Alcohols intramolecular lactone formation

Applications Inversion of alcohols—intramolecular lactone formation... 

Various aldehydes 184 and alcohols have been shown to be competent in the redox esterification of unsaturated aldehydes in the presence of the achiral mesityl triazo-lium pre-catalyst 186. Both aromatic and aliphatic enals participate in yields up to 99% (Table 13). Tri-substituted enals work well (entry 3), as do enals with additional olefins present in the substrate (entries 4 and 7). The nucleophile scope includes primary and secondary alcohols as well as phenols and allylic alcohols. Intramolecular esterification may also occur with the formation of a bicyclic lactone (entry 8). 

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 ... 

In Summary Carboxylic acids react with alcohols to form esters, as long as a mineral acid catalyst is present. This reaction is only shghtly exothermic, and its equilibrium may be shifted in either direction by the choice of reaction conditions. The reverse of ester formation is ester hydrolysis. The mechanism of esterification is add-catalyzed addition of alcohol to the carbonyl group followed by acid-catalyzed dehydration. Intramolecular ester formation results in lactones, favored only when five- or six-manbered rings are produced. 

Hanzawa Y, Ishizuka S, Ito H, Kobayashi Y, Taguchi T. Pal-ladium(0)-mediated intramolecular lactonization of allylic alcohol derivatives unusual substituent effect of the trifluor-omethyl group on 8-lactone formation. Chem. Commun. 1990 394-395. 

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. 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

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. 

Homopropargylic alcohols as well as propargylic epoxides and pentynols readily form cyclic ruthenium alkoxycarbenes upon intramolecular nucleophilic addition of the OH group to the electrophilic a-carbon of ruthenium-vinylidene species. Their oxidation in the presence of N-hydroxysuccinimide leads to the formation of penta-lactones. The best catalytic system reported until now for this transformation of but-3-ynols is based on RuCl(C5H5)(cod), tris(2-furyl)phosphine, NaHCOs as a base, in the presence of nBu4NBr or nBu4NPp6, and N-hydroxysuccinimide as the oxidant in DMF-water at 95 °C (Scheme 8.11) [22]. 

The overall modest yields achieved in these syntheses have recently been markedly improved by the use of the solid-phase copolymer of 4-vinylpyridine (P4-VP) (112) in the formation of the starting di-ynic esters. For example, when a suspension of P4-VP polymer in dichloromethane was stirred with the acid chloride from (1011 and then the propargyl alcohol (114), the ester (1151 was obtained excellent yield. By heating in xylene, (1151 underwent intramolecular cyclization to yield justicidin E(1041 and taiwanin C(1051 as the major products in addition, the isomers helioxanthin (1081 and retrohelioxanthin (1161 could also be isolated (Scheme 22) (113). Increased interest in these four lactone products has resulted from an assay which indicates 5-lipoxygenase inhibitory activity (114). 

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