Quinones tetracyclic

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous tumors. The first anthracyclines, doxorubicin (DOX) and dau-notubicin (DNR), were isolated from Streptomyces var peucetius they were shown to be composed of a tetracyclic ring system with adjacent quinone-hydro-quinone moieties, a short side chain with a carbonyl group, and an aminosugar bound to the C-7 of the four-ring system. DOX and DNR only differed in the side chain terminus (-CH2OH in DOX vs. -CH3 in DNR). Second generation anthracyclines, like epitubicin (EPI) and idatubicin (IDA), were obtained after minor chemical modifications of DOX or DNR, respectively (Fig- 1). 

Another formal total synthesis of ( )-yohimbine has been worked out by Wenkert et al. (229) by preparing O-methylhexadehydroyohimbine (420), which was first prepared by Kametani and co-workers (224-226) as a key intermediate toward ( )-yohimbine. In Wenkert s approach, pyridinium salt 427 was y-alkylated with acetoacetic ester anion. The product 428 then underwent intramolecular condensation, affording tetracyclic quinone 429. Methylation of 429... 

In a rather elegant approach towards colombiasin A (36) Flynn et al. [47] would access the tetracyclic carbon skeleton through an enantioselective intermolecular Diels-Alder sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence between double-diene 166 and quinone 167 (Scheme 26). A key element of the proposed approach would be the chiral sulfoxy group in 167 which controls both the regio and facial selectivity of the intermolecular Diels-Alder reaction and eliminates generation of the dienophile for the IMDA reaction. 

The asymmetric Diels-Alder cycloadditions of enantiopure (5)-5-(/ -tolylsulfinyl)-1,4-benzoquinones with Dane s diene under thermal and Lewis acid conditions produce tetracyclic quinones after spontaneous elimination of the sulfinyl group.The Diels-Alder reaction of barrelene with o-benzoquinone produces tetracyclo[6.2.2.2 .0 ]tetradeca-9,ll,13-triene-4,5-dione. Under kinetic control, the Diels-Alder cycloaddition of 2,3-dicyano-p-benzoquinone (98) with cyclopentadiene in MeOH produces the single cycloadduct (99) (Scheme 38). ... 

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). 

In a clever, convergent and regiospecific route to the aklavinone ring system, it was shown that treatment of the lithio anion of the cyanophthalide 1 with the enone lactone 2 in THF/HMPA gave the tetracyclic quinone 3 directly (25% yield after conversion to the methyl ester and purification). 

A total synthesis of ( )-royleanone from 5,7,8-trimethoxy-l-tetralone (123) has been described.129 The tetralone was converted into the tricyclic ketone (124), which was in turn converted into 11,12,14-trimethoxypodocarpatriene (125). Demethyla-tion and oxidation afforded the quinone (126 R = H) which was alkylated to give royleanone (126 R = Pr ). Synthetic studies in the resin acid series have led130 to the preparation of the dicarboxylic acid (127) with a cis a/b ring junction. The preparation of some tetracyclic ketones as intermediates for gibberellin synthesis has been described.131 132 The key reaction involves photolysis of a diazoketone (128) to afford the tetracyclic system (129). In a synthesis of phyllocladene from abietic acid... 

As depicted in Scheme 41, an intramolecular cycloaddition of the furan 2,3-double bond of a furan tethered to a cyano-substituted benzocyclobutene via an intermediate quinone dimethide was used for the synthesis of the tetracyclic core of halenaquinol and halenaquinone <2001SL1123, 2002T6097>. The reaction proceeded via an OT,7i9-transition state to produce the cycloadduct 72 exclusively. A related chemistry is shown in Equation (56), in... 

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. 

One final interesting application of CAN which exemplifies one of the many possible reactions of qui-nones comes from Hassall and coworkers in their synthesis of 4-demethoxydaunomycinone (47). Thus, oxidation of the boronate (42) with CAN gave the crude quinone (43) which was reacted with trans-1,2-bis(acetoxy)-l,2-dihydrobenzocyclobutene (44) to give the tetracyclic quinone (45) in an impressive 79% overtdl yield. Deacetalization and reductive acetylation to the naphthacene (46), followed by oxidation with anhydrous chromium trioxide and deprotection with boron trichloride afforded the target compound (47 Scheme 10). 

Tetracyclic quinone 206 was obtained from 2,3-dichloro-1,4-naphthoquinone and 2-aminopyridine in an unexpected manner (63JOC1019). 

Reaction of dibromo-202 with ethyl acetoacetate and pyridine gave a tetracyclic quinone (70JHC395), and Diels-Alder reaction transformed 202 into the extended quinones (70JHC425). 

Dichloro-1,4-naphthoquinone and 3-methyl-l-phenylpyrazolone gave 400, and the tetracyclic quinone 401 was obtained from l,2-dimethyl-4-hydroxy-6-pyridone (47CB47). Cyclization of 6-acetylamino-7-chloroquin-oline-5,8-dione in the presence of acetic anhydride yielded the oxazolo derivative 402, and from the 7-mercapto analog the thiazole quinone 403 was... 

Kraus and Zhao described the total synthesis of G-2N (48), an angnlarly fused quinone natural product, using a Diels-Alder reaction between an outerring bicyclic diene and a p-benzoquinone derivative. Sahagdn and colleagues reported the synthesis of tetracyclic ketone 49 nsing a Diels-Alder approach. Ketone 49 was intended to be used in the synthesis of new anthracychne analogs. 

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