2-pyrones, Diels-Alder reactions

Barrelene was obtained via a double Diels-Alder reaction from a-pyrone with methyl acrylate (H.E. Zimmerman, I969A). The primarily forming bicyclic lactone decarboxylates in the heat, and the resulting cyclohexadiene rapidly undergoes another Diels-Alder cyclization. Standard reactions have then been used to eliminate the methoxycarbonyl groups and to introduce C—C double bonds. Irradiation of barrelene produces semibullvalene and cyclooctatetraene (H.E. Zimmerman. 1969B). 

The use of trifluoromethyl-substituted a-pyrones in Diels-Alder reactions with all types of dienophiles provides an interesting route to trifluoromethyl-benzenes [I/Sj (equation 98)... 

Development of base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone and its application to synthesis of bioactive compounds 99YGK84. 

Pyridones from 1,3,5 triketones, 46,60 Pyrolysis, diketene to ketene, 46, SO a-PYRONE, 46,101 in Diels Alder reactions, 46, 104 4-Pyrones, 2,6 disubstituted, from 1,3,5 pentanetnones by acid cycliza tion, 46, 61... 

A careful assessment of the constitution of compound 10 led to the development of a rather efficient strategy featuring the Diels-Alder reaction (see Scheme 3). Although the unassisted intermole-cular reaction between 3-hydroxy-2-pyrone (16)23 and a,/ -unsatu-rated ester 17 is unacceptable in terms of both regioselectivity and chemical yield, compounds 16 and 17 combine smoothly in refluxing benzene and in the presence of phenylboronic acid to give fused bicyclic lactone 12 (61% yield) after workup with 2,2-... 

Because of their low reactivity, a Diels-Alder reaction of 2-pyrones usually requires such a high temperature that the initial bicyclic lactone adducts often undergo cycloreversion [30,33] with loss of CO2. In some cases this limitation has been overcome by carrying out the reaction imder high pressure conditions. Posner and coworkers have shown [34-36] that the presence of a tolylthio group or a bromine atom at the 3- or 5-position increases the reactivity of 2-pyrones. 3-Bromo-2-pyrone (35) (Scheme 2.15), as well as its regioisomer 5-bromo (36)... 

Normal Diels-Alder Reactions. Synthesis of Pyrones and Thiopyrans... 

The 2-pyrones can behave as dienes or dienophiles depending on the nature of their reaction partners. 3-Carbomethoxy-2-pyrone (84) underwent inverse Diels-Alder reaction with several vinylethers under lanthanide shift reagent-catalysis [84] (Equation 3.28). The use of strong traditional Lewis acids was precluded because of the sensitivity of the cycloadducts toward decarboxylation. It is noteworthy that whereas Yb(OTf)j does not catalyze the cycloaddition of 84 with enolethers, the addition of (R)-BINOL generates a new active ytterbium catalyst which promotes the reactions with a moderate to good level of enantio selection [85]. 

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

Table 4.25 Diels-Alder reactions of 3-hydroxy-2-pyrone (145) catalyzed by cinchona alkaloids...

Table 5.4 High pressure Lewis-acid catalyzed Diels-Alder reactions of 2-pyrone 165 with benzylvinylether 166 ...

Protic solvents such as i-PrOH and t-BuOH favor the diastereoselectivity of the reaction of 3-hydroxy-2-pyrone with acrylates [49b]. Further examples of proton-promoted Diels-Alder reactions are reported in Section 4.8. 

Okamura H., Iwagawa M. and Nakatani M. Development of Base Catalyzed Diels-Alder Reaction of 3-Hydroxy-2-Pyrone and Application to Synthesis of Biologically Active Compounds Org. Chem. Japan 1999 57 84... 

Marko I. E., Evans G. R., Seres P., Chelle L, Janousek Z. Catalytic, Enantiose-lective, Inverse Electron-Demand Diels-Alder Reactions of 2-Pyrone Derivatives... 

