The Marschalk Reaction

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.  

The general process, which involves reaction of aldehydes with anthrahydroquinones, is outlined in the conversion 1 to 2. 

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Marschalk reaction (8, 456-457). Reaction of leucoquinizarin (1) with acetaldehyde results in 2. Products of this type have been considered to be intermediates in the Marschalk reaction. 

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. 

Annelation of hydroxyanthraquinones. Leucoquinizarin (2), the reduction product of quinizarin with sodium dithionite, reacts with sucdndialdehyde (excess) to give, after oxygenation, the naphthacenequinone derivative 3 in 62% yield. This annelation is related to the Marschalk reaction by which an alkyl group is introduced into the 2-position of a 1-hydroxyanthraquinone by reaction of an aldehyde with the leuco derivative of the quinone. 

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). 

Intramolecular Marschalk reaction. Ai. intramolecular Marschalk reaction (9, 376) can be used to effect a synthesis of anthracvclinones from anthraquinones. Thus the oi-hydroxy aldehyde 2, formed on saponification of the a-hydroxydichloride 1, on reduction of the quinone group cyclizes in the alkaline medium to the tetracyclic tran.s- and ci/j-diols(3and4)inaboutequal amounts. Cyclization underphase-transfer conditions results in improved yields and, more importantly, can alter the stereoselectivity. Triton B is the most effective catalyst for stereoselective cyclization to the desired natural tran -diol. 

Electrophilic reactions on the electron-deficient anthraquinone are normally not possible. However, in 1936 Marschalk described the facile alkylation of the anthraquinone nucleus by aldehydes after reduction of the quinone to the electron-rich hydroquinone using dithionite [34]. This strategy might be called a redox Umpolung , since the chemical reactivity of the anthracene core is reversed by the redox reaction. 

Dioxolanone 58c, when reduced to lactol 61, is a masked 1,4-dialdehyde (64) equivalent. The aldehyde, which is freed by ozonolysis and acidic hydrolysis, undergoes a Marschalk reaction with leucoquinizarine (65) to give rhodomycinone 66 in 45% yield [22] (Scheme 9). 

Ayyanger et al. introduced the 10-carbon through formylation of the Marschalk product 94. Intramolecular Marschalk reaction then gave ( )-4,7,9-trideoxycarminomycinone 97 [76]. The same workers also treated leucoquiniz-arin with the bromoaldehyde 96. In this case Marschalk reaction was accompanied by cyclisation to give 97 in one pot [77]. 

There has been further activity in the use of sugars as precursors for the A ring of anthracyclinones. The aldehyde (3), previously reported (Vol. 18, p, 248), has been prepared by an improved procedure and converted into (4), a suitable intermediate for an AB + CD approach to the tetracycle. Similar routes to those described earlier (Vol. 18, p. 248) have been used in the synthesis of (5), containing the key tertiary carbinol function, from diiso-propylidene glucose via a Marschalk reaction, and earlier work has... 

Anthracyclinones of the rhodomycinone type (type A) can efficiently be synthesized by Marschalk reaction of -hydroxy aldehydes 1. Both diastereoisomeric cyclization products 2 and 3 are obtained in aqueous-methanolic reaction medium but the natural configuration 2 is formed almost exclusively under phase transfer conditions. 

The search for a convenient method of fusing an anthracycline A-ring to a preformed anthraquinone nucleus has led to a revival of the rather obscure Marschalk reaction, and is illustrated by the annelation of the /euco-derivative (168) of 1,4-dihydroxyanthraquinone with succindialdehyde to give the tetra-hydronaphthacenequinone (169) ° and, in the same manner, deoxydaunomy-cinone (162) after deacetalization of the intramolecular cyclization product from (170). ° ... 

Marschalk alkylation (8, 456). The intramolecular Marschalk alkylation is useful in syntheses of the tetracyclic ring system of the cytostatic anthracycline antibiotics. A bimolecular version of the reaction involves condensation of 1 with glyoxylic acid and alcoholic KOH. The product of this reaction is reduced and esterified to afford 2 in 33% overall yield. Less than 5% of the isomeric product 3 is obtained. 9-Deoxy-e-rhodomycinone 4 is available from 2 in two steps (details not provided). ... 

Manchalk reaction. Some years ago Marschalk et al. found that leucoquinizarin (1), prepared in situ by reduction of quinizarin with alkaline dithionite, reacts with aldehydes to form 2-alkylquinizarins (2). It is not possible to obtain 2,3-disubstituted quinizarins in this way. Lewis found that pyridinium acetate with isopropyl alcohol as solvent is superior to a base or an acid catalyst for this reaction yields as high as 90% of 2 can be obtained. In addition, aromatic aldehydes can be used successfully. The leuco forms of 2 can be alkylated in this way to give 2,3-dialkylquinizarins in 40-70% yields. 

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... 

Marschalk alkylation of unsymmetrical leuco compounds such as 83 under alkaline conditions occurs selectively at the 2-position [69,70], while reaction in the presence of piperidinium acetate (Lewis conditions) [71] occurs at the 3-position [70]. This allows regiospecific syntheses in which the regiochemistry of formation of ring A is controlled by the distant 4-hydroxyl function. This is... 

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