Quinones annelation

Hydroxyquinone annelation. The lithio anion (2) of 1 adds to the vinylogous silyl ether 3 to provide the adduct 4. Conversion to the aldehyde and epoxidation results in 6, which undergoes cyclization in base to a hydroxyquinone, best isolated as the methyl ether 7. This quinone annelation fails when applied to an acyclic vinylogous silyl ether. 

With the Robinson annelation in mind, we can get back ic a cyclohexadienone (2) by a Wittig disconnection. One of the double bonds could be put in by quinone oxidation leaving cyclohexenonc (3), which we have already made by a Rotjinson annelation and by another route (p 380). 

The photolysis of benzo-annellated quinone diazides such as 2m should preferentially lead to products with intact benzene rings. Monochromatic irradiation... 

The first total synthesis of D/E-trans annellated yohimbines, e.g., ( )-yohim-bine (74) and ( )-pseudoyohimbine (88), was published in preliminary form by van Tamelen and co-workers (218) in 1958, while full details (219) appeared only in 1969. Key building block 393, prepared from butadiene and p-quinone, was condensed with tryptamine, yielding unsaturated amide 394, which was subsequently transformed to dialdehyde derivative 396. Cyclization of the latter resulted in pseudoyohimbane 397. Final substitution of ring E was achieved via pyrolysis, oxidation, and esterification steps. As a result of the reaction sequence, ( )-pseudoyohimbine was obtained, from which ( )-yohimbine could be prepared via C-3 epimerization. 

Substituted quinone ketals, prepared in this manner, serve nicely in annelation strategies leading to natural products. Two are illustrated, one in Scheme 20 leading to (+)-4-demethoxydaunomycinone (87) and (+)-daunomycinone (88) [46-48], the other in Scheme 21 serving as a pathway to a-citromycinone (94). The first calls for a Michael addition of (84) to quinone ketal (83) followed by capture of the intermediate enolate, and leads to annelated... 

Cycloaddition Anodically generated phe-noxy cations, o-quinones, and o-quinone methides react with olefins to bicyclic and tricyclic annelated compounds in stereoselective cycloadditions [250-252]. In the synthesis of a Euglobal skeleton, a quinone methide has been generated in situ by anodic oxidation mediated by DDQ. The cycloaddition was promoted by the use of lithium perchlorate... 

A rather difficult double Wittig reaction (Eq. 3.24) has been effected with enhanced efficiency under sonication [123], The process constitutes a novel type of annelation of an aromatic ring when applied to o-quinones. 

The half-wave reduction potentials for a series of annelated 1,4 naphthoquinones (102-106) increase upon alkylation, and decrease as ring size decreases (Table 13). The more cathodic reduction potentials of 2,3-dimethylnaphtho-l,4-qui-none (106, 0.846 V) and l,2,3,4-tetrahydro-9,10-anthroquinone (105,0.854 V) as compared to 1,4-naphthoquinone (0.685 V) are expected from inductive electron donation of alkyl groups. A decrease in reduction potential from 105 to 2,3-cyclobutanaphtho-l,4-quinone (103) (0.695 V) as ring size decreases is observed such that the reduction potential of 103 is only slightly higher than the parent 1,4-naphthoquinone. 

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

Vinylindoles are also efficient 47r-components in cycloaddition reactions and provide the corresponding [c]-annelated carbazoles which react, for example, with NPMI, MA, and quinones [82CJC419 83IJC(B)1004 88HCA1060] (Scheme 6). Although in the more usual cases the result of... 

In a study of annelation reactions of 4-alkynylcyclobutenones <91JOC6104>, thermolysis of a 4-alkynyl-4-(propargyloxy)cyclobutenone was observed to give a high yield of a quinone methide as evidenced by the formation of a hetero-Diels-Alder product in the presence of butoxyethene as a... 

The use of quinone monoketals in the reaction with an exocyclic enaminoester is a new variation150. It is not a typical Nenitzescu reaction since an enamine anion is used. Tricyclic intermediates are obtained, which nevertheless formally give typical Nenitzescu products in high yield and regioselectively (equation 58). In this way annelated indoles of mitomycin type become accessible. 

We have used the reaction extensively to prepare the indole moiety of several natural products. For example, the key step in the synthesis of the bacterial coenzyme methoxatin (36) is the formation of the indole (35) by intramolecular nitrene insertion from the azide (34), readily prepared from commercially available 4-aminosalicyclic acid. The third ring was annelated onto the indole (35) using conventional chemistry to give, after oxidation to the orrho-quinone, the natural product (36). 

Annelation of quinones This mixed acetal (and related acetals) reacts regioselectively with 2-chloro-l,4-quinones to form annelated quinones. Examples ... 

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. 

Quinones with a sulfur-containing annelated ring are strong electron acceptors and some of their charge transfer complexes with electron donors show high electrical conductivity (86CC1489). 

Substituted quinone ketals serve nicely in annelation strategies. The methodology has been skillfully applied to the total synthesis of several natural products, including (+)-4-demethoxydaunomycinone (237) and (-i-)-daunomycinone (238) [57-59]. One annelation strategy calls for a Michael addition of 234 to quinone ketal 233 followed by capture of the intermediate enolate, and leads to annelated product 235 when R = H, and to 236 when R = OMe. These materials were converted to the natural products 237 and 238 in the manner shown in Scheme 19 [59]. 

Anodically generated phenoxy cations, o-quinones, and o-quinone methides react with olefins to give bicyclic and tricyclic annelated compounds stereoselectively [359-366]. 

Another class of indole syntheses involve annelations of pyrroles. One new example of this type of indole synthesis involved the electrocyelization of a 2-alkenyl-3-allenylpyrrole intermediate <04H(63)1765>. This was exploited for the synthesis of indole-4,7-quinones. 

There is no ambiguity in the first step of the synthesis as only (4) can enolise and HC02Et is more electrophilic. The Robinson annelation was carried out in two stages, and the final oxidation used a quinone DDQ (5), a good reagent for dehydrogenation. 

The Diels-Alder reaction is a useful method of synthesis of six-membered rings. Since diaza quinone (497) (Equation (78)) and its annelated analogs, for example, (498) (Equation (79)), are good dienophiles, this method also provides a versatile way to the corresponding heterocycles containing the pyridazino[l,2-a]pyridazine moiety. The diazaquinones are usually generated in situ owing to their low stability. Tables 7 and 8 show some examples of the reaction. 

The major structural motif of steroids is the decalin unit, which is readily accessible by the Diels-Alder reaction. A famous early example is its masterful application by R. B. Woodward. A methyl quinone was reacted with butadiene to yield cw-decalone, a possible precursor for bile acids and after base treatment the thermodynamically more stable trans diastereomer, which may be applied in hormone syntheses. Another classical approach to substituted decalins is the Robinson annelation (Scheme 1.3.2), consisting of a sequence of aldol and Michael additions. 

In a novel approach to phenanthroid commands Evans et al. have demonstrated that the protected quinones (103) and (104) may he viewed as hypothetical aryl cation equivalents (105) in their annelative behaviour towards certain binucleophilic... 

Dimethyl-5-methoxyindole prepared via the VNS cyanomethylation of 3-methyl-4-methoxynitrobenzene has been used as starting material for the synthesis of cyclopropano-annelated quinone methide, a reductive alkylating agent for in vitro studies of its interactions with deoxyguanosine-5 -monophosphate (Scheme 67) [185]. 

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