Lactones allylic reactions

Several indium-mediated intramolecular carbonyl allylation reactions have been investigated, and it has been found that these reactions provide an easy access to a variety of cyclic compounds. The intramolecular cyclization of 49a-c mediated by indium in aqueous media proceeds smoothly to afford carbocyclic systems containing y-hydroxy-Q -methylene esters 50a-c, which either spontaneously or readily cyclize to give fused o -methylene-y-butyrolactones 51a-c (Scheme 52). The same cyclization of 49d is too slow to compete with the side-reaction, in which the bromide is substituted by a hydroxy group. The ring junction stereochemistry of fused lactones 51 has been found to be cis in all cases. Of the two possible transition states, the one leading to the m-fused compounds is preferred, because the chair-chair conformation is favored over the chair-boat conformation.209... 

Tsuji-Trost allylation reactions offer multiple pathways to tetrahydrofuran synthesis including C-C bond-formation steps. A palladium-catalyzed sequence of allylic alkylation and Hiyama cross-coupling provides a convenient synthesis of 4-(styryl)-lactones (Scheme 67) <2006SL2231>. 

The cyclization of ort/zo-allyl phenols was reported by Murahashi in the late 1970s. The reaction of the 2-(2-cyclohexenyl)phenol (Equation 16.110) was one of the early examples of Wacker-type reactions with alcohol nucleophiles and has been re-investigated in more recent years with chiral catalysts. Intramolecular reactions of alkene-ols and alkenoic acids form cyclic ethers and lactones. These reactions were reported by Larock and by Annby, Andersson, and co-workers, and examples are shown in Equations 16.111 and 16.112. °° ° The use of DMSO as solvent was important to form the lactone products. More recently, reactions with alcohols were reported by Stoltz to form cyclic ethers by the use of pyridine and related ligands in toluene solvent. - The type of ligand, whether an additive or the solvent, is crucial to the development of these oxidative processes. However, the features of these ligands that lead to catalysis are not well understood at this time. 

Waldmann and coworkers later developed and explored the solid-supported carbonyl allylation reactions for the stereoselective solid-phase synthesis of a collection of NP-inspired 8-lactones. To identify reaction conditions that would give rise to the allylation products with high enantioselectivity and in high yield, immobilized aldehyde 26 was synthesized as model compound and was then subjected to allylation with different chiral allylboron reagents. After some experimentation, it was found that treatment of the resin-bound aldehyde with 4 equiv of D-Ipc2BAll 28 at 78°C in THF/ether 5 1 (v/v) followed by... 

Scheme 7.6. Synthesis of 5-lactones using enantioselective solid-phase allylation reaction.

Homoenolate Reactivity. Since the previous e-EROS report, a number of examples have been described using the cyclopropanone acetals. Thus, the zinc homoenolate, known to undergo a highly regioselective and stereoselective Sn2 allylation reaction (eq 6), is used in the synthesis of moenomycin analogues. The activated titanium homoenolate reacts with aldehydes or ketones to give y-hydroxy esters that serve as precursors to y-lactones. ... 

In the carbonyl allylation with allylic bromides mediated by tin(ll) halide, organotin(iv) compounds were generally postulated (Mukaiyama et al, 1980). Tin(ll) chloride in the acidic aqueous medium MeOCHjCHjOH/HjO/AcOH/HCl (Uneyama et al, 1986b) or tin(ll) chloride with Amberlyst 15 in THF/HjO (Talaga et al, 1990) served as the promotor in allylation reactions yielding a-methylene-y-lactones. 

Blum et al. [38] obtained a highly effective synthesis of trisubstituted y-butenolide 52 from allyl allenoate 51 via sequential Au-catalyzed cyclization (oxyauration) and the following allylation reaction of vinyl Au species (Scheme 24). This reaction was successfully applied to the synthesis of allylated isocoumarins containing six-membered lactone structures. 

Chen et al. [112] investigated organocatalytic enantioselective y-allylation reaction of indolone derivative 164 with a-angelica lactone 140a in the presence of 3-isoquinidine-derived catalyst 166 (Scheme 66). 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

The reaction of perfluoroalkyl iodides with alkenes affords the perfluoro-alkylated alkyl iodides 931. Q.a-Difluoro-functionalized phosphonates are prepared by the addition of the iododifluoromethylphosphonate (932) at room temperature[778], A one-electron transfer-initiated radical mechanism has been proposed for the addition reaction. Addition to alkynes affords 1-perfluoro-alkyl-2-iodoalkenes (933)[779-781]. The fluorine-containing oxirane 934 is obtained by the reaction of allyl aicohol[782]. Under a CO atmosphere, the carbocarbonylation of the alkenol 935 and the alkynol 937 takes place with perfluoroalkyl iodides to give the fluorine-containing lactones 936 and 938[783]. 

Many examples of stereospecific allylation consistent with the above mechanism have been reported. As one example, the regioselective and highly diastereoselective allylation of the lactone 17 with the optically active allylic phosphate 16 proceeded with no appreciable racemization of the allylic part to give the lactones l8 and 19, and the reaction has been used for the synthesis of a polypropionate chain[26]. 

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

The reaction can be applied to the synthesis of q, /3-unsaturated esters and lactones by treatment of the ketene silyl acetal 551 with an allyl carbonate in boiling MeCN[356]. The preparation of the q,, 3-unsaturated lactone 552 by this method has been used in the total synthesis of lauthisan[357]. 

The slow oxidation of primary alcohols, particularly MeOH, is utilized for the oxidation of allylic or secondary alcohols with allyl methyl carbonate without forming carbonates of the alcohols to be oxidized. Allyl methyl carbonate (564) forms 7r-allylpalladium methoxide, then exchange of the methoxide with a secondary or allylic alcohol 563 present in the reaction medium takes place to form the 7r-allylpalladium alkoxide 565, which undergoes elimination of j3-hydrogen to give the ketone or aldehyde 566. The lactol 567 was oxidized selectively with diallyl carbonate to the lactone 568 without attacking the secondary alcohol in the synthesis of echinosporin[360]. 

The reaction can be applied to allyl malonates. Alkylation of diallyl mal-onate (734) with bromoacetate and acetoxymethylation afford the mixed triester 735. Treatment of the tricster 735 with Pd catalyst affords allyl ethyl itaconate (736). In a similar way, a-methylene lactone and the lactam 737 can be prepared[462]. 

The first step of the reaction is the oxypalladation of the triple bond with PdCl2 as shown by 228 to form the alkenylpalladium species 229, and the Pd is displaced with proton to regenerate Pd(TI) species and the lactone 224. The alkenylpalladium species 229 can be utilized for further reaction. When allyl chloride (230) is added, double bond insertion is followed by elimination of... 

PdCb, and the allylated lactone 232 is formed. Regeneration ofPdCl2 as shown by 231 makes the reaction catalytic. In this reaction, use of the Li salt 227 of 4-pentynoic acid (223) is recommended. Reaction of lithium 3-octynoate (233) with allyl chloride affords the unsaturated lactone 234, which is converted into the 7-keto acid 235 by hydrolysis[126]. 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

There appear to be few examples of the formation of azetidin-2-ones by closure of the C(2) —C(3) bond. One reaction which fits into this category involves reaction of the iron carbonyl lactone complexes (144) with an amine to give the allyl complexes (145) which on oxidation are converted in high yield to 3-vinyl-/3-lactams (146) (80CC297). 

Pd-catalyzed intermolecular coupling reactions of allyl alkynoates with formation of bioactive y-lactones 98SL115. 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

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