Thioesters, protonation

All three elimination reactions--E2, El, and ElcB—occur in biological pathways, but the ElcB mechanism is particularly common. The substrate is usually an alcohol, and the H atom removed is usually adjacent to a carbonyl group, just as in laboratory reactions. Thus, 3-hydroxy carbonyl compounds are frequently converted to unsaturated carbonyl compounds by elimination reactions. A typical example occurs during the biosynthesis of fats when a 3-hydroxybutyryl thioester is dehydrated to the corresponding unsaturated (crotonyl) thioester. The base in this reaction is a histidine amino acid in the enzyme, and loss of the OH group is assisted by simultaneous protonation. 

In contrast to oxoesters, the a-protons of thioesters are sufficiently acidic to permit continuous racemization of the substrate by base-catalyzed deprotonation at the a-carbon. Drueckhammer et al. first demonstrated the feasibility of this approach by performing DKR of a propionate thioester bearing a phenylthiogroup, which also contributes to the acidity of the a-proton (Figure 4.14) [39a]. The enzymatic hydrolysis of the thioester was coupled with a racemization catalyzed by trioctylamine. Owing to the insolubility of the substrate and base in water, they employed a biphasic system (toluene/H2O). Using P. cepacia (Amano PS-30) as the enzyme and a catalytic amount of trioctylamine, they obtained a quantitative yield of the corresponding... 

We shall see later (see Box 10.17) that nature can employ yet another stratagem to increase the acidity of the a-protons in thioesters, by converting acetyl-CoA into malonyl-CoA (see Section 15.9). 

This enzyme [EC 5.1.1.11], also known as phenylalanine racemase (ATP-hydrolyzing), catalyzes the reaction of ATP with L-phenylalanine to produce o-phenylalanine, AMP, and pyrophosphate. In this unusual racemase reaction, a thiol group of an enzyme-bound pantotheine forms a thiolester from an initial aminoacyl-AMP intermediate then, as is typical of acyl thioesters, the a-proton becomes labile, thereby permitting reversible inversion of configuration to produce an equilibrated mixture of thiolester-bound enantiomers. Hydrolysis of the thiolester yields the product. 

In this section, dynamic kinetic resolution of substrates having a proton with low pKa is discussed. Racemization occurs by performing the DKR in the presence of a weak base. Enzyme- and base-catalyzed DKRs are categorized, according to the nature of the substrates, as being thioesters, -activated esters, oxazolones, hydan-toins or acyloins. 

In contrast to oxoesters, the a-protons of thioesters are sufficiently acidic to permit continuous racemization of the substrate by base-catalyzed deprotonation at the... 

The thioester linkage in acetyl-CoA activates the methyl hydrogens, and Asp375 abstracts a proton from the methyl group, forming an enolate intermediate. 

The stereochemistry of /1-elimination reactions catalysed by D-galactonate dehydratase (GalD) and D-glucarate dehydratase (GlucD) enzymes is apparently not dictated by the pKas of the 7-protons of the carboxylate anion substrates.74 It had been observed previously that enzyme-catalysed dehydration initiated by abstraction of the a-proton (P a > 29) from a carboxylate anion substrate usually proceeds via anti elimination, whereas syn elimination occurs when the proton is a- to an aldehyde, ketone, or thioester and correspondingly more acidic (pKa < 25). 

Sulfur as Heteroatom. Thiols and sulfides are protonated on sulfur in superacid media and give mono- and dialkylsulfonium ions, respectively.136 Thio-carboxylic acids, 5-alkyl esters, thioesters, dithioesters, and thiocarbonates in similar media also form stable protonated ions541,647 such as cations 348-353. 

DKR of thioesters (Scheme 21.2) with a chiral center at the a-carbon has been achieved in a water/acetonitrile biphasic system by racemization with mild organic bases, such as trioctylamine, coupled to enantioselective hydrolysis of the thioester with subtilisin Carlsberg.28 Such an approach can be applied to a wide variety of thioesters but not oxoesters, which have less acidic a-protons. 

Oxo-l,3-pyridothiazines. Most work on TAs fused with heterocycles has been devoted to 4-oxo-l,3-pyridothiazines. A number of pyrido-TAs 166 were obtained from 2-chloronicotinamide and thioesters in the presence of sodium hydride (89T4153) (Scheme 57). The role of sodium hydride consists in eliminating a proton from the amide group the resulting N-anion attacks the thiocarbonyl function, forming intermediates 165 whose cyclization gives pyrido-TAs 166. 

Heterobimetallic asymmetric complexes developed by Shibasaki et al. are known as effective catalysts for asymmetric Michael additions. They achieved a catalytic asymmetric protonation in Michael additions of thiols to a,P-unsaturated carbonyl compounds using LaNa3tris(binaphthoxide) and SmNa3tris(binaphthoxide) complexes (SmSB) 37 [42]. For instance, treatment of thioester 48 with 4-fert-butyl(thiophenol) and 0.1 equivalents of (P)-SmSB 37 (Ln=Sm) in CH2C12 at -78°C gave the adduct 49 in 93% ee and in 86% yield (Scheme 4). The high enantiomeric ratio is considered to be attributable to an... 

The mechanism of these reactions was proposed to take place by initial electron transfer to the carbonyl group of the thioester, generating a ketyl-like radical anion such as 103 (Scheme 7.43). Subsequent radical addition to the electron-deficient alkene (acrylamide or acrylate), possibly guided by pre-complexation to a Sm(III) metal ion, generates a new radical centre, which is reduced to the corresponding Sm(III) enolate by a second equivalent of Sml2. Protonation of this enolate and hydrolysis of the hemithioacetal upon work-up then lead to the y-ketoamide or ester. 

In these reactions a proton is abstracted from a carbon adjacent to carbonyl, carboxylic acid, or the carboxylate anion group by active cite residues. In water the pKa of a-protones of most aldehydes, ketons, thioesters, and carboxylate anions lies between 16-32, whereas pKa of most carboxylate bases is usually < 7. Thus, the thermodynamic barrier for the... 

Among the very few papers published after the above review appeared, two deserve some comment. The asymmetric protonation of the lithium enolate of a thiopyranic thioester by an ephedrine-derived chiral aminoalcohol described by Ward and coworkers leads to the desired enantiomer in 99% yield and 82% e.e., provided the reaction was performed in carefully designed conditions (Scheme 79)373. 

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