Unsaturated lactones Butenolides

Diazotisation of (5)-glutamic acid results in loss of N2 with formation of strained a-lactone (28) via an internal 8 2 displacement, followed by a second Si, 2, giving a-lactone (29) with overall retention. Conversion to unsaturated lactone (butenolide) (30) is standard. Lithium dimethylcuprate adds with 1,2-diastereoselection exclusively anti to the silyloxymethyl substituent, and the resulting enolate undergoes electrophilic hydroxylation anti to the newly formed stereocentre giving (31). 

One of the earliest and most important discoveries in metal-catalyzed asymmetric synthesis is Sharpless s Ti-catalyzed epoxidation of allylic alcohols. A mere mention of all the total syntheses that have used this technology would require a separate review article Here, we select Trost s masterful total synthesis of solamin (100, Scheme 14), for its beautiful and multiple use of Sharpless s asymmetric epoxidation.1161 Optically pure epoxy alcohol 95 is converted to both epoxy iodide 96 and diol 97 The latter two intermediates are then united to give 98, which is oxidized and converted to dihydrofuran 99 by a Ramberg-Backlund transformation. The Re catalyzed butenolide annulation that is used to afford the requisite unsaturated lactone only adds to the efficiency of this beautiful total synthesis. 

Rauter s group exploited the synthesis of sugar derived bicyclic butenolides ( e.g. 140, Fig. 44),60 which possess cytotoxic and antitumor activities. The key structural feature of such compounds consists of the presence of the a,(3-unsaturated lactone, which allows them to act as Michael acceptors for the addition of enzymes nucleophiles. 

For a long period, a butenolide or a 2-pyrone ring in the 17y -position of the steroid system has been considered an essential feature for digitalis-like cardiotonic activity. However, it turned out that the unsaturated lactone ring can be replaced without loss of activity by some other moieties, including the 4-pyridazinyl group. 

Triphenyl phosphite ozonide, 334 Unsaturated lactones a-Alkylidene-7-lactones Chloromethyldiphenylsilane Butenolides... 

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... 

Substituted 2(5ff)-furanones were also synthesized from allenyl alcohols 36 (Eq. 18) [28]. In the presence of 1 mol % of Ru3(CO)12, Et3N and 10 atm CO, 36 underwent cyclocarbonylation to afford the butenolides 37 in excellent yields. Remarkably, the ruthenium(0)-catalyzed cyclocarbonylation protocol is applicable to the syntheses of 6-8-membered a,/ -unsaturated lactones 38-40 in good yields (Eq. 19) [28,29]. 

Oxidation of a cyanohydrin derived from a conjugated aldehyde (as the 0-TMS derivative) using py-ridinium dichromate (PE)C) in DMF gave an a,3-unsaturated lactone (5 -butenolide) as the major product (equation 12). Simple nonconjugated cyanohydrins are not satisfactory substrates for the synthesis of acyl cyanides using PDC, because they seem to add to the initially formed acyl cyanides, leading ultimately to cyanohydrin esters. Oxidation of cyanohydrin to acyl cyanides can be carried out either by means of manganese dioxide, ruthenium-catdyzed oxidation with t-butyl hydroperoxide or NBS. ... 

A fundamentally different route to unsaturated lactones involves the oxidation of furanes e.g. 320) with NBS and subsequent debromination with Zn to give the butenolide (321 equation 112). The alternative regioisomer (323) may be prepared by using MCPBA as the oxidant to furnish the hydroxy lactone (322), which is then reduced to (323 equation 113). ... 

Diels-Alder cycloaddition of the racemic butenolide reported in reaction C with an enantiomerically pure diene leads to the formation of a single cycloadduct and allows recovery of the unreacted (S)-enantiomer of the unsaturated lactone in 36% yield and > 98% e.e. High pressure and ZnCl2 catalysis were applied to ensure milder and more stereoselective reaction conditions [31]. 

Unsaturated lactones occur widely in nature (1.) and possess an unusually wide range of biological activity (2.). Evaluation of these natural products, commonly called butenolides, has shown them to have promise as insecticides (3), herbicides (4.), and plant growth regulators (5). Discovery of butenolide activity has stimulated development of syntheses of these valuable compounds ( ). 

Acylbutyrolactones (55) have been prepared in high yields by a rearrangement reaction between j3y-butenolide (54) and an aldehyde in the presence of boron trifluoride etherate. Japanese workers have also reported a study of the scope of photoadditions of olefins and acetylenes to unsaturated lactones to give products of type (56). Conditions have been recorded for the reduction of a-hydroxyamino-butenolides to the corresponding a-aminobutyrolactones. 

Triethylammonium formate is another reducing agent for q, /3-unsaturated carbonyl compounds. Pd on carbon is better catalyst than Pd-phosphine complex, and citral (49) is reduced to citronellal (50) smoothly[55]. However, the trisubstituted butenolide 60 is reduced to the saturated lactone with potassium formate using Pd(OAc)2. Triethylammonium formate is not effective. Enones are also reduced with potassium formate[56]. Sodium hypophosphite (61) is used for the reduction of double bonds catalyzed by Pd on charcoal[57]. 

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... 

Both butenolides 50 and 51, one tethered to an a, -unsaturated ester, the other to an unsaturated nitrile, failed to undergo cyclization. Instead, the C=C 7i-bond of the butenolide was reduced, leading cleanly and efficiently to saturation of that bond, and to compounds 54 and 55, respectively. In contrast, the corresponding alkylidene malonate 52, as well as the alkylidene malononitrile 53, both cyclize to afford a mixture of the cis-anti-cis and cis-syn-cis linearly fused lactones 56 and 57. 

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. 

Many examples of natural furans are recorded as having been prepared from five-membered heterocycles such as 2(5H)-furanones (butenolides), which are reduced to furans with diisobutylaluminum hydride. The facile elimination of selenoxides derived from a-phenylseleneyl-y-lactones with formation of endocyclic a,/3-unsaturated butenolides is reported (75JOC542) as a useful route to 2,4- and 2,3,4-substituted furans via their corresponding butenolides. The mixture of dihydrofurans obtained from the tosylhydrazone of tetrahydro-2-furanone (Scheme 88) was oxidized to furans by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (66CJC1083). 

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