Lactones, reaction with alcohols

All the foregoing syntheses of 0,0,0-orthoesters required at least two steps because 0,0,0-orthoesters cannot usually be prepared directly from esters by reaction with alcohols under add conditions analogous to the preparation of acetals from aldehydes and ketones. There are some exceptions.237 -239 For example. reaction of the racemic mixture of cis- and fraftf-lactones in Scheme 2.115 with (/ ,/ )-butane-2,3-diol in refluxing benzene afforded a mixture of four diastereoisomeric orthoesters (99%) in the ratio 6 6 1 1 that could be sepa-... 

The methods discussed so far are applicable to aldehydes, ketones, esters and lactones. Hie a-haloge-nation of acids has received relatively little attention, although the traditional Hell-Vollaid-Zelinski conditions are adequate in most instances (equation 2). Alternative conditions have been developed, however, in which the acyl halide may be halogenated using NBS. ( eiKhing the reaction with alcohols or amines offers the opportunity of forming carboxylate derivatives. 

Lactones, due to their ring structure, are easily opened with nucleophiles (35) to yield the corresponding 5-hydroxy substituted derivatives (Scheme 12). Table 1 lists the relative rates of derivitization of meadowfoam fatty acids, y-lactones, and 8-lactones in reactions with alcohols and amines. All of the relative rates were compared with the rate of esterification for meadowfoam fatty acids (FA). These data clearly demonstrate the enhanced reactivity of the 8-lactone structure with respect to fatty acids and even its analog, y-lactone. 

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. 

Esters of aldonic acids are prepared from 6-lactones, slowly from 7-lac-tones, by reaction with alcohols in the presence of hydrogen chloride or of the free aldonic acid (26). The acids may be recrystallized from boiling methanol without much esterification taking place (27). At the melting point, ethyl mannonate is converted to the 7-lactone with the loss of ethyl alcohol. 

Generally, lactones with five-membered and six-membered rings are not too reactive. They are relatively stable in acidic solutions, where they typically arise by spontaneous dehydration of hydrox-ycarboxylic adds. In aqueous solutions, particularly in alkaline solutions, the lactone ring opens with the formation of a salt of the hydroxycarboxylic acid. The original lactone may result after acidification, especially on heating. Lactones react with alcohols to form esters and, similarly, the lactone ring opens on reaction with amino compounds to form amides. 

The hemlacetal nature of the anomeric hydroxyl group makes it the most reactive of that type. Direct oxidation can be carried out with several reagents, most classically, hypoiodite. This results in rapid oxidation to the aldono-lactone and is only exhibited by aldoses. Alternatively, reaction with alcohols results in the formation of full acetals (glycosides). A very large variety of such structures have been made. 

Conversion of Esters into Alcohols Grignard Reaction Esters and lactones react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol in which two of the substituents are identical (Section 17.5). The reaction occurs by the usual nucleophilic substitution mechanism to give an intermediate ketone, which reacts further with the Grignard reagent to yield a tertiary alcohol. 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

An (E)-selective CM reaction with an acrylate (Scheme 61) was applied by Smith and O Doherty in the enantioselective synthesis of three natural products with cyclooxygenase inhibitory activity (cryptocarya triacetate (312), cryptocaryolone (313), and cryptocaryolone diacetate (314)) [142]. CM reaction of homoallylic alcohol 309 with ethyl acrylate mediated by catalyst C led (E)-selectively to d-hydroxy enoate 310 in near quantitative yield. Subsequent Evans acetal-forming reaction of 310, which required the trans double bond in 310 to prevent lactonization, led to key intermediate 311 that was converted to 312-314. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

The reaction of lactones of benzyl alcohols with Et3SiH/TFA results in complete reduction of the alcohol part of the lactone to the methylene group while preserving the carboxylate function (Eq. 148).305... 

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