Of daunomycinone

Oxidative decyanation (6,430). Two laboratories have reported regiospedfic syntheses of anthracyclines based on conjugate addition of the enolate of a nitrile to an O, /3-unsaturated ester. For the synthesis of daunomycinone (7), the reaction involved addition of the enolate of 1 to 2 to give 3 in 94% yield. The ester group of 3 was hydrolyzed and the resulting acid was cyclized to 4. Oxygenation of the enolate of 4 by the procedure of Watt results in the quinone 5, which is oxidatively demethylated deketalization of the product led to 6, which had been converted previously into 7. 

Diels-Alder reactions have played an eminent role (c/. Schemes 25, 26, 45, 53, 107, 109 and 124) in the synthesis of analogs of daunomycinone (624) and aldavinone (625), two representative aglycones of the tumor-inhibiting anthracyclines (Scheme 140). ... 

In a total synthesis of daunomycinone (b, the aglyconc of an antitumor antibiotic). Ho et effected selective ether cleavage of (6, daunomycinone trimethyl ether) to (7, 4-0-demethyl-7-0-methyldaunomycinone) by treatment with aluminum chloride at room temperature. 

This is also the reason for the many attempts to introduce one or more additional carbohydrate moieties. Reaction of daunomycinone with diols providing its 7-0-hydroxyalkyl derivatives enabled attachment of the sugars in a different manner leading to derivatives with lower toxicity [48]. 

The trimethylsilylethynylcerium reagent, which was initially prepared by Terashima et al., is useful for adding ethynyl groups to carbonyl moieties This method was successfuUy employed in the preparation of daunomycinone and related compounds. Illustrative examples are shown in heme 21. ... 

The chiral auxiliary substituents shield one face of the dienophile so the diene approaches the other. This methodology has been applied by Martinelli [418] to the synthesis of thromboxane receptor antagonists and by Hauser and Tomasi to the synthesis of daunomycinone antibiotics [417]. 

Intramolecular Marschalk cyclization. This reaction is a key step in a total synthesis of daunomycinone (3), the aglycone of an anthracycline antibiotic. Thus treatment of 1 with Na2S204 and NaOH in dioxane at 25°-90° results in... 

The two successive Diels-Alder additions (tandem cycloadditions) of the C2v-symmetrical tetraene 11 are not regioselective, i.e., mixtures of all the possible regioisomeric bis-adducts are obtained when utilizing non-symmetrical dienophiles. There is no control of the monoadduct on the regio-selectivity of the second cyclo addition. As we have seen with the synthesis of daunomycinone, control of the substitution pattern of the two remote rings A and D of the anthracyclinones can be achieved provided a number of adequate manipulations are carried out with the benzoquinone monoadduct of 11. A more efficient and more versatile way to control the regioselectivity of the tandem cycloadditions is through appropriate and stereoselective double substitutions of tetraene 11. 

Synthetic approaches to anthracycline antibiotics have been reviewed. Several papers report syntheses of daunorubicin analogues by the glycosidation of daunomycinone derivatives with amino-sugars glycosides of daunomycinone have been prepared from 3-epf-L-daunosamine, D-acosamine, D-daunosamine, D-ristosamine, and 3-ep(-D-daunosamine, and 4-demethoxy-9-deoxy-9-methyl... 

The 7-0-j3-D-glucosamine derivative of daunomycinone was the first compound prepared in which the daunosamine residue is replaced [70]. The compound is however inactive in vivo [223] due to its inability to bind to DNA [213]. Esterification of the 7-OH group of daunomycin has also been attempted, for example compounds (89-93) show some activity in vivo [86,224]. It is interesting to compare the related compounds (94) and (95). The latter appears to have the greater degree of cellular penetration since it is about three times more active as an inhibitor of cellular nucleic acid synthesis, yet it shows no in vivo activity whereas compound (94) shows low activity [72]. The simpler analogue (95) therefore has an unfavourable distribution or is more rapidly hydrolysed. 

Arcamone F, Penco S, Vigevani A, Redaelli S, Franchi G, DiMarco A, Casazza AM, Dasdia T, Formelli F, Necco A, Soianzo C. Synthesis and antitumor properties of new glycosides of daunomycinone and adriamycirmne. J Med Otem 1975 18 703-707. 

Marek M, Valentovi O, Demnerova K, jizba J, Blumauerova M, Kas j. Immobilized preparations foe the biatransformation of daunomycinone. Biotechnol Lett 1981 3 327-330. 

Yoshimoto A. Oki T, Umetawa H. Biosynthesis of daunomycinone from aklavinone and t-ihodomycinone. J Antibiot 1980 33 1199-1201. 

Anthracyclines, doxorubicin, daunomycin and idarubicin, belong to the most widely used anticancer agents and many efforts have been made in order to remove their undesirable side effects. Recently, convenient syntheses of daunomycinone-7-D-glucuronides and doxorubicinone-7-D-glucuronides have been reported by Rho et who fully characterised their anomeric configuration and conformation by the assignment of H NMR chemical shifts and H-H couplings. 

New anthracycline antibiotics rubomycins F and H, isolated from S. coeruleorubidus along with other daunomycinone derivatives, have been shown to be A -acylated derivatives of daunorubicin. Rubomycin M and N are disaccharide derivatives of daunomycinone, having a daunosamine unit glycosylated at C-4 with either of two 2,6-dideoxy-L-hexopyranoses. 

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