Anthraquinone dye intermediates as precursors of aklavinone-type anthracyclinones

Murphy R.A., Cava M.P.

The cheap, available dye-intermediate 1,8-dihydroxyanthraquinone (2) is converted efficiently to a useful aklavinone precursor (3). A Mitsunobu alkylation-Claisen rearrangement sequence and an unprecedented vicarious aromatic substitution on an anthraquinone are employed as key steps.

Trost B.M., Shibata T., Martin S.J.

Boddy I.K., Boniface J., Cambie R.C., Craw P.A., Larsen D.S., McDonald H., Rutledge P.S., Woodgate P.D.

Gentle heating of allyloxyanthraquinones with sodium dithionite in dimethylformanide - water effects a rapid and controlled rearrangement to give high yields of 2-allyanthraquinones.

Ahmed Z., Cava M.P.

1-Hydroxyanthraquinone has been annelated to a tetracyclic ketoester containing the major structural features of 4-deoxyaklavinone. The cyclization of the A-ring involves the first case of an anionic alkylation of an anthraquinone at a position which is not ortho to a phenolic function.

Rao D.V., Stuber F.A.

Hydroquinone and alkyl hydroquinones are obtained from the corresponding phenols by alkylation with cyclopentadiene followed by isomerization and oxidation.

Mitsunobu O.

The reagent formed by combining diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP) could be utilized in the intermolecular dehydration between an alcohol and various acidic components such as carboxylic acids, phosphoric diesters, imides, and active methylene compounds. By the use of DEAD and TPP, diols and hydroxy acids gave cyclic ethers and lactones, respectively. The reaction of nucleosides with DEAD and TPP afforded triphenylphosphoranylnucleosides. Alcohols reacted with 2,6-di-t-butyl-4-nitrophenol in the presence of DEAD and TPP to give aci-nitroesters which converted into the corresponding carbonyl compounds.

Makosza M., Winiarski J.

Alexander J., Bhatia A.V., Mitscher L.A., Omoto S., Suzuki T.

Nicolaou K.C., Claremon D.A., Barnette W.E., Seitz S.P.

Krohn K., Hemme C.

Die Alkylierungen des 2-(9,10-Dihydro-1,4-dihydroxy-9,10-dioxo-2-anthryl)essigsaure-methylesters (1b) an der Benzylstellung und an C-3 werden untersucht. Reaktion von 1b mit Methylvinylketon fuhrt zum offenkettigen Keton 5 und dem tetracyclischen Cyclisierungsprodukt 7. Eine Zweitalkylierung am Anthrachinonkern an C-3 ist mit Formaldehyd moglich, und man erhalt den methylierten Ester 11b und das Lacton 8. Synthetic Anthracyclinones, VI.-Synthesis of Anthracyclinone Analogues Alkylation of methyl 2-(9,10-dihydro-1,4-dihydroxy-9,10-dioxo-2-anthryl)acetate(1b) at the benzylic position and at C-3 are investigated. Reaction of 1b with methyl vinyl ketone yields the open-chain ketone 5 and the tetracyclic cyclisation product 7. A second alkylation of the anthraquinone nucleus with formaldehyde is possible, and the methylated ester 11b and the lactone 8 are obtained.

Goliński J., Makosza M.

Castonguay A., Brassard P.

Various methods of substituting 1,3-dihydroxyanthraquinones in the 2-position were investigated. It was eventually found that direct hydroxyalkylation in the presence of definite amounts of sodium bicarbonate could be carried out. The reaction of 1,3,6,8-tetrahydroxyanthraquinone with 5-oxohexanal or 4-hydroxybutanal gave, respectively, among other products, (±)-averufin and (±)-bipolarin.

Roberts J., Rutledge P., Trebilcock M.

For substituted anthraquinones methods are reported which allow the oxidation of a β-methyl to a formyl group when the α- or both the ortho positions contain protected hydroxyls.

Ong B.S., Chan T.H.

Abstract Dithioacetals and ketals are useful synthetic intermediates.1 In general, they are obtained by the acidcatalysed addition of thiol to carbonyl compounds.2 The reaction is however a reversible one, and an excess of thiol together with continuous removal of water are often required for optimum yield. Recently, it was reported3 that methylthiotrimethylsilane converted carbonyl compounds to dithioacetals and ketals. The reaction however can not be applied to other thiols.

