Lactones unsaturated carboxylic acids

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

Rearrangements and other side-reactions are rare. The ester pyrolysis is therefore of some synthetic value, and is used instead of the dehydration of the corresponding alcohol. The experimental procedure is simple, and yields are generally high. Numerous alkenes have been prepared by this route for the first time. For the preparation of higher alkenes (> Cio), the pyrolysis of the corresponding alcohol in the presence of acetic anhydride may be the preferable method." The pyrolysis of lactones 9 leads to unsaturated carboxylic acids 10 ... 

PGF2a- The cyclopentane ring of the Corey lactone (9) is the host of four contiguous stereogenic centers. Retrosynthetic simplification of 9 provides 10, a construct which is more complex than 9 Nevertheless, intermediate 10 possesses structural features that satisfy the requirement for the iodolactonization transform. The iodolactone in 10 constitutes the retron for the iodolactonization transform.11 Cleavage of the indicated bonds in 10 sacrifices two of the five stereocenters and provides unsaturated carboxylic acid... 

The adjacent iodine and lactone groupings in 16 constitute the structural prerequisite, or retron, for the iodolactonization transform.15 It was anticipated that the action of iodine on unsaturated carboxylic acid 17 would induce iodolactonization16 to give iodo-lactone 16. The cis C20-C21 double bond in 17 provides a convenient opportunity for molecular simplification. In the synthetic direction, a Wittig reaction17 between the nonstabilized phosphorous ylide derived from 19 and aldehyde 18 could result in the formation of cis alkene 17. Enantiomerically pure (/ )-citronellic acid (20) and (+)-/ -hydroxyisobutyric acid (11) are readily available sources of chirality that could be converted in a straightforward manner into optically active building blocks 18 and 19, respectively. 

Curran s synthesis of ( )-A9(l2)-capnellene [( )-2] is detailed in Schemes 30 and 31. This synthesis commences with the preparation of racemic bicyclic vinyl lactone 147 from ( )-norbomenone [( )-145] by a well-known route.61 Thus, Baeyer-Villiger oxidation of (+)-145 provides unsaturated bicyclic lactone 146, a compound that can be converted to the isomeric fused bicyclic lactone 147 by acid-catalyzed rearrangement. Reaction of 147 with methylmagne-sium bromide/CuBr SMe2 in THF at -20 °C takes the desired course and affords unsaturated carboxylic acid 148 in nearly quantitative yield. Iodolactonization of 148 to 149, followed by base-induced elimination, then provides the methyl-substituted bicyclic vinyl lactone 150 as a single regioisomer in 66% overall yield from 147. 

Like unsaturated ketones, a,0-unsaturated carboxylic acid derivatives, e.g. lactones and anhydrides, undergo cycloadditions to alkenes. As for the preparative conditions (direct irradiation or sensitized experiments) these compounds are situated somewhere in between enones on the one side and olefins on the other. 

Limited progress has been achieved in the enantioselective hydrogenation of a,/ -unsaturated carboxylic acid esters, amides, lactones, and ketones (Scheme 26.10). The Ru-BINAP system is efficient for the hydrogenation of 2-methy-lene-y-butyrolactone, and 2-methylene-cyclopentanone [98]. With a dicationic (S)-di-t-Bu-MeOBIPHEP-Ru complex under a high hydrogen pressure, 3-ethoxy pyr-rolidinone could be hydrogenated in isopropanol to give (R)-4-ethoxy-y-lactam in 98% ee [39]. 

Gassman and co-workers have recently investigated the photoinduced cy-clization of y,5-unsaturated carboxylic acids to y-lactones [100]. 5-Methyl-4-hexenoic acid 51 is converted into the radical cation 52. The cyclization of 52 is expected to yield the distonic radical cations 53 and 54, which leads to the anti-Markonikow products 55 and 56 in ratio 5 1. Fine-tuning of the sensitizer improved combined yields up to 89% [101],... 

