Of 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... 

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]. 

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). 

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

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 reactionAn intramolecular Marschalk reaction (9, 376) can be used to effect a synthesis of anthracyclinones from anthraquinones. Thus the a-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 trans- and cw-diols (3 and 4) in about equal amounts. Cyclization under phase-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 trans-diol. 

Kantola J, Kunnari T, Hautala A, Hakala J, Ylihonko K, Mantsala P (2000) Elucidation of Anthracyclinone Biosynthesis by Stepwise Cloning of Genes for Anthracyclines from Three Different Streptomyces spp. Microbiology 146 155... 

Krohn K (1989) Building blocks for the total synthesis of anthracyclinones. In W Herz H Grisebach GW Kirby Ch Tamm (eds) Prog Chem Org Nat Prod Springer, Wien, New York,p 37... 

Diels-Alder Reaction. The Diels-Alder reaction of methacrolein with 1,3-dienol derivatives can also be catalyzed by the chiral BINOL-derived titanium complex BINOL-T1CI2. The endo adduct was obtained in high enantioselectivity (eq 15). The sense of asymmetric induction is exactly the same as observed for the asymmetric catalytic reactions shown above. Asymmetric catalytic Diels-Alder reactions with naphthoquinone derivatives as a dienophile provide an efficient entry to the asymmetric synthesis of anthracyclinone aglycones (eq 16). ... 

The tetrakis(methylidene)-7-oxabicyclo[2.2.1]heptane (527) offers an interesting route to linear poly-annulated ring systems, e.g. 4Klemethoxydaunomycinone (641), via a sequence of two Diels-Alder reactions (Scheme 124). Monoadduct (528) could be isolated and subjected to the [4 + 2] cycloaddition of benzyne. An alternative synthesis of anthracyclinone analogs starts with the Diels-Alder addition of 3-methoxybenzyne to a derivative of the bis-cisoid tetraene (527). ... 

Swenton and coworkers have devised and achieved an exceptionally elegant synthesis of anthracyclinone aglycons. Key to the successful outcome is the ability to intercept the intermediate radical cation 226 formed in the oxidation of aromatic ethers, either inter- or intramolecularly, with the alkoxy radical, CH30, which is also formed electrooxidatively [55,56]. As illustrated, the methodology leads to the facile assembly of substituted quinone mono- or bisketals, 230 and 231. 

Ruano, J. L. G., Paredes, C. G. Intramolecular asymmetric Pummerer reactions as a key step in the synthesis of bicyclic precursors of anthracyclinones. Tetrahedron Lett. 1999,41,261-265. 

Blumauerova, M., Kralovcova, E., Mateju, J., Jizba, J., and Vanek, Z. (1979) Biotransformations of anthracyclinones in Streptomyces coeruleorubidus and Streptomyces galilaeus. Folia Microbiol. 24,117—127. 

This same asymmetric synthesis has been used to convert 3,4-dihydro-2-naphthoic acid (7) into R-(-)-8 in about 95 7o optical purity. This acid was prepared because it serves as a model for the A and B rings of anthracyclinones. 

In the enantioselective synthesis of anthracyclinone AB building blocks Japanese workers continue to successfully exploit their methodology based on the addition of Grignard reagents to the a-carbonyl group of the ketals obtained from tetralone and (2S,3S)-l,4-dimethoxybutane-2,3-diol (60) [76]. This highly diastereoselective reaction was apphed in the synthesis of (-)-7-deoxydaunomycinone [77,78]. Later it was extended to the synthesis of AB segment 58, an intermediate in the first enantioselective synthesis of (-)-y-rhodomycinone (65) [71,79]. 

Enantioselective syntheses of anthracyclinone tetracyclic intermediates or AB building blocks have also been carried out by Diels-Alder reactions uti-... 

Reductive hydrolysis with Raney nickel [112] yielded aldehyde 93, which was reacted with leucoquinizarine (86) with aeration to give the epimeric mixture 94. Reduction of the benzyUc hydroxy group in 94 with sodium dithionite followed by hydrolysis of the isopropyhdene protection and subsequent periodate oxidation furnished aldehyde 95. Sequential treatment of 95 with sodiiun dithionite in 7% NaOH and air oxidation provided a 4 1 C-7 epimeric mixture of anthracyclinones. The major diastereoisomer, 4-demethoxyfeudomycinone C (96) was isolated by column chromatography. 

In spite of the tremendous progress in catalytic asymmetric synthesis [36,177] its use in the syntheses of anthracyclinones is limited, apart from Baker s yeast reduction and Sharpless epoxidation and dihydroxylation. In the recent anthracyclinone literature two contributions have appeared on the application of catalytic enantioselective synthesis. Both are based on the desym-metrization of a meso compoimd, but in entirely different chemical contexts. 

Scheme 1 Retro-synthetic analysis for the convergent and combinatorial synthesis of anthracyclinones and analoguous linearly condensed polycyclic compounds...

When we embarked on the synthesis of anthracyclinones, our goal was to develop a strategy that would allow one to prepare not only the aglycones of natural anthracyclines but also a large variety of modified derivatives. Our methodology had thus to be highly versatile, meaning short and tolerant as far as the nature and the number of substituents that could be introduced... 

Unsymmetrically substituted anthraquinones have been synthesised through addition of the isobenzofuranone 52 to arynes generated in situ from haloarenes, the regioselectivity of the reaction being controlled by substituents in the aryne moiety [61]. This approach is unlikely to allow regiospecific synthesis of anthracyclinones other than 11-deoxy analogues, but the unsubstituted phthalide 51 has been condensed with 68 to give 69, a precursor of 4-demethoxydaunomycinone 6. 

Diels-Alder reactions offer an excellent strategy for synthesis of polycyclic systems consisting of 6-membered rings, and it is not therefore surprising that such approaches have been widely applied to the synthesis of anthracyclines. Six of the eight possible vertical disconnections (a-d,f,g) in 98 have been employed, while a seventh (e) has been investigated in a model study [78], but has yet to be applied to the synthesis of anthracyclinones. 

Many of the homochiral AB synthons described above have been utilised in syntheses of anthracyclinones which are based on Friedel-Crafts cyclisations. As was noted earlier such reactions often require vigorous conditions, and there is some controversy concerning the enantiomeric purity of the products so obtained. While some groups claim that condensation of the hydroxy ketone 174 with phthalic anhydride in an intimate mixture of sodium chloride and aluminium chloride yields optically pure ( —)-4-demethoxy-7-deoxydauno-mycinone [16, 141] others report a considerable degree of racemisation under virtually identical conditions [135, 142], although the problem may be avoided under the somewhat milder conditions employed in a recent condensation of 174 with phthaloyl dichloride [143]. In contrast, stereochemical integrity of the product is assured under the mild conditions employed in Swenton s carbanion based synthesis of (4-)-daunomycinone 5 [53] and in our Diels-Alder based... 

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