Lactone hydrolysis

In the aforementioned compounds, functional derivatization, described83 to increase the dispersion of their n.m.r. spectra, caused63 enhanced rate of lactone hydrolysis (apparent from their electrolytic conductivities). 

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... 

In Sect. 7.6, we examined the hydrolysis of lactones. Emphasis was placed on the reversibility of the reaction and the possibility of both chemical and enzymatic catalysis. Some enzymes active in lactone hydrolysis and the hydrolytic inactivation of a number of pharmacologically active lactones were discussed. 

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. 

Thiol elimination to create a C=C bond is also seen in the metabolism of spironolactone (11.101, Fig. 11.13) [131]. This diuretic drug undergoes a number of metabolic reactions in humans, one of which is ready hydrolysis at the thioester bond to yield deacetyl-spironolactone (see Chapt. 7). This reaction is in competition with other pathways such as lactone hydrolysis, S-oxygenation, and dethioacetylation. The latter reaction is the one of interest here, since the elimination of CH3CO-SH transforms the C(5)-C(6) bond into a C=C bond to produce the active metabolite canrenone (11.102, Fig. 

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). 

For a review of the mechanisms of lactone hydrolysis, sec Kaiser Kczdy Prog. Bioorg. Chem. 1976, 4. 239-267, pp. 254-265. 

An additional example of lactone hydrolysis includes the API lovastatin (9). In addition to lactone cleavage reactions, lactone formation can also occur as in the case of the API cephalosporin cefuroxime sodium (Fig. 4) (10). 

Increasing the substrate range of an enzyme could be thought of as improving a promiscuous activity. However, here we will use a more strict definition in which a promiscuous activity involves catalysis of a reaction with a different class of substrate. Many enzymes are promiscuous in the sense that they can catalyze other reactions. This is not surprising considering that the enormous variety of enzymes that exist utilize only a small number of active site chemistries and structural scaffolds. Thus, an almost identical enzyme could catalyze lactone hydrolysis or phosphotriester hydrolysis. Because these activities are often very weak to begin with, directed molecular evolution experiments to improve these activities often result in remarkable improvements. 

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. 

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