom half" compound (154) has been prepared and exploration made of its union with a "top-half" model system,using the methods previously developed (, 110) based on the ester-enolate Claisen rearrangement, ... 

Chlorothricins. The structure of chlorothricolide methyl ester, derived from the aglycone of the antibiotic chlorothricins (from Streptomyces antibioticus), has been deduced as (104). ... 

Leucomycins. A review of the chemistry and biological activity of leucomycins has been published, and Omura et alJ have described some conformational studies on the 16-membered-ring lactone (106), which forms the aglycone of the antibiotic. 

Maridomycins. The maridomycins are a new group of macrolide antibiotics from Streptomyces hygroscopicus and are designated maridomycins I— VI. The aglycones of the antibiotics have the general structure (108). ... 

Structural investigations on ristomycin A, an antibiotic related to vancomycin, have been reported. This antibiotic comprises o-mannose and a tetra-saccharide 0-D-arabinofuranosyl-(l -> 2)-0-D-mannopyranosyl-(l -> 2)-0-[a-L rhamnopyranosyl-(l -> 6)]-D-glucopyranose linked to the aglycone, part of whose structure was also elucidated. Chemical and spectroscopic evidence has been presented to support the presence of three oxygenated phenylglycol residues in the aglycone of the antibiotic vancomycin. ... 

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Chlorothricolide, the aglycon of the chlorothricin antibiotic, is a complex molecule containing an octahydronaphthalene unit. Roush and Sciotti [121] recently reported the total enantioselective synthesis of chlorothricolide. The multiple Diels-Alder reaction between poliene 130 and chiral dienophile (R)-131 was the key step in the synthetic process (Scheme 2.50). The interaction... 

The method was used for oxidation of an unsaturated nitrile (1) to an aromatic acyloin (2) in a projected synthesis of a model for olivin (4), an aglycone of olivomycin antibiotics.2... 

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

This reaction was used for an asymmetric synthesis of aklavinone (8), an aglycone of the anthracycline antibiotics. The key step was the reaction of the acetal 6 with 2,... 

Intramolecular biaryl couplingA novel, concise route to the benzonaphtho-pyranone ring system (4) of the aglycones of the gilvocarcin antibiotics uses an... 

Two superior, alternative reagents for the Corey method are the disulfides 23 and 24 [19], For example, in the first synthesis [20] of erythronolide B (27), the aglycone of the important antibiotic erythromycin B, cyclization of the hydroxy acid 25 to the 14-membered lactone 26 was effected in 50% yield via the thiol ester of 4-r-butyl-iV-isopropyl-2-mercaptoimidazole by heating in dry toluene under reflux (Scheme 9). 

Reactions [99] of active methylene nucleophiles other than aldehydes and ketones with carbonyl compounds are also used for cyclizations. An example is the coupling reaction between sulfone and carbonyl. A sulfonyl group is easy to introduce and easy to remove. Yoshii and coworkers [100] used a sulfone-mediated macrocycliza-tion in the synthesis of ( )-0(26)-methyl-28,29-bisnor-kijanolide 171), the aglycone of the antitumor antibiotic kijanimicin. As shown in Scheme 56, treatment of the linear precursor 169 with 1 equiv of sodium r-amylate at room temperature for 10 min. afforded the macrocycle 170 in 82% yield. On the other hand, a diastereoisomer of 169 with opposite configuration at all the stereocenters in the octalin system resisted cyclization under the same conditions. This failure comes from a severe steric hindrance in the transation state of cyclization. Once again, stereochemistry is also an important factor for macrocyclization (cf. Section 2.10). 

The Wittig-like reactions are well known for C=C bond formation. An intramolecular process can serve as a ring closure and has been generally employed in the synthesis of numerous macrocyclic natural products [150]. Oishi and coworkers [151] applied this strategy to the synthesis of the aglycone (252) of the antibiotics venturicidins A and B. Thus, as shown in Scheme 84, the aldehyde phosphate 250 was subjected to the modified intramolecular Wittig-Homer condensation with a mild base, yielding the macrocycle 251 in 48% yield. 

The closure of large rings via Heck reactions has not received extensive attention. A pioneering example was reported in 1981 by Ziegler and co-workers during a model study for the construction of carbonolide B (100), the aglycone of the antitumor antibiotic carbomycin B (Scheme 6-16) [36]. In this study, vinyl iodide 98 was converted to the 16-membered macrocycle 99 using stoichiometric amounts of a palladium catalyst. Additional... 

---