Lactones, hydrolysis acids

Enantiomerically pure 4,5,6-trihydroxy-norleucins (for instance 325) were obtained (197) from the hex-2-enono-1,4-lactone-2-mesylates (such as 152). These butenolides were stereoselectively hydrogenated to afford, upon treatment with sodium azide, the C-2-inverted derivatives, such as 324. Reduction of the azide function and hydrolysis of the acetal group gave the amino acids (namely 325), which were converted into lactones in acid media. 

Lactone hydrolysis is similar to ester hydrolysis in terms of catalytic mechanisms, but differs as far as reaction kinetics and products are concerned. Whereas esters are hydrolyzed to two metabolites/products, lactones generate a hydroxy acid as the sole metabolite/product of hydrolysis. In fact, the reaction should be designated as hydration rather than hydrolysis according to the definitions given in Chapt. 1. Another characteristic of hydrolytic... 

The reversibility of lactone hydrolysis in HMG-CoA reductase inhibitors has been demonstrated at gastric pH and temperature (pH 2.0, 37°) [186], For the prodrug lovastatin (8.148), reversible lactone hydrolysis to its active hydroxy acid (8.149) occurred with a f1/2 value of ca. 1 h and an equilibrium constant close to one. Similar results were obtained for some closely related compounds. In contrast, this reversible hydrolysis was much slower under the nearly neutral pH conditions of the intestine. 

M. J. Kaufman, Rate and Equihbrium Constants for Acid-Catalyzed Lactone Hydrolysis of HMG-CoA Reductase Inhibitors , Int. J. Pharm. 1990, 66, 97-106. 

In order to decrease the number of chemical steps in the synthesis of l-[4- F]fluorophenylalanine, a potential marker for probing protein synthesis [140a], [4- F]fluorobenzaldehyde has been directly condensed with an imino-lactone. Hydrolysis then chiral HPLC yield the S amino acid in 5 % radiochemical yield (Scheme 33). 

Hart and de Pauw 98) used this emulsion technique on the system vinyl acetate-acrylic acid. It is well known that the copolymerization parameters rx and r2 are unfavorable in this system therefore the relative solubility of the two monomers exerces only a small influence on the composition of both sequences. The degree of homogeneity of the sequences has been evaluated, after alkaline hydrolysis, by measuring the tendency to lactonization in acid medium. While 72% of the acetate groups could be lactonized in the case of a random copolymer containing 37% vinyl acetate, only 14% are transformed in a block copolymer with the same initial composition. 

Electroreduction of benzal chloride in the presence of carbon dioxide in DMF solvent gives very low yield of phenylacetic acid (131) (equation 70). The study suggests that the monoanion adds C02 to yield intermediate a-chlorophenylacetate which forms a-lactone. The acid is obtained following hydrolysis of the a-lactone by adventitious moisture in the DMF as shown in Scheme 910. 

Electrolysis of a solution containing calcium bromide and lactose causes smooth oxidation of the disaccharide to lactobiono-1,5-lactone, presumably by the formation of free bromine at the anode. After hydrolysis of the lactone, lactobionic acid is usually isolated as its insoluble calcium salt [(CjsH2iOi2)2Ca"5 H2O]. 

To make this an asymmetric synthesis, a chiral substituent was attached to the nitrogen atom 113. The tandem reaction then gave a not very high selectivity (60 40 diastereoisomeric mixture) but the isomers could easily be separated by crystallisation of the salt of 115 with bromocamphor sulfonic acid. Removal of the a-methylbenzyl group and lactone hydrolysis gave the pipecolic acid 117 as a single enantiomer. This was needed for the synthesis of an HIV protease inhibitor. 

Condensation of 1 with 3,4-dimethoxybenzyl cyanide afforded the epimeric cyano alcohols 2, which on alkaline hydrolysis gave the epimeric y -lactones 3 in 64% yield. Treatment of 3 with crotyl bromide afforded the a,a-disubstituted lactone 4. Acid-catalyzed debenzy-lation of 4 afforded the alcohol 5, which on sequential saponification, periodate cleavage and reduction gave the lactone 7 via 6. Palladium-catalyzed oxidation of 7 afforded 8, which underwent intramolecular cyclization to produce 9 in 66% yield. Treatment of 9 with methylamine gave 10 (41%) and 11 (7%) however, the former can be cyclized into the latter in 85% yield. Reduction of 11 furnished 12 in 77% yield. 