Oxetanes can be formed by intramolecular reaction between a carbonyl group and an alkene, and this has been used (4.74) in making analogues of thromboxane A, (one of the compounds responsible for the control of blood clotting), albeit usually as the minor product. A special case of intramolecular reaction is seen for a,p-unsaturated carboxylic acids 14.75), where the product is an oxete that is tautomeric with a p-lactone. Oxetes may also be formed by photocycloaddition of ketones or aldehydes with alkynes the oxete normally ring-opens at room temperature to give an a,p-unsaturated carbonyl compound (4.76), but at lower temperatures its spectral... 

Barnett and Sohn (12, 13, see also 14) have discovered that the iodolactoni-zation of b,r-unsaturated carboxylic acid salts 37 yield, under kinetically controlled conditions, the Y-iodo-B-lactones 39 in preference to the more stable B-iodo-Y-lactones l. Similar results were obtained in the course of the bromolactonization reaction. Thus, here again, the formation of a four-membered ring is more facile than that of a five-membered ring. This can be rationalized on the basis of Stork s analysis, i.e. the internal opening by the carboxylate anion of the three-membered ring iodonium ion (or bromonium) 38 39 is preferred over the other mode of opening 40 41 for stereoelectronic reason. 

Chlorolactonization. Unsaturated carboxylic acids are converted into chloro lactones in moderate yield by reaction with chloramine-T and methanesulfonic acid. Example ... 

The Chinese plant Amoora yunnanensis contains dammaranes 642 and 643 (746), and oleanane 644 was isolated as a triacetate from Mentha villosa (747). It is conceivable that 644 is an artifact formed by HC1 acting on the corresponding unsaturated carboxylic acid, since this type of acid-catalyzed lactone formation is well known (748). 

Treatment of aryl-substituted alkenes with hypervalent iodine compounds can lead to the formation of phenyliodinated intermediates, which can be stabilized by the aryl substituent via the formation of phenonium ions. Subsequent nucleophilic attack might then lead to rearranged products. This behavior can be nicely seen by comparing the unsaturated carboxylic acids 78 in their reaction with (diacetoxyiodo)benzene 3. The substrate 78a without the phenyl substituent is cyclized to the phenyliodinated intermediate 79, which is then attacked by the acetate under the formation of lactone 81 [142]. Substrate 78b is, however, then stabilized by the formation of an intermediate phenonium ion 80 and attack by the acetate is accompanied by a 1,2-phenyl migration and 82 is generated, Scheme 35 [143]. 

Dienes (allenes) are also used for heteroannulation with 68 and 69. The eight-membered nitrogen heterocycle 78 is constructed by the reaction of 1,2-undecadiene (77) with o-(3-aminopropyl)iodobenzene (76) [34]. The lactones are prepared by trapping the 7i-allyl intermediates with carboxylic acids as an oxygen nucleophile. The unsaturted lactone 81 is prepared by the reaction of /1-bromo-v,/ -unsaturated carboxylic acid 79 with the allene 80 [35]. In the carboannulation of 82 with 1,4-cyclohexadiene (83), the 1,3-diene 85 is generated by / -elimination of 84, and the addition of H-PdX forms the 7i-allylpalladium 86, which attacks the malonate to give 87 [36],... 

The unsaturated 3a-acetoxy-17-formyl-16-etiocholen-lip-ol-18-one lip,18-lactol is hydrogenated in the presence of palladium catalyst to saturate the 16,17-double bond, and then saturated aldehyde are oxidized by treatment with chromic oxide in pyridine to give 3a-acetoxy-lip-ol-18-one-pregnane lip,18-lactone 17-carboxylic acid. 

Iodocyclization.1 This reagent converts various unsaturated alcohols into ethers and unsaturated carboxylic acids into lactones. It is particularly useful for synthesis of 2-(l-iodomethyl)oxiranes from allylic alcohols and of 2-(l-iodomethyl)oxetanes from homoallylic alcohols. 