Treatment of bicyclic lactones 66, derived from Diels-Alder reaction of 3-carboxy-2-pyrone under standard radical conditions using (TMSlsSiH, leads to bridged lactones 67, which can smoothly be converted to bicyclo[3.3.0]-lactones 68 (Scheme 10). For X = CHaOMe, this cascade of rearrangements took place in a 78% overall yield, providing 68 in diastereomerically pure form. Three additional steps provided a novel route toward Corey s lactone 69. 

The Baccatin III synthesis by K. C. Nicolaou and co-workers is summarized in Scheme 13.54. Diels-Alder reactions are prominent in forming the early intermediates. In Step A the pyrone ring served as the diene. This reaction was facilitated by phenyl-boronic acid, which brings the diene and dienophile together as a boronate, permitting an intramolecular reaction. 

Reaction of pyrones under dassical conditions requires the use of high temperatures to obtain low to moderate yields. The Diels-Alder reaction of pyrones has been performed in a commercial microwave oven under solvent-free conditions on solid supports such as silica gel, montmorillonite, fitrol clay and alumina. The reaction time was dramatically reduced - from 4 h to 4 min (Scheme 9.9) [50],... 

Isochromones lose carbon dioxide on heating via retro-Diels-Alder pathway to result in o-quinodimethanes (equation 81)1241,129. An isochromone route to podophyllotoxin derivative has been described (equation 82)130. Diels-Alder adducts of a-pyrone readily extrude carbon dioxide on thermal activation to furnish cyclohexadienes, which are useful substrates in tandem Diels-Alder reactions (equation 83)131. 

Guitian and colleagues126 performed some Diels-Alder reactions between in situ generated cyclohexyne and several a-pyrones. The reactions were performed at 100° C which resulted in immediate loss of carbon dioxide from the primary cycloadducts. Reaction yields were generally above 80%. The reaction between 184 and cyclohexyne, derived from 185, to give 186 has been depicted in equation 51. 

Okamura and coworkers151 studied the base catalyzed Diels-Alder reactions between 3-hydroxy-2-pyrone (224) and chiral l,3-oxazolidin-2-one based acrylate derivatives. Catalysis of the reaction between 224 and 225 by triethylamine gave fair to good de values, somewhat dependent on the solvent system used (equation 63, Table 7). Addition of 5% of water to the solvent isopropanol, for example, increased the de of the endo adduct 226 substantially. When the amount of water was increased, however, the triethylamine catalyzed reaction became less endo and diastereofacially selective, a small amount of exo 227 being obtained. Replacing triethylamine by the chiral base cinchonidine also improved the de, but now independently of the solvent system used. 

Mark6 and colleagues178 studied the Eu(hfc)3 catalyzed inverse electron demand Diels-Alder reactions between (—)-pantolactone derived chiral a-pyrones 279 and vinyl ethers and thio ethers 280. This auxiliary proved superior to other auxiliaries in these reactions. The reactions generally proceeded with high yields, affording the endo adducts 281 with de values generally above 95%. The de proved independent of the chirality or achirality of the Lewis acid employed, as (+)-Eu(hfc)3, (—)-Eu(hfc)3 and Eu(fod)3 all afforded the same diastereomer with >95% de (equation 78, Table 13). 

These phenomena can be illustrated by the cycloaddition reactions of fulvenes with electron-deficient a-pyrones. In general, the Diels-Alder reactions of electron-deficient dienes such as 458 with 6-alkyl substituted fulvenes favor addition across one of the endocyclic... 

The intermediate J4 was prepared by an "intramolecular Narasaka type Diels-Alder reaction" of dienophile 10 and 3-hydroxy-2-pyrone (J L) in the presence of phenylboronic acid [7] ... 

Diels-Alder reactions of 2-pyrones are efficient methods towards construction of bridged cyclohexene derivatives for natural product syntheses. Early studies by... 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Another enantioselective synthesis of longifolene, shown in Scheme 13.27, uses an intramolecular Diels-Alder reaction as a key step. The alcohol intermediate is resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the pyrone ring is introduced by y addition of the ester enolate of methyl 3-methylbutenoate. 

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