Alkenoic acids, lactonization

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]. 

Epoxidative lactonization.1 This reaction can be used for a diastereoselective synthesis of 5-hydroxyalkylbutanolides (3) from (E)- and (Z)-4-alkenoic acids (1). Thus epoxidation of (E)-l results in an epoxide (2) that in the presence of acid is converted into erythro-i. In contrast, (Z)-l is converted into threo-3. Yields are essentially quantitative. 

With respect to the biosynthesis of the solvents it has been speculated on the basis of quantitative data and the identification of (3,y-unsaturated acids in primitive oxytelid beetles that pairs of 1-alkenes and y-lactones are synthesized from corresponding 3-alkenoic acids by either lactonization or by decarboxylation [118]. 

In the presence of a strong acid as catalyst, alkenoic acids will add internally to furnish a valuable route to lactones (Scheme 4).460 Regardless of the position of the double bond in the chain, the product obtained is always the y- and/or 8-lactone due to acid-catalyzed double bond migration to a position favorable for ring closure.461 The choice of catalyst and the reaction temperature are important in minimizing the amount of cycloalkenone side product that usually accompanies lactone formation.462... 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

Among the fragrance and aroma substances a great variety of mono- and polyole-finic aliphatic alcohols, aldehydes, ketones, carboxylic acids, and their esters, as well as lactones are found 158). Of these aroma substances, (J5)-2-alkenals, ( )-2-alkenoic acids, ( )-2-alkenoic esters as well as (JS)-2-alken-l-ols are predestinated for the synthesis via the Wittig reaction because of the ( )-stereoselectivity of the olefination using resonance-stabilized ylides. 

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. 

Table I. > - Versus 5-Lactone Formation Upon lodo- and Bromo-lactonization of ( )-4-Alkenoic Acids...

As an alternative to the halo- or selenolactonization, a palladium-catalyzed procedure allows the preparation of unsaturated lactones starting from alkenoic acids. Since the palladium hydride generated during the process decomposes to palladium(O), oxygen as reoxidant is required for the catalytic process in palladium45. 

Lactones are common subunits in natural products and are therefore of high biological relevance. An approach to 7- and 5-lactones starts from Merrifield resin-bound to-alkenoic acids 99 (Scheme 26). Epoxidation and nucleophilic ring-opening of the oxiranes 100 produced the hydroxy acids 101, which cyclized upon treatment with trifluoroacetic acid to give five- and six-membered lactones 102. Treatment of the epoxides 100 with trifluoroacetic acid provided the lactone 102 (Nuc = OH) [41],... 

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. 

Alkenoic acids given in Scheme 20 are also cyclized to give good yields of lactones.f t The relative reactivity of alkenes generally follows the order disubstituted > trisubstituted > monosubstituted, probably due to a fine balance between the electron density and steric bulkiness. exo-Methylene-y-butyrolactones can similarly be synthesized from the corresponding alkenyl carboxylic acids. ... 

Scheme 13 Lactonization of alkenoic acids using HTIB...

Recently, a method for the stereoselective preparation of the cw-substituted /3-lactones using catalytic methylaluminum bis(4-bromo-2,6-di-f-butylphenoxide) has been described (eq 11). This method is reported to work well for alkyl, aryl, and unsaturated aldehydes. Stoichiometric amounts of catalyst lead to desi-lylation followed by ring opening to afford (Z)-alkenoic acids. 

Metal-catalysed ring-opening reactions of lactones can be useful in synthesis. For example, a one-pot procedure for the formation of (Z)-4-alkenoic acids, the esters of which are components of various perfumes and flavours, relies on the cis nature of addition of dialkylcuprates to acetylenes to afford (Z)-alkenyl-cuprates. These cuprates induce ring opening of -propiolactone in a regioselec-tive manner by alkyl oxygen fission to give the desired compounds in excellent yield. ... 

To develop a general, catalytic route to unsaturated lactones, in 1993, Larock and coworkers reported a Pd(OAc)2-catalyzed cyclization of alkenoic acids to five- and six-membered lactones (Scheme 3.39) [72]. The methodology is very mild, and a broad scope of mono-, di-, and trisubstituted alkenes could be converted to the desired products in high yields. 

Scheme 3.39 Palladium-catalyzed cyclization of alkenoic acids to synthesize lactones.

An enantioselective oxidative cyclization of 4-alkenoic acids to give y-lactone derivatives via palladium-catalyzed allylic C-H activation was also disclosed by Sasai in 2011 (Scheme 3.42) [76]. In the presence of 10mol% Pd(OAc)2 and 15mol% spiro bis(isoxazoline) ligand, a variety of five-membered ring lactones could be constructed in moderate to excellent yields. However, the enantioselectivity is highly depended on the structures of substrates. 

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