Unsaturated y-lactonization

Unsaturated y-lactones, c.g., a- (23) and / -angelica lactone (24), are well known. Compounds 23 and 24 are both converted by alkaline catalysts into an equilibrium mixture in which 23 predominates, the amount of the hydroxy form (25) present at equilibrium being exceedingly small. True a-hydroxy furans are unknown, and, although the preparation of both a- and / -bydroxyfurans has been reported, these claims have often been refuted (see, e.g., reference 14). 

In contrast, (benzyloxymethoxymethyl)lithium underwent addition to the a,/(-unsaturated y-lactone in the nonchelated confonnation to give, after reductive desulfurization, a protected (S)-dihydro-4-(hydroxymethyl)-2(3/f)-furanone19. 

The 1,3-dipolar cycloadditions of nitrones (551), (595), (614), (615) and their enantiomers (595 ent), (614 ent), (615 ent) (Fig. 2.40) to a.p-unsaturated y-lactones, such as achiral D7 g and D-glycero D7 h, provide an interesting example of double asymmetric inductions. The reactions are kinetically controlled. However, on heating and at longer reaction times, the reversibility of the cycloaddition (595 + D7 h) was observed, and the presence of a more stable thermodynamic product (620) was detected. Moreover, in the case of lactone D7 h, a... 

Diastereoselective aldol condensations. This furan (1) can undergo condensation with aldehydes as a butenolide to form 8-hydroxy-a,(3-unsaturated--y-lactones (2). The diastereoselectivity can be controlled by the choice of catalyst. Lewis... 

Saturated and unsaturated y-lactones and 5-lactones which are synthesised from the corresponding acyclic hydroxy fatty acids by intramolecular esterification are important flavour compounds found ubiquitously in fruits and also in milk and fermentation products in parts-per-million concentrations. The natural lac-... 

Enone 149, after treatment with bromine and then with anhydrous potassium carbonate gives unsaturated y-lactone 150 (73%). After hydrogenation of the double bond A and reaction with NaH in the presence of ethyl formiate, 151 is obtained in 91% yield. Then, the double bond A7 is regenerated and the aldehyde is protected in the form of acetal (54% yield). 

Normal-phase HPLC (NP-HPLC) and reverse-phase HPLC (RP-HPLC) are used to purify the final products of these chemical derivatives. For NP-HPLC a gradient of hex-ane/MeOH/THF works well for separations. Usually, acetogenins are placed on RP-HPLC because they are more easily detected in the low-ultraviolet range. The weak UV absorbance at 210 nm for the a,p-unsaturated y-lactone is one reason to use an RP-HPLC system. This weak absorbance is often overshadowed by impurities that have larger absorbances. Another reason for choosing RP-HPLC is because the solvent cutoff for the RP solvents is lower than NP solvents. In their pure form, acetogenins are white, waxy substances. 

Reduced furan rings occur in many important anhydrides, lactones, hemiacetals and ethers. Maleic anhydride is frequently used as a dienophile in Diels-Alder reactions and it is a component of alkyd resins. Several unsaturated y-lactones are natural products, while the furanose sugars are cyclic hemiacetals. 

A novel entry to decahydrocyclopentacyclooctene derivatives via the intramolecular photocycloaddition of fused a,/3-unsaturated y-lactones has been developed (80CC1011). Irradiation of the butenolide (153) in acetone solution gave both the fused and bridged photoadducts (154) and (155) (2-3 1). The major adduct was hydrolyzed, oxidized and esterified to afford (156). Reductive cleavage of the unsaturated keto ester (156) with lithium in ammonia afforded a five-component mixture of a,/3- and /3,y-unsaturated esters. Equilibration with 0.1M sodium methoxide in methanol converted the mixture into a single a,j8-unsaturated ester (157 Scheme 34). This annelative two-carbon ring expansion method may find application in the synthesis of ophiobolin and ceroplastol sesterterpenes. 

In the second group the starting molecule belongs to another class of oxygenated heterocycle, such as a coumarin, flavone, chroman, a,fi-unsaturated y-lactone, or S-sultone. 

A new synthesis of ( )-menthofuran (155) has been described which involves a three-step reaction sequence from the cyclohexanone (152) via direct C-alkylation with ethyl 2-iodopropionate to give (153) (Scheme 35). Hydrolysis of the diester (153) with hydrochloric acid afforded 3,6-dimethyl-2,4,5,6,7,7a-hexahydrobenzofuran-2-one (154). The final step in the sequence was the conversion of the a,/3-unsaturated y-lactone ring into the furan ring by reduction with lithium aluminum hydride and 2-propanol to afford (i)-menthofuran (155) in satisfactory yield (80JOC1517). 

