Hydrolysis of thioesters

Figure 8.P31 gives the pH-rate profile for hydrolysis of thioesters A-D and shows a dependence on the nature of the substituents in the alkylthio group. Propose a mechanism which would account for the pH-rate profile of each compound. 

Fig. 8.P3I. Plot of the pseudo-first-order rate constants for hydrolysis of thioesters A (O), B ( ), C (A), D (A) as a fiinction of pH at 50°C and ionic strength 0.1 (KCI). Lines are from fits of the data to = kon(K /H+)) + (k KJK + [//+])) where koH is the hydroxide term and is the intramolecular assistance term for B and C and from linear regression for A and D. Reproduced from problem reference 31 by permission of the American Chemical Society.

In the same manner, the hydrolysis of thioesters and thioamides is dramatically (and synthetically usefully) accelerated in the presence of mercury(n) compounds. Notice that a variety of reactions is occurring sequentially in the examples presented in Fig. 4-40. 

The use of extracellular lipases of microbial origin to catalyze the stereoselective hydrolysis of esters of 3-acylthio-2-methylpropionic acid in an aqueous system has been demonstrated to produce optically active 3-acylthio-2-methyl-propionic acid [41-43], The synthesis of the chiral side chain of captopril by the lipase-catalyzed enantioselective hydrolysis of the thioester bond of racemic 3-acetylthio-2-methylpropionic acid (15) to yield 5 -(-)-(15) has been demonstrated [44], Among various lipases evaluated, lipase from Rhizopus oryzae ATCC 24563 (heat-dried cells), BMS lipase (extracellular lipase derived from the fermentation of Pseudomonas sp. SC 13856), and lipase PS-30 from Pseudomonas cepacia in an organic solvent system (l,l,2-trichloro-l,2,2-tri-fluoroethane or toluene) catalyzed the hydrolysis of thioester bond of undesired enantiomer of racemic (15) to yield desired S-(-) (15), R-(+)-3-mercapto-2-methylpropionic acid (16) and acetic acid (17) (Fig. 8A). The reaction yield of... 

The S -(-)-a-[(acetylthio)methyl]phenylpropionic acid (21) is a key chiral intermediate for the neutral endopeptidase inhibitor (22) [48], We [44] have demonstrated the lipase-catalyzed stereoselective hydrolysis of thioester bond of racemic a-[(acetylthio)methyl]phenylpropionic acid (21) in organic solvent to yield A-(+)-a-[(mercapto)methyl]phenylpropionic acid (23) and Y-(-)-(21). Using lipase PS-30, the Y-(-)-(21) was obtained in 40% reaction yield (theoretical max. 50%) and 98% e.e. (Fig. 9). 

The DKR hydrolysis of thioesters described previously has also been extended to transesterifications in toluene, using triethylamine and Candida antartica lipase.28 This general approach can therefore be applied to the resolution of a wide range of both water-soluble and water-insoluble thioesters by selecting an appropriate solvent, base, and enzyme system. 

The C27-C35 segment 238 was prepared from 32 (O Scheme 30), which is the synthetic intermediate of erythronolide A. Oxidative cleavage of 32 gave aldehyde 251, which was subjected to aldol reaction with TBDMS-enol ether and TiCl4 to provide 252. Hydrolysis of thioester and deacetalization with TFA were accompanied by furanose-to-p)ranose interconversion and... 

Triethylamine has been used as a racemizing agent in the hydrolysis of thioesters (10.26).48... 

Figure 7.P28 (page 710) gives the pH-rate profile for the hydrolysis of thioesters 28-A-D and indicates differing dependence on pH, depending on the thiol substituents. Propose a mechanism that would account for the observed pH dependence in each case. 

All that remains to generate the benzene ring is to enolize both ketones. This step is favored by aromatic stabilization. Finally, hydrolysis of thioester gives the acid. 

On the other hand, various biocatalytic hydrolysis methods have been developed on the basis of DKR. The a-hydrogens of thioesters are more acidic than those of (non-activated) oxoesters, although the rates of base-catalysed hydrolysis of thioesters and oxoesters are very similar. Several thioesters have been subjected to enzymatic resolution by lipases, but their exceptional a-H-acidity has more rarely been exploited for a dynamic resolution process this concept having been verified with several thioesters of a-(phenylthio)pro-pionate (Scheme 3.36). 

Racemization is an unavoidable problem when hydrolysis of thioesters is carried out under basic conditions. PS-SOsH-catalyzed hydrolysis of an optically active thioester proceeded with only a slight loss in enantiomeric excess imder water-reflux conditions (Scheme 3.34). This is one of the advantages of the acid-catalyzed hydrolysis of thioesters. 

By performing the hydrolysis of thioesters in the presence of benzylic alcohols, transprotection of thiols could be successfully carried out in water. The reactions proceeded smoothly to give benzylic thioethers from thioesters in good yields (Scheme 3.35). 

The gold(III)-promoted hydrolysis of thioesters has a ligand substitution as its first step [equation (27)]. ... 

The final step before the cleavage of the triazene linker to release desired product is to attach alligator clip 11 (Scheme 3.75). Unfortunately, the H NMR spectra of crude liberation product 37, from using 10% HCl in THF solution, indicated a plethora of products. One of the possible side-reactions may be hydrolysis of thioester to form disulfides, which under these conditions would exhibit extremely low solubility. 

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