DKR of Thioesters

DKR of thioesters for carboxylates One-pot H20, MeCN Trioctylamine Subtilisin Carlsberg 28... 

DKR of thioesters for oxo-esters One-pot Toluene Triethylamine CA lipase + n-BuOH 28... 

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. 

DKR of Thioesters The acidity of the H in the a-position of a thioester is higher than the acidity of the same positioned H in esters, amides, or acids. This fact and the ability of subtUisin Carslberg to hydrolyze a-amino acid thioesters have been the keys to the successful DKR of several N-Boc-a-amino thioesters rac-118 developed by Servi et al. Reactions were carried out in a biphasic system of TBME/-water, at 37°C and pH = 8.0, with trioctylamine as the base to remove the acidic a-H of the substrates (Scheme 57.34). pH was kept constant at 8.0 throughout each process, which was stopped when all the starting substrate had been consumed. Finally, the L-Af-Boc-a-amino acids 119 were easily... 

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... 

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. 

Scheme 5.6, Equation 5.1) [19]. Although the acidity of the a-proton is much greater than that of the oxoesters, the presence of a tertiary amine has been shown to be indispensable for quantitative conversion. Biochemical transesterification has also been reported for the DKR of a variety of chiral trifluoroethyl thioesters [20]. The DKR of trifluoroethyl thioesters, using either lipase-catalysed hydrolysis [20b,d,e] or transesteriflcation with 4-morpholine ethanol [20c], has allowed the isolation of enantiomerically pure profen esters based on (S)-naproxen, (S)-fenoprofen and (S)-suprofen in >75% yield with up to 95% ee. Some oxoester with relatively higher... 

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). 

Scheme S.S Resolution of thioesters comparison between kinetic resolution (no base) and DKR (with base) base employed is trioctylamine (TOA).

Tessaro, D., Cerioli, L., D Arrigo, P., Pedrocchi-Fantoni, G., Servi, S., and Viani, F. (2011) Deracemization of Non-Natural Amino-Acids Based on DKR of the Corresponding N-Protected Thioesters, Biotrans 2011. 

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. 

The hydrolysis of carboxylic acid derivatives using a DKR-based approach is not hmited to cyclic carhonyl compounds as exemplified in Scheme 5.6. For example, when an acyclic racemic thioester (possessing an electron-withdrawing arylsulfanyl group at the a-position) is subjected to enzymatic resolution, hydrolysis occurs smoothly to give the chiral carboxylic acid in high enantiomeric excess... 

The aim of this overview is to focus the attention toward the racemization conditions of two specific acyl donors commonly used for enzyme-catalyzed synthesis, namely the oxoesters and the thioesters. The former are often the substrates of choice because their mild reactivity (in contrast to anhydrides, for instance) limits their susceptibility to parasitic reactions such as spontaneous transacylation or condensation reactions, while at the same time they are easily transformed by enzymes. Thioesters, though being activated substrates from a thermodynamic point of view, possess a peculiar relative kinetic stability against spontaneous hydrolysis [10], which permits their use in biocatalysis moreover, they are far more prone to base-catalyzed racemization as compared to their oxygenated analogs [llj. This combination of features makes them attractive as candidates to be employed in DKRs as alternatives to oxoesters, and examples will be discussed to support this concept. 

Despite the fact that thioesters of optically active amino acids have long been known to racemize promptly even in the presence of rather weak bases [48], and that they are able to act as irreversible acyl donors in enzyme-mediated acyl transfers [49], it was only in 1995 that they were reported to be good substrate candidates for DKR, where they are continuously racemized by an organic base while a hydrolytic enzyme acts preferentially on one of the two enantiomers [50]. In later works, the same authors reported on a more detailed and systematic study of the same reaction system applied to a broader array of substrates. The reactions were ran in a biphasic water/toluene mixture in the presence of trioctylamine as a hydrophobic organic base, so that the substrate racemization takes place in the organic phase while the hydrolysis product is continuously extracted into the water phase. Under racemizing conditions, the authors obtained almost complete conversion and significantly better optical purity (Scheme 8.8) [51], which is attributable to the continue depletion of the unreactive substrate enantiomer. 

Because ofthe presence ofalarge amount of water appears to considerably narrow the field of the previously illustrated resolution system, experiments were started with immobilized enzymes in organic solvents, in which the water concentration was considerably reduced. This proved to be quite an effective strategy, permitting to carry out a nicely working DKR on a representative array of aliphatic N-Boc-amino acid thioesters [62], which could be resolved in high yield and with excellent optical purity. Moreover, the choice of an immobilized form of the enzyme (Alcalase -CLEA ) permitted recovery and reuse of the catalyst for several consecutive batches [63]. The solvent of choice proved to be tert-butanol, which was able to dissolve the hydrophobic substrates, the organic base, and the strictly necessary amount of water (Table 8.6). 

Table 8.6 Results obtained with the hydrolysis of N-Boc-amino acid thioesters under DKR conditions.

The racemization of the unreacted substrate can be accomplished either by spontaneous equilibration between the two enantiomers or by using a chemical or biological catalyst. The basic requirements for a successful DKR are that (i) the KR conditions must be compatible with the racemization process, (ii) the KR process must be very stereoselective, (iii) the catalyst for the racemization must not react with the product, and (iv) the racemization must be faster than the reaction of the slow reacting enantiomer k c 2> ksiow [la,b]. The concept of DKR has been applied to a variety of compounds such as a-amino acids, hemithioacetal esters, a-(hetero) arylcarboxylic acids, a-substituted nitriles, beta-keto esters, cyanohydrin esters, a-substituted thioesters, 4-substituted oxazolin-5-ones and thiazolin-5-ones [la]. 

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