5-Menthyloxy-2 -furanone

In connection with the total synthesis of grandisol, an asymmetric addition of ethylene on chiral heterocyclic aminals and ketals was examined (Scheme 23). The selectivity can be high, with a preferred approach of ethylene from the less hindered side, especially when chiral pyrrolidone 97 or furanones 100 were used in place of cyclic enones [70]. The diastereoisomeric excess of 101 or 102 remains modest with 5-menthyloxy furanone, even if the dark addition of nucleophiles or radicals on 100 occurs with a total facial selectivity. From a detailed analysis of the dependence of the product ratio with temperature and substituents, it was proposed that a pyramidalization of the (3-carbon in the relaxed of the... 

A versatile synthetic route to enantiomeric ally pure Diels-Alder adducts was deduced and found dependent on the application of enantiomerically pure 5-methoxy-174a (R=Me) and 5-(l-menthyloxy)-2(5//)-furanones 174b (R = menthyl), which were expected to undergo tt-face-selective cycloaddition with dienes. The reaction was effected by heating no Lewis acid catalysts were required (Scheme 55) (88JOC1127). 

The two diastereomers 210a,b are epimeric at the carbon bearing the methoxy group i.e., they are the result of the concurrent endo- and exo-addition of the diene 208 to the 5-menthyloxy-2(5//)-furanone (91TA1247). 

It was found that the introduction of a sulfonyl substituent considerably enhances the furanone reactivity in Diels-Alder reaction. Thus, (55)-5-(reacted with cyclopentadi-ene at room temperature in benzene with complete conversion to the adduct 212. Also, the reaction of 211 with 2,3-dimethyl-1,3-butadiene was readily performed in refluxing benzene to give the adduct213 in 98% yield (Scheme 57) (91TL7751). 

The use of chiral dipolarophiles, such as the nitrile oxide additions to chiral furanones, have received much interest. The cycloaddition of various 1,3-dipolar reagents to the enantiomeric ally pure furanones 170 and 227 showed excellent diastereofacial control by the menthyloxy substituent, especially in nitrone and nitrile oxide additions (cf. Table II) (88TL5317). 

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

It was stated that tertiary amines 304 derived from pyrrolidines [R = alkyl, benzyl, SiMcs, Si(t-Bu)2Me] add very efficiently (yields up to 94%) to (5R)-5-menthyloxy-2(5//)-furanone 170 under photosensitized conditions to give the isomeric adducts 305 and 306 (Scheme 82) (99TL3169). 

In y-alkoxyfuranones the acetal functionality is ideally suited for the introduction of a chiral auxiliary simultaneously high 71-face selectivity may be obtained due to the relatively rigid structure that is present. With ( + )- or (—(-menthol as auxiliaries it is possible to obtain both (5S)- or (5/ )-y-menthyloxy-2(5//)-furanones in an enantiomerically pure form293. When the auxiliary acts as a bulky substituent, as in the case with the 1-menthyloxy group, the addition of enolates occurs trans to the y-alkoxy substituent. The chiral auxiliary is readily removed by hydrolysis and various optically active lactones, protected amino acids and hydroxy acids are accessible in this way294-29s-400. 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

Very high levels of diastereomeric and enantiomeric excess have been observed in the cycloadditions of (5R) and (5S)-5-menthyloxy-2(5H)-furanones 28 and 29 (Figure 2.2), readily available from furfural and d- and /-menthol [28]. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

In a full study devoted to the use of 5-(l )-menthyloxy-2(5H)-furanone in 1,3-dipolar cycloadditions, use of ultrasonic conditions accelerates the reaction (30 min) giving diastereomerically pure adduct in high yield. This adduct has the trans-configuration ( H NMR). Cesium fluoride leads to unidentifiable products.441 The adduct may serve as a precursor to 3,4-c -(bis) functionalized pyrrolidines. 

Recently, an efficient photocatalytic method has been reported for the radical addition of tertiary amines to electron-deficient double bonds (Scheme 59) [134]. N-methylpyrrolidine was added to the furanone 216. The radical attack occurred specifically anti with respect to the menthyloxy substituent, and the adducts 217 and 218 were isolated in high yields in the presence of sensitizers having electron-rich substituents or in the presence of semiconductors like Ti02-However, the configuration of the chiral center in the a-position of the nitrogen atom could not be controlled. Although the diastereoselectivity was almost the... 

Table 28 Noncatalyzed Dids-Alder Reactions of 5-(Menthyloxy)-2(5//)-furanone with 1,3-Dienes (Scheme 101)...

B. (5S)-(d-Menthyloxy)-2(5H)-furanone. A 500-mL, round-bottomed flask equipped with a magnetic stirring bar, 10-mL Dean-Stark trap, and reflux condenser is charged with d-menthol (51.9 g, 0.330 mol), 5-hydroxy-2(5H)-furanone (37.3 g, 0.370 mol), D-(-i-)-camphorsulfonic acid (3.96 g, 0.170 mol), and 190 mL of dry benzene (Note 8). The stirred suspension is heated to reflux under argon with an oil bath preheated to 100°C (Note 9). After 1-2 hr, a total of 5.1 mL of water is collected and no residual menthol is apparent by TLC analysis (Note 10). The reaction mixture is cooled in an ice bath and treated carefully with 100 mL of saturated sodium bicarbonate solution. After completion of the addition, stirring is maintained for 90 min as the mixture is allowed to warm to room temperature. The... 

The synthetic utility of (5S)- and (5R)-menthyloxy-2(5H)-furanones has been extensively explored and is well documented. The ready availability of these enantiomerically pure butenolides via the singlet photooxygenation of furfuraF and their wide range of reactivity contribute to their popularity as chiral building blocks. The present procedure for the preparation of the title compound and the useful epimerization step are modifications of methods originally reported by Feringa and co-workers. ... 

Bertrand, S., Glapski, C., Hoffmann, N., Pete, J. P, Highly Efficient Photochemical Addition of Tertiary Amines to Electron Deficient Alkenes. Diastereoselective Addition to (5R) 5 Menthyloxy 2 5H furanone, Tetrahedron Lett. 1999, 40, 3169 3172. 

Methyl-5-(+)-menthyloxy-2[5f/]-furanone (minor isomer, mixture with the main isomer) ... 

A solution of 6 g of (+)-(55)-4-methyl-5-menthyloxy-2[5//]-furanone 1.2.8b in 250 mL of acetone is carefully flushed with ethylene and irradatiated for 8 h at -25°C (quarz glass immersion well with vacuum jacket, HPK 125 (Philips)). The solvent is evaporated and the residue is chromatographed (silica gel, 3% ethylacetate/cyclohexane, column 210 mL) in order to seperate the diastereomers. Yield quant., 9% de for (l/ ,45,55)-4-(+)-menthyl-oxy-5-methyl-3-oxa-2-oxobicyclo[3.2.0]heptane, major diastereomer [a]j) = +143.4° (1.13,CHCl3). 

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