Lactone saponification

When the compound for identification fails to respond to test 4 (aldehyde or ketone), the next class reactions to apply are the hydroxatnic acid teat and saponification, i.e., hydrolysis in alkaline solution. These are the class reactions for esters and anhydrides the rarely-encountered lactones react similarly. 

Composition. Shellac is primarily a mixture of aUphatic polyhydroxy acids in the form of lactones and esters. It has an acid number of ca 70, a saponification number of ca 230, a hydroxyl number of ca 260, and an iodine number of ca 15. Its average molecular weight is ca 1000. Shellac is a complex mixture, but some of its constituents have been identified. Aleuritic acid, an optically inactive 9,10,16-trihydroxypalmitic acid, has been isolated by saponification. Related carboxyflc acids such as 16-hydroxy- and 9,10-dihydroxypalmitic acids, also have been identified after saponification. These acids may not be primary products of hydrolysis, but may have been produced by the treatment. Studies show that shellac contains carboxyflc acids with long methylene chains, unsaturated esters, probably an aliphatic aldehyde, a saturated aliphatic ester, a primary alcohol, and isolated or unconjugated double bonds. 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

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). 

Saponification of Esters or Lactones and Reaction of Persilylated Amides and Lactams with Alkali I 71... 

The procedure was proved to be general for the preparation of protected hydroxy acids from lactones (121). This apparently trivial process is often difficult to carry out, as the attempted derivatization of y or J-hydroxyacids frequently results in relactonization rather than hydroxyl protection. The method was applied to several aldonolactones to produce the corresponding intermediate hydroxyamides. Protection using [(2-trimethylsilyl)-ethoxy]methyl chloride, methoxymethyl chloride, ter/-butylchlorodimeth-ylsilane, or zm-butylchlorodiphenylsilane followed by ozonolysis gave the protected N-(y- or <5-hydroxyacyl)indole derivatives. Mild saponification gave indole and the acetal- or silyl-protected hydroxy acids. 

Esters are hydrolysed under basic conditions in the presence of quaternary ammonium salts [e.g. 1-7], Microwave activation of basic soliddiquid systems without an added solvent enhances the rate of saponification and the reaction is not affected by steric factors [3], Microwave irradiation has also been used in the hydrolysis and decarboxylation of malonic esters [8] and p-keto esters [9] (>90%). Lactones... 

D. After saponification of D to the corresponding diol, oxidation of the primary hydroxy group with tetra(n-propyl)ammonium perruthenate produced lactone... 

A synthesis of 149, cucujolide VIII, proceeded via the tert-butyldimethylsi-lyl-(TBS)-ether of methyl (E)-12-hydroxydodec-4-enoate B [293] (Fig. 7). Deprotonation in a-position and reaction with di(4-methoxyphenyl)diselenide furnished C. This was transformed to the macrolide E after saponification of the ester moiety, deprotection of the hydroxy group, and Mitsunobu lactonization. Alternatively, the unsaturated lactone F was synthesized from B following a sequence similar to that from C to D. Oxidative elimination of the arylseleno group... 

Batatins V (234) and VI (235) are acylated tetrasaccharide ester-t3 pe dimers isolated from Ipomoea batatas, which yielded operculinic acid C through saponification. A mild alkaline hydrolysis of both afforded compound 30, one of the monomeric units, identified by coelution in UPLC with natural batatinoside 111 (31), placing the lactonization at C-3 of the second saccharide in the macrocyclic portion. C-3 of the third saccharide unit was identified as the position for the ester linkage. Both dimers showed acylations at C-4 of the terminal rhamnose... 

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