A new alkaloid, crotalarine (17) has been isolated from Crotalaria burhia Buch.-Ham. The structure (17) proposed for crotalarine is based on alkaline hydrolysis to retronecine, 3-methyl-2-pentanone, lactic acid, and a lactone, crotalaric acid (18) the i.r. spectrum of which was similar to those of monocrotalic (19) and trichodesmic... 

On treatment with hot aqueous alkali, only hydrolysis of the lactone ring occurs. However, on treatment of 19-oxodehydroheteratisine (24) with potassium t-butoxide in t-butyl alcohol, a y-lactone carboxylic acid (28) was isolated. This product may be formed as indicated in the Scheme. The rearrangement to (28)... 

The 2 4-2 cycloaddition of ketene to chloral in toluene at —50 °C in the presence of 4 mol% of cinchonine results in the formation of j -lactone 886 in high yield with 84% ee. Recrystallization from methylcyclohexane furnishes optically pure (R)-lactone. Mild acid hydrolysis of the lactone to the trichloromethyl hydroxy acid 887 followed by careful basic hydrolysis gives optically pure (R)-malic acid (885) in 79% overall yield [196]. 

Each step of an isolation procedure requires confirmatory thin layer chromatographic (TLC) analysis to determine if isolation artifacts are produced (Fig. 3). Unwanted reactions include enzymatic and chemical hydrolysis during water extraction, esterification or lactonization of acidic saponins when using alcohol solvents, hydrolysis or transesterification of labile ester functions, and cyclopropane cleavage during acidic hydrolysis [10]. 

The pH dependence of die interconversion kinetics, equilibrium, and solubilities of die lactone and hydroxyacid forms of calcium (R-(R, R ) )-2-(4-duorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl- 4r((phenylamino)-carbonyl)-lH-pyrrole-l-heptanoate (CI-981 atorvastatin calcium) are described. Over a pH range of 2.1-6.0 and at 30 °C, the apparent solubility of die sodium salt of CI-981 increases about 60-fold, and die profile yields a pKa for die terminal carboxyl group of 4.46. In contrast, over a pH range of 2.3-7.7 at the same temperature, die apparent solubility of die lactone form of CI-981 varies lidle, and die mean solubility is 1.34 meg/ml. The kinetics of interconversion and die equilibrium between the hydroxyacid and lactone forms have been studied as a function of pH, buffer concentration, and temperature at a fixed ionic strength. The rate constant for lactone formation is well described by specific acid-catalyzed and spontaneous lactonization padiways, whereas die rate constant for lactone hydrolysis is well described by specific acid-, water-, and specific base-catalyzed padiways."... 

H202 As equal to 30. Conversion to the Baeyer-Villiger products is based on H2O2. ester represents also lactone and acid denotes hydroxycarboxylic acids formed by hydrolysis of lactones. The yields are based on the ketone consumed. Yield of lactone or ester based on the consumed hydrogen peroxide. 

Specific acid and base Hydrolysis of y-lactones Hydrolysis of amides Hydrolysis of esters 1 0 1 R CO-NH2 + H2O = R COONH4 R,C00R2 -I- H2O = Ri-COOH -1- R2OH... 

With synthetic scholarisine A in hand, the chemistry of this scaffold was briefly explored (Scheme 45). For example, treatment of scholarisine A (12) with sodium hydroxide in warm isopropanol overnight, followed by acidification and purification led to a new product. Extensive NMR characterization permitted identification of this product to be indolenine 321. This product is proposed to arise via initial lactone hydrolysis, followed by an aza retroaldol fragmentation to form aldehyde 323. Cyclization could then result in reversion to 322, or lead to carboxylate 324, a C—5 epimer-ized congener. Acidification of324 would then provide carboxylic acid 321. This fragmentation is considered to be the reversal of the proposed biosyn-... 

The carboxylic acid, resulting from the amide hydrolysis, forms a seven-membered lactone with the alcohol liberated from the lactone hydrolysis. 

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