Andrieux J., Barton D.H., Patin H.

The versatile rhodium trichloride trihydrate has been employed in catalytic amounts to promote double-bond migration. This method allows good yields in otherwise difficult, or impossible, exocyclic–endocyclic isomeris-ations. The rearrangement of ergosterol was found to be more complex. Besides known isomers a new cis-AB-ergosterol isomer has been isolated.

Noori Z., Moreira I.D., Bofill J.M., Poater J.

AbstractFirst synthesized in 1868, alizarin became one of the first synthetic dyes and was widely used as a red dye in the textile industry, making it more affordable and readily available than the traditional red dyes derived from natural sources. Despite extensive both experimental and computational analyses on the electronic effects of substituents on the shape of the visible spectrum of alizarin and alizarin Red S, no previous systematic work has been undertaken with the aim to fine tune the dominant absorption region defining its color by introducing other electron‐withdrawing or electron‐donor groups. For such, we have performed a comprehensive study of electronic effects of substituents in position C3 of alizarin by means of a time dependent DFT approach. These auxochromes attached to the chromophore are proven to alter both the wavelength and intensity of absorption. It is shown that the introduction of an electron‐donor group in alizarin causes the transition bands to be significantly red‐shifted whereas electron‐withdrawing groups cause a minor blue‐shifting.

Pullella G.A., Wild D.A., Nealon G.L., Elyashberg M., Piggott M.J.

1,5,7-Trihydroxy-6H-indeno[1,2-b]anthracene-6,11,13-trione (1), proposed to be the antitubercular natural product eucapsitrione, has been synthesized in 43% overall yield and six steps, including a key Suzuki-Miyaura biaryl coupling and a directed remote metalation (DReM)-initiated cyclization. The physical and spectroscopic properties of 1 do not match the data reported for the natural product. At this time there is insufficient information available to enable a structure reassignment. During the optimization of the Suzuki-Miyaura coupling, an unprecedented biaryl coupling ortho to the borono group was observed. The scope of this unusual reaction has been investigated.

Chang M., Tai H.

A convenient preparation of racemic 2-substituted 9,10-anthraquinones that included 2-triazoylethyl skeleton 1 and 2-alkylethyl skeleton 6 is reported. The products were obtained in good yields by a three- or four-step synthetic route based on a sequence of N-bromosuccinimide (NBS)–mediated bromination of 2-ethyl-9,10-anthraquinone 2, nucleophilic substitution, and CuI-catalyzed 1,3-dipolar cycloaddition or alkylation/reductive desulfonylation. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

Gao J., Orso Simon J., Rodrigo R., Assoud A.

The S-dienol (-)-4 containing 10 carbons and one oxygen of the final product was prepared in 98.6% ee and 39% yield from cyclohexan-1,3-dione. It was attached to the aromatic ring as a monoether of catechol S-(-)-6 and subsequently subjected to oxidative ketalization in methanol. The allylated phenanthrofuran obtained was selectively oxidized at the terminal double bond. The fifth ring was completed by a "one-pot" amidation-cyclization process promoted by palladium acetate. The final homochiral indolinocodeine (-)-31 was obtained in 16 steps and 3.6% overall yield from cyclohexan-1,3-dione.

Minatti A., Dötz K.H.

A short and efficient synthesis of a novel family of quinone-substituted BINOL-type ligands exploiting the chromium-templated [3+2+1]benzannulation reaction as the key step is reported.

Roy A., Paul T., Drew M.G., Mukherjee D.

A stereocontrolled total synthesis of methyl (±)-O-methyl podocarpate ( 4 ) has been successfully accomplished using the trans-fused diester 21 as a key intermediate. Intramolecular Michael reaction of the enone-diester 18 afforded the cis-fused keto-diester 19 in high yield which was stereoselectively converted into 21 via the enone 20 .

Müller K., Altmann R., Prinz H.