The intramolecular version of photoaddition of alcohols to alkenes was also reported. Mizuno and Otsuji reported the DCA-sensitized photocyclization of co-hydroxy-l,l-diphenylalkenes (n = 3-5) via exciplex in benzene [38]. The long chain cu-hydroxyalkenes (n = 6,10) do not give the corresponding cycHzed ethers. Gassman reported the photocyclization of unsaturated carboxylic acids by the use of a sensitizer system consisting of sterically hindered electron acceptors and biphenyl to give y-lactones (Scheme 10) [39]. 

Oxyselenation ofalkeues, - Treatment of olefins with 1 or 2, water, and an acid catalyst (e.g., p-TsOH) in CH2CI2 affords j3-hydroxy selenides in excellent yield. Unsaturated carboxylic acids, phenols, alcohols, thioacetates, and urethanes react with 1 or 2 and an acid catalyst ( —78- 25°) to afford products of oxidative cyclization. These reagents are superior to benzeneselenenyl halides for selenium-induced ring closures. This reaction is also useful for synthesis of 14- and 16-membered lactones. Benzeneselenenyl halides and benzeneselenenic acid do not promote macrolide formation under similar conditions. 

Oxidative iactonization. Oxidation of S-unsaturated carboxylic acids with LTA produces y-lactones in satisfactory yield see 2,236). Corey and Pearce found this reagent uniquely effective for the key double Iactonization of 1 in their total synthesis of picrotoxiniri. The double bond of 1 is extremely hindered as a consequence the usual oxidants are ineffective. 

Thermodynamic control of the lactonization can be achieved by reaction of unsaturated carboxylic acids with iodine in acetonitrile in the absence of a base19. The halocyclization occurs in high yield and selectivity via the protonated lactone that affords the more stable isomer. Under these conditions 3-substituted 4-alkenoic acids 10 and 4-substituted 5-alkenoic acids (e.g., 12) give the Y/ .v-isomer with very high stereoselectivity. 

Stereoselective cyclization4 takes place upon bromolactonization of substituted 3-unsaturated carboxylic acids 1 under basic conditions. Thus, the tra .y-3,4-disubstituted /J-lactone 2 is obtained by treatment of 2-methyl-3-butenoic acid (1, R = CH3) under basic conditions, with no accompanying y-lactone. 

Phenylsclenenyl triflate shows highly electrophilic character since it reacts even at — 78 °C with unsaturated carboxylic acids to afford the corresponding lactones. In some cases, the reaction of selenyl halides in the presence of the nucleophilie halide anion causes unfavorable side reactions, such as addition of the halogen atom, and decreased stereoselectivity. On the other hand, reactions of Ar-(phenylseleno)imides, which are not effected by the nucleophile, require a strong acid catalyst because of their lower reactivity. 

Generation of seleno carboxylates occurs instantaneously on treatment of selenenyl halides with carboxylic acids and, consequently, the phenylseleno-lactonization of unsaturated carboxylic acids by phenylselenenyl chloride may be formally considered as intramolecular addition of phenylselenenyl carboxylate to the C-C double bond. The reaction of 4-cyclohep-tene-l-carboxylic acid with phenylselenenyl chloride to give lactone 40 is a good example. 

Lactones, electrophilic heterocyclization of unsaturated carboxylic acids in the synthesis of 88KGS1299. 

The following lactones were similarly prepared from the appropriate unsaturated carboxylic acids. ... 

Meyers approach to a-chiral lactones may be expanded to the 8-lactone series with ee values comparable to those achieved for lactones (equation 118). Mercuri- and similarly halo-lactonizations of 8,8-unsaturated carboxylic acid derivatives are an efficient way to achieve stereocontrolled heteroatom-carbon ring closure, e.g. of (333) to (334 equation 1IQ). ... 

Sturtz et al. have described the deprotonation of the allyl bis(dimethylamido)phosphonate (9). Treatment of (9) with two equivalents of base, followed by reaction with an epoxide and hydrolysis, yields the y-lactone (Scheme 10). Alkylation with alkyl and alkenyl halides occurs at the y-carbon and hydrolysis yields the saturated and unsaturated carboxylic acids respectively. 

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