Intramolecular reactions alcohol-lactone formation

Tiithioorthoester Activation. Electron-rich aromatic rings undergo electrophilic aromatic substitution with tris(phenylthio) methane in the presence of DMTSF. Subsequent hydrolysis results in an aldehyde and a net electrophilic formylation . Intramolecular reaction between a tris(phenylthio)methane unit and an alcohol represents an approach to lactone formation which utilizes the chemoselectivity of DMTSF ... 

Intramolecular Reactions of Alkynes with Carboxylic Acids, Alcohols, and Amines. Addition of carboxylic acids, alcohols, and amines to alkynes via oxypaUadation and aminopallada-tion proceeds with catalysis by Pd salts. Intramolecular additions are particularly facile. Unsaturated y-lactones are obtained by the treatment of 3-alkynoic acid and 4-alkynoic acid with Pd(PhCN)2Cl2 in THF in the presence of Et3N (eq 54), and -lactones are obtained from5-alkynoic acids. 5-Hydroxyalkynes are converted to the cyclic enol ethers (eq 55). The oxypalla-dation is a irons addition. Thus stereoselective enol ether formation by reaction of the alkynoic alcohol with Pd(PhCN)2Cl2, followed by reduction with ammonium formate, has been applied to the synthesis of prostacyclin (eq 56). Intramolecular addition of amines affords cyclic imines. 3-Alkynylamines are cyclized to 1-pyrrolines while 5-alkynylamines are converted to 2,3,4,5-tetrahydropyridines (eq 57). ... 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

Intramolecular oxysulfenylation.1 Intramolecular oxysulfenylation (11, 205) of y,8-unsaturated alcohols or acids can be used for preparation of cyclic ethers or lactones, respectively. A base is not essential, but optimal yields are obtained in the presence of diisopropylethylamine (1.1 equiv.). Formation of five-membered rings is favored over formation of six-membered rings. The reaction is carried out at 25° and requires 1-3 days. 

While still useful for large-scale esterification of fairly robust carboxylic acids, Fischer esterification is generally not useful in small-scale reactions because the esterification depends on an acid-catalyzed equilibrium to produce the ester. The equilibrium is usually shifted to the side of the products by adding an excess of one of the reactants—usually the alcohol—and refluxing until equilibrium is established, typically several hours. The reaction is then quenched with base to freeze the equilibrium and the ester product is separated from the excess alcohol and any unreacted acid. This separation is easily accomplished on a large scale where distillation is often used to separate the product from the by-products. For small-scale reactions where distillation is not a viable option, the separation is often difficult or tedious. Consequently Fischer esterification is not widely used for ester formation in small-scale laboratory situations. In contrast, intramolecular Fischer esterification is very effective on a small scale for the closure of hydroxy acids to lactones. Here the equilibrium is driven by tire removal of water and no other reagents are needed. Moreover the closure is favored entropically and proceeds easily. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

An orf/io-directed lithiation allows the conversion of 25 to aryl iodide 40. Reductive ether formation of aldehyde 40 with crotyl alcohol yields compound 41. Intramolecular Heck reaction of 41 affords a mixture of the olefins 42 and 43. The undesired alkene 42 can be isomer-ized quantitatively to the desired enol ether 43 with Wilkinson s catalyst. Sharpless dihydroxylation ee 94 %) of the enol ether 43 provides lactol 44, which is oxidized directly to lactone 45. Finally, the pyridone-O-methyl ester is cleaved under acid conditions (45 — 7). 

This reaction proceeds in one flask as follows (i) conjugate addition of unsaturated alcohols (6) to P-alkoxy-substituted nitroalkene (5), (ii) reversible elimination of ethanol, with the formation of the intermediate (8), (iii) intramolecular HAD reaction of the resulting transetherihed compound leading the bicyclic nitronate (9), and (iv) further transformation of (9) to bicyclic lactones (7) as outlined in Figure 2.2. 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

Formation of 2-Ethyl-2(5H) Furanone. The presence of artifacts with increased retention times suggests the formation of components of increased polarity and/or the formation of higher molecular weight constituents from condensation or addition reactions. The acids, aldehydes and alcohols present can undergo oxidation to form y- and 6-lactones (14, 15). The formation of the lactone, 5-ethyl-2(5H)-furanone, probably occurs by the steps outlined in Figure 4. A plausible sequence would be reaction of 2-hexenoic acid to form a peroxy radical at the y-position followed by production of the hydroperoxide. Cleavage of the 0-0 bond with the subsequent addition of H could lead to 4-hydroxy-2-hexenoic acid. Intramolecular esterification would then produce the identified lactone. 

Leighton constructed the complex molecule of the CP-263,114 core ring system 641 by elegant application of Pd-catalyzed carbonylation of the 1,3-butadienyl 2-triflate moiety in 637 via the methylene-7r-allylpalladium 638 to afford the unsaturated lactone 640. The lactone was subjected to Cope rearrangement to produce 641 as shown by 640 in 56 % overall yield. Formation of the unsaturated lactone 640 by intramolecular acetalization involving the alcohol, ketone, and acylpalla-dium as shown by 639, is a key reaction [228]. 

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