A series of 2-arylalkyl-substituted anthracenones were tested as inhibitors of three types of 12-lipoxygenase isoforms in epidermal homogenate of mice, bovine platelets and porcine leukocytes. Their inhibitory activities were compared with those to inhibit the 5-lipoxygenase enzyme in bovine leukocytes. The compounds were synthesised by Marschalk, Wittig or Horner–Emmons reaction at the anthracenedione stage and then reduced to the anthracenones. Structure–activity relationship for the chain linking the anthracenone nucleus and the phenyl ring terminus was investigated. The 2-phenylethyl analogues were among the most potent inhibitors, and 3,4-dimethoxy-substituted 10f was identified as a selective inhibitor of the 12-LO enzymes over 5-LO. Selectivity for 12-LO isoforms was observed with an increase in the overall lipophilicity of the inhibitors. However, none of the linker chains of the 2-substituted anthracenones provided inhibitors that were able to discriminate between the 12-LO isoforms.

Mąkosza M., Nizamov S.

Carbanions of dimethyl chloromalonate, ethyl 2-chloroacetoacetate and dimethyl malonate react with naphthoquinone derivatives mainly via vicarious nucleophilic substitution or oxidative nucleophilic substitution of hydrogen processes. These reactions in 2-halo substituted naphthoquinones are generally faster processes than vinylic nucleophilic substitution of halogen (SNV). Introduction of one Cl substituent into position 2- of 1,4-naphthoquinone increases substantially its electrophilic activity resulting in much faster addition of the carbanion in the position occupied by hydrogen. On the other hand addition of the carbanions to 2,3-dichloro-1,4-naphthoquinone proceeds slower than to 1,4-naphthoquinone.

Sharghi H., Aghapour G.

Cava M.P.

Sulfur Reports proudly presents the latest addition to its Grand Old Men of Sulfur Chemistry hall of fame, the chemical autobiography of our distinguished editorial board member Michael P. Cava. Professor Cava's most significant and impressive achievements in organic sulfur chemistry and organic chemistry at large, starting with the legendary total synthesis of strychnine and culminating with a wealth of highly topical organic metals work, are documented in a complete bibliography with 410 research papers. This high priest of chalcogenology's lasting contributions include major landwinnings in the areas of nonclassical thiophenes and a plethora of other sulfur heterocycles, exotic thiocarbonyl compounds such as thioquinones, and, for good measure, novel selenium and tellurium compounds. The autobiography proper is lucid, concise, and contagious with its pervasive love of adventure and joy of organic synthesis. While the author's contemporaries will enjoy to relive some of the great moments of the...

Ma̧kosza M.S., Nizamov S., Urbańczyk-Lipkowska Z.

Carbanions of chloromethyl phenyl sulfone and chloromethyl p -tolyl sulfone react with anthraquinone containing electrondonating substituents in two major ways: vicarious nucleophilic substitution (VNS) of hydrogen and addition to the carbonyl group. The reaction course depends on electrondonating effects of these substituents-strong electron donors promote the VNS reaction. Graphic

Cambie R.C., Milbank J.B., Rutledge P.S.

(1997). REDUCTIVE CLAISEN REARRANGEMENTS OF ALLYLOXYANTHRAQUINONES. A REVIEW. Organic Preparations and Procedures International: Vol. 29, No. 4, pp. 365-407.

Krohn K., Rohr J.

General and recent aspects of chemical syntheses on angucyclinones and selected related natural products are summarized here. In the first part of this review on angucyclines, the chemical reaction used as a key step for the construction of the angucyclinone frame is discussed. In the second part, new members of the angucycline group of antibiotics, their bioactivity and recent biosynthetic studies including modern aspects of molecular biology (genetics) are reviewed.

Cambie R.C., Milbank J.B., Rutledge P.S.

Reductive Claisen rearrangement of allyloxyanthraquinones can be carried out effectively with sodium metabisulfite. Unlike sodium dithionite, the reagent does not effect loss of methoxy groups para to the rearranging allyl group.

Prinz H., Müller K.

The synthesis of 2‐substituted anthracenonyl acetic acid (2‐AA) derivatives is described. The key step is the Marschalk reaction of 1‐hydroxy‐8‐methoxy‐anthracenedione with glycolic acid. After protection of the resulting 2‐anthracenonyl acetic acid derivative, the 2‐monoalkylated derivatives are selectively obtained by direct alkylation. The methodology proves quite general and allows for the introduction of various substituents onto the 2‐position of the carboxylic side chain. Reduction of the anthracenediones proceeds with concomitant protecting group removal and provides final 2‐AA products in good yields. The results of initial biological studies demonstrate enhanced 5‐lipoxygenase inhibition compared to anthralin.