Hydroxy acids from lactones

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. 

Lactones, l xictides, iMciams, and Lactims. When the hydroxy acid from which water may be considered to have been eliminated has a trivial name, the lactone is designated by substituting -olactone for -ic acid. Locants for a carbonyl group are numbered as low as possible, even before that of a hydroxyl group. 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

Chloro-l-methylpyridinium iodide (683) functions as an important mediator in a variety of different reactions. Esters are formed in high yield from acids and alcohols when reacted with one equivalent of (683) in the presence of two equivalents of triethylamine (Scheme 158) (75CL1045). cv-Hydroxy acids are lactonized under similar conditions (76CL49). The pyridinium salt (683) will also convert thioureas into carbodiimides (77CL575) and pyridine-2-thiones to pyridyl sulfides (75CL1159). 

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. 

On the other hand, two of the possible structural isomers (LXXIV, LXXV) (1 3, 1 4) of Ar,JV-dimethyl-i-butylcycloheptyIamine have been synthesized. The IR-curves were very close to those of the saturated Hofmann base CisH N none of them proved, however, to be identical with that of the base from dioscorine. Since configurations have not been taken into consideration, these data are not conclusive. Nevertheless, a new tentative formula has been suggested (84) which takes account of the formation of a >C = CHg group on decarboxylation of the hydroxy acid from dioscorine, i.e., that of the c-lactone of a tropine derivative with a j8-methyl-a,/3-butenoic acid side chain in... 

It s also easy to make hydroxy acids from amino acids by diazotization. You saw this being done in Chapter 33, but as a reminder nitrous acid generates a diazonium salt, which undergoes substitution by water via an intermediate a-lactone. Two configurational inversions are involved, so the product alcohol retains S stereochemistry. 

A simplified synthesis relies on the potential to protect difunctional compounds as cyclic derivatives. For example, 1,2-diols are masked as cyclic acetals (Section 24-8), hydroxy acids as lactones (Section 19-9), amino acids as lactams (Section 19-10), and dicarboxylic acids as anhydrides (Section 19-8). The last two possibilities merit consideration as applied to Asp. However, direct lactam formation can be quickly ruled out because of the complications of ring strain (although /3-lactams have been used in the preparation of aspartame). This problem is absent with respect to dehydration to the five-membered ring anhydride. Because anhydrides are activated carboxylic acid derivatives (Section 20-3), the Asp anhydride can be coupled directly with Phe-OCHa without the help of added DCC. Nucleophilic attack of the amino end of Phe-OCHs occurs preferentially at the desired position, albeit not completely so 19% of the product derives from peptide-bond formation at the /3-carboxy group of Asp. 

Lactones are formed predominantly from y-, (5-, and e-hydroxy acids. Most lactones of the aliphatic series are converted easily under the influence of water to corresponding hydroxy acids. For the hydrolysis of aromatic lactones heating with alkalies is necessary. The reactions of lactones with ammonia and phenylhydrazine, which can be used in certain cases for identification purposes, are described in greater detail in a special monograph (134). Aliphatic y-lactones react in benzene solution with thionyl chloride, with the formation of hydroxy acid chlorides, from which suitable derivatives can be prepared (135). 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

Bicucine, C20H19O7N, H2O. This alkaloid has m.. 222° (dec.) and — 115 4° (N/10, KHO) but in N/HCl it shows mutarotation — 145° to — 100°,due to the formation of an equilibrium mixture of bicucine and bicuculline. Alkaline permanganate oxidises it to 3 4-methylene-dioxyphthalic acid, isolated as the ethylimide. In view of its formation from bicuculline by the action of alkali, Manske has suggested for its formula (II) or (III), the former representing it as the nomarceine (p. 208) analogue of bicuculline, whilst (III) makes it the hydroxy-acid corresponding to the lactone, bicuculline and is preferred. 

CHsjOH. CHlCgHg). CH(COOH). CH. COOH COOH. CHlCgHg). CH(CHaOH). CH. COOH COOH. CH(C2Hg). CH(COOH). CH. CH OH AomoPilopic acid is very stable, and is probably therefore the y-lactonic acid of one of these three hydroxy-acids. Further, pilopic acid seems to be produced from its higher homologue by loss of carbon dioxide and oxidation of the contiguous carbon atom. Of the four y-lactonic acids derivable from these three hydroxy-acids only two (I and II) answer these conditions,... 

By analogy, thermal cyclization was described also for 6-nitro-2 -hydroxy-biphenyl-2-carboxylic acids, e.g. 14, obtained by other methods. The same product 15 was also formed from lactone 17, prepared by oxidation of fluorenone 16 (Scheme 2). If the reaction was performed in DMF, the corresponding dimethylamide was isolated (82KGS703, 86KGS852, 87KGS314, 89MI1). 

The product is the lactone derived from the hydroxy acid that would result from a normal Cannizzaro reaction. 

The cyclization constant (7, which may be evaluated from the observed ratio of the two products at a given concentration c, affords a measure of the tendency for a given bifunctional compound to cyclize. A plot of log C vs. the ring size n for the lactonization of w-hydroxy acids... 

The principles set forth above account reasonably well for the course of bifunctional condensations under ordinary conditions and for the relative difficulty of ring formation with units of less than five or more than seven members. They do not explain the formation of cyclic monomers from five-atom units to the total exclusion of linear polymers. Thus 7-hydroxy acids condense exclusively to lactones such as I, 7-amino acids give the lactams II, succinic acid yields the cyclic anhydride III, and ethylene carbonate and ethylene formal occur only in the cyclic forms IV and V. 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

Table 2.19 y-Hydroxy-a-amino acids and lactones derived from cycloadducts 491 a-c... 

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