A Diels-Alder Approach

It is noteworthy that there had been very few reports of [4 + 2] cycloaddition reactions using y-pyrones as dienophiles when our studies commenced.15 The only examples of 4-//-benzopyran-4-ones employed as dienophiles were 3-acylchromones reported by Wallace,16 while the first examples of 3-acyl-4-//-pyran-4-ones in [4 + 2] cycloaddition reactions were described in the preparation of reduced flavones.17 

We focused on 3-cyanochromone derivatives, for the dienophilic reactivity of these compounds has gone unnoticed.18 In addition, these 3-cyanochromones could serve as excellent model systems for exploring the potential of our strategy and investigating the scope [i.e. regio- and stereoselectivity] of y-pyrones in [4 + 2] cycloadditions. As a result, this cycloaddition also became a subject of research by other groups.19 

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Similarly, the P-phosphono-a,P-unsaturated carbonyl compounds thus synthesized have been used as dienes in a Diels-Alder approach toward the preparation of analogues of myo-inositol 1,4,5-triphos-phate,45 as well as other carbohydrate-related materials.46-48... 

Rokach and colleagues79 made use of a Diels-Alder approach to synthesize iso-prostanes. Starting with dienes 67a/67b and enantiomerically pure (>99% ee) dienophile 68, they were able to obtain the desired adducts with high diastereofacial and regioselec-tivities (equation 23). Endo 69 and exo 70 were formed by attack of the diene at the less shielded upper face of the dienophile, whereas exo 71 resulted from attack at the more shielded lower face of 68. 

A Diels-Alder approach to varenicline was recently published by Dr. Reddy s Laboratories. Entry to a key bicyclic intermediate is achieved by an iodide-catalyzed Diels-Alder reaction of tetrabromo dimethyl pyrazine (47) with excess norbomadiene. Dihydroxylation of 48, oxidative cleavage, and reductive amination prepares N-p-methoxybenzyl varenicline (50), which is deprotected under transfer hydrogenation conditions to give varenicline (1) in 10% yield for the sequence.47 This approach continues the theme of building the piperidine of 1 through olefin oxidative cleavage and reductive amination, but by doing so late in the sequence however, the approach... 

There are two main synthetic routes to naphthalene the Haworth synthesis and a Diels-Alder approach. In the Haworth synthesis (Scheme 12.1), benzene is reacted under Friedel-Crafts conditions with succinic anhydride (butanedioic anhydride) to produce 4-oxo-4-phenylbutanoic acid, which is reduced with either amalgamated zinc and HCl (the Clemmensen reduction) or hydrazine, ethane-1,2-diol and potassium hydroxide (the Wolff-Kischner reaction) to 4-phenylbutanoic acid. Ring closure is achieved by heating in polyphosphoric acid (PPA). The product is 1-tetraione and reduction of the carbonyl group then gives 1,2,3,4-tetrahydronaphthalene (tetralin). Aromatization is achieved by dehydrogenation over a palladium catalyst. 

Pyrolytic scission of cyclobutenes leads to a diene which promises to be useful in a Diels Alder approach to catechols. Heating of the sllyl derivative of the acyloin product from dimethyl glutarate in the presence of dlenophiles affords adducts of the transient diene. The adduct obtained with dimethyl acetylene dicarboxylate was converted in several steps to phthalic acid derivative. ... 

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. 

Ducrot <99SL240> used the four carbons of furan to build a cyclohexyl unit by oxidation of 263 followed by a direct aldol cyclization to give 264. Casiraghi <00JOC6307> prepared the lactone portion of 265 from a silyloxy furan aldol reaction followed by another aldol process to produce 266 as a precursor to various carbasugars, Miyashita used furan in a non-traditional way in a Diels-Alder approach to zoanthamine <02TL1705>. The pendant furan of 267 was oxidatively opened to produce a dienophile, ultimately leading to tricycle 269. 

The strategy for the constructing the ABC carbocyclic ring system of chaparrinone (226) was based on a Diels-Alder approach which necessitates, at some point in the synthesis, the inversion of configuration at C(9) (cf. structure 286). 

A Diels-Alder Approach to Functionalized c/s-Hydroisoquinolines. Attemtpts to Prepare a Tricyclic Core of Manzamine A. Imbroisi, D. de O. and Simpkins, N. 

Scheme 6.14 Retros)fnthetic disconnection of a cyclohexane derivative to allow a Diels-Alder approach...

In cases where the six-membered ring in the target structure already possesses a double bond, it is almost compulsory to check the viability of a Diels-Alder approach. The position of the double bond with respect to substituents may, however, be such as to contraindicate a Diels-Alder... 

The subsequent syntheses by Boukouvalas (Scheme 11.17) [22] and by Danishefsky (Scheme 11.18) [23] focus on the double bond in the six-membered ring, which allows a Diels-Alder approach. That however, requires activating groups at the dienophile that have to be removed in additional steps. Scheme 11.19 presents a combination of the syntheses by Forsyth [24] and by Maier [25]. They, too, implement a Diels-Alder reaction, again requiring an activating group on the dienophile. That leads in the end to a side chain that is short by one carbon atom, a fact that has to be corrected by a sequence of further steps. 

The potential for introduction of chiral centres using a Diels-Alder approach makes this a particularly attractive route to benzo-fused cyclohexanes. However, the chemistry of orthoxylylenes is relatively unexplored as previous routes to this elusive intermediate involved the use of reagents such as disodium tetracarbonylferrate. This reagent is extremely intolerant of other functional groups, mainly as a result of its high basicity and the yields obtained are only a fraction of those available using the zinc/ultrasound route. 

Develop a Diels-Alder approach to pumiliotoxin-C that involves construction of the bonds labeled a (below) in a Diels-Alder reaction. Discuss problems and potential solutions (where available). (Pumiliotoxin-1)... 

The synthesis of carbadisaccharides by way of a Diels-Alder approach has been reported (Scheme 13). ... 

Microwave irradiation was found to be an effective tool for accelerating IMDAF cycloadditions, and the Wipf group used microwave assistance in a Diels-Alder approach to 4-substituted indoles. Thermolysis of 155a in boiling toluene... 

Chen C, Hart DJ. A Diels-Alder approach to Stemona alkaloids total synthesis of stenine. J. Org. Chem. 1993 58 (15) 3840-3849. 

Martin, J. C. Synthesis of Pyridines from Dicyanopyrimidines. A Diels-Alder Approach to the C-Ring of Streptonigrin. J. Heterocycl. Chem. 17, 1111 (1980). 

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