3-Hydroxy-4-pyrone

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

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-... 

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...

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... 

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. 

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] ... 

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). 

Many decomposition products of DHA are probably the same as those observed in the decomposition of AA (40), Fifteen products from DHA decomposition in aqueous solution were reported (41), Of these fifteen, the five main volatile products were 3-hydroxy-2-pyrone, 2-furan-carboxylic acid, 2-furaldehyde, acetic acid, and 2-acetylfuran. DHA also undergoes a benzilic acid rearrangement in alkaline solution (42),... 

Although reaction between 3-hydroxy-2-pyrone 315a and 4-hydroxy-2-butenoate 396a (R = H) does not occur in refluxing benzene, the cycloaddition in CeHe containing PhB(OH)2 followed by treatment with HOCH2C-... 

Hydroxy-2-pyrone 162 was isolated (76ABC1287) from the ether ex-... 

The oyoloaddition of 3-hydroxy-2-pyrone 34 with an electron-deficient dienophile can be catalyzed by triethylamine as illustrated in Scheme 10 <95TL5939 00TL8317>. Reaction with methyl acrylate provided cycloadduct 37 as a mixture of endo exo- isomers (11 1) in 98% yield after 12 h at ambient temperature. No cycloaddition was observed when the reaction was conducted in the absence of base. 

Scheme 10. Base-catalyzed Diels-Alder cycloaddition of 3-hydroxy-2-pyrone 34...

Narasaka and coworkers have reported the IMDA reaction of 3-hydroxy-2-pyrone 34 (Scheme 36) with 4-hydroxy-2-butenoate 144, which was temporarily tethered with phenylboronic acid, to provide a single cycloadduct 147 in 75% yield <91S1171>. This elegant strategy was further elaborated by Nicolaou and coworkers for the synthesis of 151 as the C-ring intermediate in their initial synthetic endeavors towards the total synthesis of taxol <92JCS(CC)1118 95JACS624>. 

Both 9-epiamino derivatives of 9-deoxyquinine and 9-deoxyquinidine promote exo-selective Diels-Alder reaction of 3-hydroxy-2-pyrones with enones. Actually, great latitude exists for tuning the reaction by partial structural changes of the catalysts. ... 

DIELS-ALDER REACTIONS Benzocyclopropene. 1,2-BisC3-tosyIethoxycarbonyl)-diazene. Cyclobutadiene iron tricarbonyl. 1,2-Dicyanocyclobutene. Diethyl ketomalonate. 1,3,4,6-Heptatetraene. 2-Hydroxy-5-oxo-5,6-dihydro-2/f-pyrone. 3-Hydroxy-2-pyrone. Isopropylidene isopropylidenemalonate. Lithium tetra-methylpiperidide. 4-Methoxy-5-acetoxymethyl-o-benzoquinone. 4-Methoxy-5-methyl-o-benzoquinone. frans-l-Methoxy-3-trimethyl-silyloxy-l,3-butadiene. Per-fluorotetramethylcyclopentadiene. 4-Phenyl-l, 2,4-triazoline-3,5-dione. Potassium f-butoxide. 

In an effort to improve asymmetrical induction, Okamura and co-workers investigated the cinchona-alkaloid-promoted reaction of 3-hydroxy-2-pyrone with enantiomerically pure -acryloyloxazolid-inone dienophiles. These cycloadditions proceed smoothly at 0 °C to give bicyclic lactone adducts in good yields and with good to excellent levels of diastereocontrol. The diastereoselectivities depend... 

A full report has been published on the preparation of fused valerolactones from cyclopentadiene anions by condensations with epoxides, carboxylation, and finally cyclization (Scheme 26). Diels-Alder reactions of 3-hydroxy-2-pyrones usually lead to benzene derivatives by decarboxylation of the intermediate lactone. It has now been shown that these lactones can be isolated in good yields by suppression of the CO2 loss by carrying out the cycloadditions under a high pressure of carbon dioxide. 

The allylalkohol 6 turns out to be the obvious precursor of the protected diol 5, and 6 reasonably arises from a Shapiro coupling of cyclohexadienyllithium 7 with the cyclohexene-4-aldehyde 8 which is the product of oxidation and subsequent diol protection of the bicyclic hydroxylactone 9 the latter emerges from rearrangement of the Diels-Alder cycloadduct 13 of 3-hydroxy-2-pyrone 14 as the diene and 4-hydroxy-2-methyl-2-butenoate 15 as the electron-deficient dienophile. The cyclohexadienyllithium 7 originates from the sulfonylhydrazone of the ketone 10 which is, once again, a Diels-Alder cycloadduct of the protected 3-hydroxymethyl-2,4-dimethyl-l,3-pentadiene 12 and ketene 11 as the dienophile. 

In order to prepare the cyclohexenaldehyde 8, 3-hydroxy-2-pyrone 14 and ethyl 4-hydroxy-2-methyl-2-butenoate 15 are subjected to a Diels-Alder reaction in the presence of phenylboronic acid which arranges both reactants to the mixed boro-nate ester 19 as a template to enable a more efficient intramolecular Diels-Alder reaction with optimal control of the regiochemical course of the reaction. Refluxing in benzene affords the tricyclic boronate 20 as primary product. This liberates the intermediate cycloadduct 21 upon transesterification with 2,2-dimethylpropane-l,3-diol which, on its part, relaxes to the lactone 22. Excessive i-butyldimethyl-silyltriflate (TBSTf) in dichloromethane with 2,6-lutidine and 4-7V,A-dimethyl-aminopyridine (DMAP) as acylation catalysts protects both OH goups so that the primary alcohol 23 is obtained by subsequent reduction with lithiumaluminum-hydride in ether. 

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