Anthracyclinone

Friedel-Crafts reaction of i)-methoxyben2ene with y-butyrolactone gives the dimethoxytetralone, which serves as an intermediate for anthracyclinones, such as daunomycinone [21794-55-8J (96). 

Anthracene, 9,10-dihydro-9,9-dimethyl-as antidepressant, 1, 169 Anthracene, 1,4,5,8,9-pentamethyl-synthesis, 2, 537 Anthracyclinones... 

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... 

An elegant example of sequence of reactions involving the Henry reaction, the Michael reaction, and elimination of HN02 is demonstrated in a short synthesis of anthracyclinones. Nitromethane is used to introduce the C 10-group simultaneously with the C9-hydroxy group (Eq. 7.136).183... 

Anthracyclinone synthesis. Wulf and Xu1 have reported a high-yield formal synthesis of 11-deoxydaunomycinone (5) in which the first step is a benzannelation of the chromium carbene 1 with the acetylene 2 to provide the naphthol 3, which is not isolated but treated with TFA to induce cleavage of the /-butyl ester and to... 

Anthracyclinones.1 Phthaloyl dichlorides undergo Friedel Crafts reactions with hydroquinones or the dimethyl ethers to give 1,4-dihydroxyanthraquinones in one step. 

Oxygenation of a silane. In the course of an anthracyclinone synthesis, Vedejs and Pribish2 found that a benzylic trimethylsilane can be converted into a hydroxyl group by reaction with TASF in the presence of oxygen and trimethyl phosphite (2 — 3,95% yield). The conversion is considered to involve formation of a benzylic... 

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]. 

The chiral alcohol (66) is a valuable intermediate for the asymmetric synthesis of optically active anthracyclinones (67). These aglycones of anthracycline antibioties are currently attracting much attention because of their promising anticancer activities. 

Asymmetric reduction of a,fi-enon s. This combination of reagents (1 1) in conjunction with N-cthylaniline (2 equivalents) reduces alkyl aryl ketones to alcohols with high stereoselectivity.1 Under these conditions 2,/1-unsaturated ketones arc reduced to optically active (S)-allylic alcohols. Optical yields of 80 98% have been reported for open-chain enones. Reduction of cyclic enones is somewhat less efficient. The method was used to reduce 1 to 2, which has been used as an intermediate in an anthracyclinone synthesis.2... 

A novel route to anthracyclinones is based on the chemistry of quinone-isobenzofuran adducts (77TL3537). The 3-methoxybenzyne-furan adduct (1) was reacted with a-pyrone to give a mixture of lactones (2). Thermolysis of this intermediate in the presence of quinone (3) gave in 93% yield the tetracyclic adduct (4) as a stereoisomeric mixture. Aromatization with sodium acetate in acetic acid gave quinone (5) which was subjected to reduction, C-ring oxidation and mild acid hydrolysis to afford a mixture of ( )-7-deoxydaunomycinone (6) and its 1-methoxy regioisomer (Scheme 1). 

Marschalk reaction.1 Leucoquinizarin (1) reacts with propionaldehyde and DBN (or DBU) in DMF to form 2-(l-hydroxypropyl)quinizarin (2) in high yield. This nonbasic and nonaqueous version of the Marschalk reaction was developed in order to permit use of aldehydocarbohydrates in a diastereoselective route to anthracyclinones. 

Oxidation of a phenol to an acetoxy enone The key step in a recent synthesis of anthracyclinones is the oxidative dearomatization of the A ring of 1 to the enone 2 in 50-55% yield. The product was converted in several steps into the aglycone SM-173B (3). 

Anthracyclinones The anthraquinone 1, available from the commercial dyestuff l,4,5-trihydroxy-9,10-anthraquinone, reacts regiospecifically because of the halo substituent with 2-methoxybutadiene to give 2. The product can be converted by ketalization and oxidation into the quinone 3, a known precursor to anthracyclinones. 

Anthracyclinones.1 In a short synthesis of these quinones, nitromethane is used to introduce the Qo-group simultaneously with the C9-hydroxyl group (equation I). 

The Me3Si group in ( )-l,3-bis(trimethylsilyloxy)buta-l,3-diene (177) provides the necessary steric requirement to react with 10-amino-9-hydroxy-l,4-anthraquinone derivatives 176 in a regio- and stereospecific manner (equation 74)230. Thus a single anthracyclinone derivative (178) is obtained in an excellent yield through the Diels-Alder process. 

It was stated in a Tetrahedron Report that the Marschalk reaction is "By far the most important reaction for anthracyclinone synthesis using anthraquinones as starting materials."... 

This methodology provides a regiocontrolled synthesis of anthracyclinones such as daunomycinone (2) as outlined in Scheme (I).3... 

Anisylcyclohexylmethylphosphine, 31 Anthracyclinones, 254 Anthraquinones, 189-190 Antimetabolitc AT-125, 146 Aphidicolin, 558 Aplasomycin, 57-58 Ara-7-deazaguanosine, 403, 404 Arene ally la t ion, 516 Arenediazonium fluoroborates, 161 Arenesulfonyl chlorides, 429, 495 Arene(tricarbonyl)chroniium complexes, 131-132... 

Also 2 -halo-3 -hydroxy derivatives of various anthracyclinones show a high activity against P 388 mouse leukemia in certain in-vivo tests. A compound like 98 has been prepared in the 2-deoxy-2-iodo-a-L-ma no-series by Horton et al. [59, 60] starting from di-O-acetyl-L-rhamnal (28). Similarly, Thiem et al. have also successfully prepared the tetracenomycinone-C glycoside 99 [61]. From 4-0-acetyl-3-0-(p-methoxy)-benzyl-L-fucal (102) the glycoside derivatives 103 and 104 in the talo-series were obtained. 

Mitoxantrone (mitozantrone) (Figure 3.57) is a synthetic analogue of the anthracyclinones in which the non-aromatic ring and the aminosugar have both been replaced with aminoalkyl side-chains. This agent has reduced toxicity compared with doxorubicin, and is effective in the treatment of solid tumours and leukaemias. 

Hydroxymethylation of anthraquinones (Marschalk reaction). Krohn1 has reviewed this reaction, particularly for the synthesis of anthracyclinones. It is particularly useful for preparation of optically active rhodomycinones by use of chiral aldehydes (166 references). 

A facile route to isothiochromans involves the base-catalyzed reaction of a benzyl dibromide with an a-thiocarbonyl compound. The method has been extended to the synthesis of an anthraceno[2,3-f]thiopyran, a heterocyclic analogue of an anthracyclinone (Equation 169) <1994S363>. In like manner, alkylation of the 2-aryl-1-bromoethane 491 by thiourea and subsequent liberation of the thiol function creates an isothiochroman precursor. An intramolecular Michael addition to the cr, )-unsaturated ester side chain yields the 1-substituted heterocycle (Scheme 179) <1992JOC1727>. 

Another annellation reaction starts from a,a -dibromo-o-xylene, an activated olefin and zinc.63 This reaction, according to the authors proceeds by a Diels-Alder cycloaddition via the o-xylylene (Scheme 15.10), and was employed in carbohydrate chemistry to prepare anthracyclinones analogues.64 No reaction occurs without sonication. Instead of a cycloaddition, another explanation can be postulated, consisting first of addition of a mono-organozinc reagent to the activated olefin, followed by alkylation of the resulting enolate by the second benzylic bromide. 

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