A-Methylene--y-butyrolactones

Further examples of the utility of the allylic sulfoxide-sulfenate interconversion in the construction of various biologically active natural products include intermediates such as the /Miydroxy-a-methylene-y-butyrolactones (e.g. 63)128 and tetrahydrochromanone derivative 64129. Interestingly, the facility and efficiency of this rearrangement has also attracted attention beyond the conventional boundaries of organic chemistry. Thus, a study on mechanism-based enzyme inactivation using an allyl sulfoxide-sulfenate rearrangement has also been published130 131. 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

A variety of functionalities, tether lengths, and alkene substitution patterns were tolerated (Equation (35)).52,53 Of particular significance is the synthesis of a-methylene-y-butyrolactone 55, as only Zhang had reported successfully using Alder-ene chemistry to gain access to this novel system (see Section 10.12.4.3). The reaction was sensitive to the length of the tether, since there was a marked decrease in yield for the formation of the six- and seven-membered carbocycles (53 and 54, respectively) compared to the five-membered case 52. 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

Danieli et al. 116), both of which utilize an alkylation process of 1-methyl-3,4-dihydro-(3-carboline (150) in the key ring-forming step. In the first one, treatment of 150 with a-methylene- y-butyrolactone gave enamide 172, which, when reduced with lithium aluminum hydride, afforded indolo[2,3-a]quinolizine derivative 173. The desired ethylidene substituent at C-20 has been developed from the hydroxyethyl side chain in a four-step sequence as shown below. 

Allenyl ethers are useful key building blocks for the synthesis of a-methylene-y-butyrolactones [129, 130], The synthesis of the antileukemic botryodiplodin was accomplished with the crucial steps briefly presented in Scheme 8.56. Bromoallenyl ethers 225 were easily prepared by base-induced isomerization from the corresponding /3-bromoalkyl alkynyl ether compounds and then subjected to electrophilic bro-mination with NBS. The resulting acetals 226 were converted into 2-alkoxy-3-methy-lenetetrahydrofurans 227 by dehydrohalogenation of the alkenyl bromide unit to an alkyne and subsequent radical cyclization employing tributyltin hydride [130],... 

Recently, a cell-permeable inhibitor of the human Gcn5 named MB-3 8 was discovered (Figure 11.3). This compound is structurally related to the a-methylene-y-butyrolactone class of compounds, a common structural element in a plethora of natural products. MB-3 was developed by appropriate derivatization of the basic y-butyrolactone motif without the arbitrary screening of large compound libraries. Interestingly, the length of the aliphatic side-chain is crucial for biological activity [17, 18]. 

When (R,R)-Me-Duphos, (R,R,R,R)-BICPO [9] or BINAP [10] is used, the rhodium-catalyzed asymmetric cycloisomerization of 3 affords 4 with up to >99.5% enantiomeric excess (Scheme 7 2). This methodology was applied to the synthesis of functionalized a-methylene-y-butyrolactone derivatives 6 such as (-i-)-pilocarpine 7 (Scheme 7.3) [11]. 

Diiodomethane-Zinc-Titanium(IV) isopropoxide, 115 Iodomethyltrimethylsilane, 315 Tributyl(iodomethyl)tin, 314 a-METHYLENE-y-BUTYROLACTONES (see Un-saturated Lactones)... 

Homoallyl chloroformates cyclize catalytically to a-methylene- y-butyrolactones in moderate yields at 130 C with tetrakis(triphenylphosphine)palladium(0) (equation 44).l0s This reaction only gives 1-2% of product when it is carried out intermolecularly. The presumed intermediate in the homoallyl chlorofor-mate cyclization has been isolated and kinetic measurements show that that cyclization is inhibited by an excess of triphenylphosphine. A chelated ir-alkene intermediate is proposed.1 6... 

An aluminium-catalysed tandem Claisen-ene sequence has been developed for the synthesis of homoallylic alcohols (89) and thence a-methylene-y-butyrolactones (90) in good overall yields. Extensive investigation has revealed that Et2AlSPh catalyses Claisen rearrangement of ft -substituted allyl vinyl ethers (85) into 0,5-aluminium... 

Radical cyclization with iodine atom transfer of a highly functionalized propiolic ester 103 using dibenzoyl peroxide as an initiator gave the a-methylene-y-butyrolactone 104 in good yield [95T11257]. The relative stereochemistry at carbon atoms 4 and 5 are established during the reaction. The intermediate 104 has been converted to the anti-tumor agent (-)-methylenolactocin 105. 

Several a-aminomethylatedy-oxoesters 173 can be prepared in good yield. However, for reasons not understood so far compounds 169 with R1 = H do not undergo this C-C-bond forming cyclopropane cleavage. Products 173 can serve as precursors for syntheses of acrylate derivatives or a-methylene y-butyrolactones (Eq. 75)91). 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

To ascertain the relative stereochemistry of 213, attempts to isomerize it into the thermodynamically more stable cw-isomer 212 were undertaken. This plan could be realized as anticipated by catalysis with trimethylsilyl triflate in the presence of hexa-methyl disilazane (cf. section 4.5.1). However, without this base an unexpected desi-lylation, ring enlargement, and condensation occurs finally affording a-methylene y-butyrolactone 214 in high yield. This type of product could also be prepared by use of trimethylsiloxycyclopropanes 215 and 218, respectively (Eq. 88, 89). In the first case, the intermediate unsaturated ester 216 has been isolated and further converted to lactone 217 by acid treatment96 b). 

The reaction can be extended to allene-aldehydes. Kang et al. [16] reported on the Ru3(CO)12-catalyzed cyclocarbonylation of allene-aldehydes or allene-ketones leading to a-methylene-y-butyrolactones (Eq. 6). The fact that a ketone moiety also functions as a two-atom unit indicates that the reaction includes metallacycle 5 as an intermediate. 

Ethyl a-(bromomethyl)acrylate has proved to be an excellent reagent for conversion of aldehydes and ketones, both acyclic and cyclic, into the corresponding a-methylene-y-butyrolactone derivatives4"9 in a Re-formatsky type reaction. The yield was excellent in the case of several spiro a-methylene-y-butyrolactones.10 Synthetic a-methylene-y-butyrolactone derivatives have been shown to possess antitumor activity.5 6,7 1112 Ethyl a-(bromomethyl)acrylate has also proven of value in the synthesis of alkylated products of enol ethers of cyclohexane-1,3-dione.13... 

Eudesmanolide sesquiterpene lactones (G6 G6 C40L) include a variety of variously cytotoxic compounds. The antifeedants alantolactone and isoalantolactone (helenin being a mixture of the two) (C6 ] C5 C40L=CH2) are antimicrobial. The pro-apoptotic activity of these compounds may derive from the reactivity of the a-methylene-y-butyrolactone ring... 

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