Thioesters compared with esters

This study revealed that only the linear (non-branched) alkyl thioesters 10 a, b, and c (ethyl, 1-propyl, and 1-butyl) were hydrolyzed efficiently (<24 hours) with appreciable enantioselectivity (>85%eep) for some enzymes [41]. The presence of any a or / branching led to, at best, low conversion and poor eep. This is in marked contrast to the ester 9 [13], which of course possesses a /> methyl group and indicated that the demands of the enzyme s active site are stricter for thioesters as compared with esters. The reaction rate and eep for all three linear alkyl thioesters were so good that we decided to forego further optimization of the choice of substrate at that time. We felt that the choice of enzyme and thioester class was sufficient for the first pilot-plant run. 

Because of their previous findings that a,/l-unsaturated thioesters were more reactive than their ester counterparts in Diels-Alder reactions85, Hart and coworkers86 performed a systematic study of the cycloaddition reactions of a,/l-unsaturated thioesters and a,ft-unsaturated selenoesters with several dienes. Thermal reactions were compared with Lewis acid catalyzed reactions at room temperature (equation 28 and Table 2). The results clearly demonstrated that use of a Lewis acid enhanced the regioselectivity (entries 1 vs 2, 3 vs 4, 5 vs 6 and 7 vs 8) as well as the endo (with respect to the thioester or selenoester group) selectivity (entries 5 vs 6 and 7 vs 8). 

In a combined experimental/ah initio MO study, Bowie and coworkers144 addressed the questions concerning the reaction site of ambident nucleophiles with Me3Si4. It was demonstrated that the reaction of Me 3 Si4 with esters, thioesters, thionoesters, anhydrides and thioanhydrides of the general formula A-C(Y)-X-B (A, B alkyl B = CO-alkyl X, Y = O, S) two possible adducts 296 and 297 of comparable energies are formed. From the product observed under ICR conditions it was concluded that structure 297 serves as precursor for dissociation reactions no firm evidence was available to support the intermediacy of 296 in the decomposition chemistry of the encounter complexes. 

The energy-rich nature of thioesters, as compared with ordinary esters, is related primarily to resonance stabilization (Figure 14.9). Most esters can resonate between two forms (Figure 14,9). Stabilization involves Pi-electron overlap, giving partial double-bond character to the C-0 link. In thioesters, the larger atomic size of S (as compared with O) reduces the Pi-electron overlap between C and S, so that the C-S structure does not contribute significantly to resonance stabilization. Thus, the thioester is destabilized relative to an ester, so that its iG of hydrolysis is increased. 

The carbonyl carbon of a thioester is more susceptible to nucleophilic attack than is the carbonyl carbon of an oxygen ester because there is less electron delocalization onto the carbonyl oxygen when Y is S than when Y is O. There is less electron delocalization because there is less overlap between the 3p orbital of sulfur and the Ip orbital of carbon, compared with the amount of overlap between the Ip orbital of oxygen and the Ip orbital of carbon (Section 17.2). In addition, a thiolate ion is a weaker base and therefore a better leaving group than an alkoxide ion. 

Thiomethyl-PS 6b, prepared from Merrifield s resin la by reaction with thioacetate followed by reduction, can be acylated to give thioesters [263]. The resin-bound thioesters have been converted to silyl enol ethers, which were shown to form aldol products that could be released from the resin by three methods [264], Thus, reduction with lithium borohydride or diisobutylaluminum hydride (DIBAL) gave diols and aldehydes, respectively alternatively, base hydrolysis afforded carboxylic acids. Resin 6b thereby extends the range of functional groups available compared with cleavage of related molecules from an ester anchor. 

Acyl Formation Compared with hydrolysis reactions, esterification and transesterification reactions are much slower and require the use of activated esters to facilitate the reaction and to make it kinetically irreversible. These include trichloroethyl esters, trifluoroethyl esters, enol esters, thioesters and vinylcarbamates. Lipases isolated from Pseudomonas species are highly selective for the hydrolysis of esters of secondary alcohols, and therefore also for the corresponding reverse reactions. 

The activation of acyl groups for transfer by CoA can be appreciated by comparing the hydrolysis of the thioester bond of acetyl-CoA with hydrolysis of a simple oxygen ester ... 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

In a comparison of fluorescence spectra between the ester and thioester derivative crystals of PDA, the ester crystal shows a strong emission whereas the thioester crystal fluoresces much more weakly. For example, the intensity of a PDA methyl thioester crystal is about one-thousandth of that of a PDA methyl ester crystal. Furthermore, the fluorescence lifetime of mixed crystals which consist of a large amount of PDA methyl ester and a small amount of the corresponding thioester moiety is much shortened, compared to the lifetime of pure PDA methyl ester crystals. In quenching experiments in solutions of PDA ester, the fluorescence of the PDA ester is dramatically quenched by thioacetate. Similar behaviour has been obtained with several types of diolefin derivatives having a thioester moiety, where crystal structures are isomorphous with the corresponding ester derivatives. 

The more favourable equilibrium constants for the addition of thiols to the carbonyl group of aldehydes and ketones compared to those for the addition of alcohols are well documented (Jencks, 1964 Lienhard and Jencks, 1966 Kanchuger and Byers, 1979), if not fully understood. There appears to be a similar tendency for thiols to add to the carbonyl (or thiocarbonyl) group of esters (or thioesters) and several tetrahedral intermediates with one or more... 

Fig. 3 Hypothetical free energy diagram proposed to account for NCA reactivity. Free energy levels of NCAs and of the transition state of their aminolysis reactions compared to those of reactions of other amino acid derivatives (AA-X). A Comparison with linear anhydrides (X = OAc) B Alkyl ester (X = OR), thioesters (X = SR) and p-nitrophenyl esters (X = ONp). The free energy regions corresponding to the possibility of pathways involving NCAs are shown hashed...

Benzo[ ]thiophene normally undergoes electrophilic substitution at the 3-position more rapidly than at the 2-position <1971AHC(13)284>, so both this and formation of the thioester group favor ketonization of 2-hydro-xybenzo[ ]thiophene which occurs 40 times faster than ketonization of 3-hydroxybenzo[ ]thiophene. The rapid rate of ketonization of the thio-ester enol 2-hydroxybenzo[ ]thiophene is also indicated by its 4.4-fold greater rate of ketonization compared to 2-hydroxyindene, which contrasts with what is found with 3-hydroxybenzo[. ]thiophene and 1-hydroxyindene <1986TL3275>. 

Silyl enolates derived from not only esters but also thioesters and ketones reacted with aldehydes to give the corresponding adducts in high yields (Scheme 2) [22]. Furthermore, acetals reacted smoothly with silyl enolates to afford the corresponding aldol-type adducts in high yields. It should be noted that the catalysts could be easily recovered from the aqueous layer after the reactions were quenched with water and could be reused, and that the yields of the second run were almost comparable to those of the first run in every case. 

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