Reduction of unsaturated y-lactones (e.g. 91) has been applied to the synthesis of furanophanes lactonization of (92) followed by reduction with DIBAL gives (93) (70TL11). 

The chemo-, regio-, and stereo-selective 1,3-dipolar cycloaddition of C-aryl-iV-phenylnitrones with 3,5-bis(arylidine)-l-methylpiperidin-4-ones produced mono- and bis-spiroisoxazolidines, with the former predominating.52 The 1,3-dipolar cycloaddition of five-membered cyclic nitrones with a, fl-unsaturated y-lactones provides an interesting example of a double asymmetric induction.53 Eu(fod)3 catalysed the ... 

Differences in activity are observed when a double bond is present or not in the lactone ring.13,25 However, several compounds without an a,(3-unsaturated-y-lactone system present higher levels of activity than GR-24. This is true for dihydroparthenolide (56) and the guaianolides 68 and 69. As these compounds cannot react in a Michael addition fashion, other recognition mechanisms different from that proposed by Zwanenburg31 could be operating in this case. 

The [2 + 2]-photocycloaddition chemistry of a,(3-unsaturated lactones has been widely explored. The factors governing regio- and simple diastereoselectivity are similar to what has been discussed in enone photochemistry (substrate class Al, Section 6.2). The HT product is the predominant product in the reaction with electron-rich alkenes [84]. A stereogenic center in the y-position of ot,P-unsaturated y-lactones (butenolides) can serve as a valuable control element to achieve facial diastereoselectivity [85, 86]. The selectivity is most pronounced if the lactone is substituted in the a- and/or P-position. The readily available chiral 2(5H)-furanones 79 and 82 have been successfully employed in natural product total syntheses (Scheme 6.30). In both cases, the intermediate photocycloaddition product with 1,2-dichloroethylene was reductively converted into a cyclobutene. In the first reaction sequence, the two-step procedure resulted diastereoselectively (d.r. = 88/12) in product 80, which was separated from the minor diastereoisomer (9%). Direct excitation (Hg lamp, quartz) in acetonitrile solution was superior to sensitized irradiation (Hg lamp, Pyrex) in acetone, the former providing the photocycloaddition products in 89% yield, the latter in only 45%. Cyclobutene 80 was further converted into the monoterpenoid pheromone (+)-lineatin (81) [87]. In the second reaction... 

Sharpless catalytic asymmetric dihydroxylation of 2-vinylfuran followed by treatment of the diol product with NBS, and subsequent Jones oxidation and Luche reduction provided a highly functionalized a,(1-unsaturated y-lactone in 70% yield overall giving a key intermediate in the synthesis of phomopsolide C <02TL8195>. Similar procedures were adopted by the same authors to synthesize 2-deoxy and 2,3-dideoxyhexoses <02OL1771>. As depicted below, Sharpless kinetic resolution was also used to prepare a pyranone from a furfuryl alcohol in 38% yield, which served as the intermediate in the synthesis of (+)-isoaltholactone <02T6799>. 

Jacobs and Scott studied the hydrogenation of various unsaturated y- and 8-lactones over Adams platinum in ethanol.93 Similar to enol esters, these enol lactones are readily hydrogenolyzed over platinum, as seen in the examples shown in eq. 13.48. In contrast, hydrogenolysis takes place only slightly with an a,P-unsaturated y-lactone 50 (eq. 13.49). The saturated lactones were not reduced at all under the reaction conditions. 

A similar lactone was prepared previously by Gilman and coworkers.343 Oxidation of 2-acetoxyfurans with bromine yields an a,jS-unsaturated y-lactone. When the reaction is carried out in carbon tetrachloride a y-bromobutenolide forms, while in a mixture of acetic acid and acetic anhydride solvolysis occurs, with the formation of y-acetoxybutenolide.242... 

A similar convergent synthetic strategy was applied in our synthesis of annona-cin, using sequential assembly of the three key fragments, aldehyde 29, phospho-nium 30, and alkyne 14 (Scheme 10-9). In this synthesis, the a,p-unsaturated-y-lactone unit was constructed after completion of the linear skeleton. A modified method was applied into the synthesis of segment 3 (Scheme 10-5), in which the six carbons, as well as two chiral centers from D-glucono-8-lactone, were all incorporated into the final target. Therefore, the efficiency of the whole... 

Less frequently, unsaturated 1,4-ketoacids were employed and these 207-209 qj. hydrazones afford 12 directly. Synthesis of 12 is also possible from unsaturated y-lactones 210-21S S-bromo-, " 3-alkylthio-, or 2-hydroxy-l,4-ketoacids. The reaction takes place with simultaneous elimination of water or other residues, although it is claimed that in some cases the elimination of water is slower since the corresponding 4-hydroxy derivatives (13) were isolated.However, the structure of the latter compounds... 

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