Anthracyclinone antibiotics

Amino-2,3,6-trideoxy-L-hexoses (A-D in Scheme 3.9) occur naturally, forming the gly-cone part of anthracyclinone antibiotics, important in anti-tumor treatment.104... 

The synthesis of quinones, including anthracyclinone antibiotics and oxidized metabolites of polynuclear aromatic hyditxarbons, has been reviewed. 

During an investigation of approaches to the total synthesis of anthracyclinone antibiotics, it has been found that carbanions derived from phenylacetonitrile add to ethyl cyclohex-2-en-l-carboxylate in a Michael fashion to give, after oxidative decyanation, the y-keto-ester (155) in good yield. 

In further developments of the method, Davis has crafted a collection of chiral (camphorylsulfonyl)-derived oxaziridines 218-220 (Equation 21). These are readily available from either enantiomer of camphorsulfonic acid, and have proven efficient for a range of enantioselective cx-hydroxyla-tion reactions [23-25, 121]. /i-Keto ester 221 was thus oxidized by oxaziridine 220 to afford tertiary alcohol 222, a key intermediate for the construction of anthracyclinone antibiotics, in >95% ee [122]. 

The compatibility with different functional groups, the remarkable regio-and stereoselectivity, and the development of asymmetric procedures have made benzannulation an attractive methodology for the synthesis of natural products with densely functionalized quinoid or fused phenolic substructures [13-20], Some pertinent examples are the syntheses of vitamins K and E [17], and the production of anthracyclinones or naphtoquinone antibiotics [13, 14a, 15, 21]. 

Hauser has used repetitive annelations of this type tor synthesis of linear aromatic systems. This methodology provides a simple regiospecific route to the tetracyclic system of the antibiotic anthracyclinones. For this purpose 5-ethoxy-2(5Ff)-furanone (2) is used as the Michael acceptor in the first annelation of the anion of 1. After methylation, 3 is obtained in 65% yield. It is then converted into 4, for a second annelation with cyclohexenone or a derivative (5). The reaction results in a tetracyclic hydronaphthacene 6. 

The most clinically significant polyketides are the anthracyclinone and tetracyclinone antibiotics produced in Streptomyces cultures. The tetracyclines demonstrate that chain initiation can occur with a malonamide unit and that a wide range of reactions can occur after the... 

Anthracyclines constitute another complex and bigger family of antibiotics. They mostly occur as glycosides of the anthracyclinones (aglycone residue). They act by intercalation with the DNA in both normal and neoplastic cells. 

Keywords Anthracyclinones - Anthracycline antibiotics Diastereoselective synthesis Enantioselective catalysis... 

The anthracyclines are pigmented glycosidic antibiotics produced by different strains of Streptomyces. The first of these naturally occurring compounds, P-rhodomycine (la), was isolated by Brockmann and Bauer in 1950 from Streptomycespurpurescens [1]. In the 1950s other rhodomycins were obtained and subsequently their structures were elucidated, mainly by Brockmann [2] and Ollis [3]. The aglycone moieties of these compounds were named anthracyclinones and belong to the various types of rhodomycinones. Examples of representative structures are shown in Fig. 1. 

Interestingly, the nature of the acetal moiety appears to affect the potency of the antibiotic. For instance, baumycins containing a carbinolaminc moiety (c.g., barmino-mycins) generally exhibit a greater cytotoxicity and antitumor activity than the classical anthracyclines (38). In addition, structural variations may occur at C4 or Cl 3 of the anthracyclinone moiety, which may affect the compound s activity (34-37). 

Cassinelli G, Ballabio M, Grein A, Merli S, Rivola G, Arcamone A, Barbicri B, Bordoni T. A new class of biosynthetic anthracyclines Anthracyclinone glucuronides. j Antibiot 1987 ... 

Pandey RC, Toussaint MW, McGuire JC, Thomas MC. Maggiemycin and anhydromag-giemycin Two novel anthracyclinone antitumor antibiotics. J Antibiot 1989 42 1567-1577. 

One important group of antibiotics are the anthracyclinones, such as daunomycinone 8.63. Clearly, various routes to this compound are possible using Dotz chemistry. ... 

A new cytotoxic antibiotic cytorhodin X from a Streptomyces strain has been shown to be an unusual anthracyclinone 9a-glycoside 6. Another new anthracycline antibiotic, dutomycin, also obtained from a Streptomyces strain, contains a disaccharide component 7 including the branched chain sugar L-axenose. ... 

A review of the synthesis of anthracyclinones by elaboration of anthraquinones includes a section on the use of sugars as chiral templates. Glycosylations of the daunomycinones (46)-(48) led to the corresponding daunomycin derivatives (49)-(51). The L-fyxo-, L-arabino- and L-nfeo-isomers of the isorhodomycin compounds (52) have been made and tested for cytotoxicity. Several analogues of the anthracycline antibiotics, eg. (53), having a 1,2,3-triazolyl moiety in the sugar, have been described. ... 

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