Enzymatic transesterification

General Preparations of Esters General Cleavage of Esters Transesterification Enzymatically Cleavable Esters Heptyl, 381... 

Lozano P, Belleville MP, Rios GM, and Iborra, JL. Transesterification enzymatic process with a dynamic membrane reactor in supercritical media. Seventh Meeting on Supercritical Fluids, Antibes, France, 2000. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

Enzymatic transesterification of cycHc diols often proceeds with very good yield and selectivity (35—39). 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

The enzymatic resolution of esters via aminolysis or ammonolysis processes represents an efficient alternative to the resolution of substrates by transesterification... 

The enzymatic KR between racemic amines and nonactivated esters using a lipase as biocatalyst is shown in Scheme 7.15. In the same manner as in the transesterification of secondary alcohols, this process fits Kazlauskas rule [32], where normally if the large group (L) has larger priority than medium group (M), the (R)-amide is obtained. In general, major size differences between both groups result in better enantios-electivities ( ). 

Aminoalcohols are an important class of compounds in medicinal chemistry because many drugs contain this structure. For their resolution, there are two possibilities acylation of amino function or an enzymatic transesterification with vinyl esters through the hydroxyl group. However, the amino or hydroxyl group must be protected, because if the starting material is the free aminoalcohol, the O- and N-acylation can take place, and in addition, there are migrations obtaining... 

The DKR of secondary alcohols can be efficiently performed via enzymatic acylation coupled with simultaneous racemization of the substrates. This method was first used by BackvaU for the resolution of 1-phenylethanol and 1-indanol [38]. Racemization of substrate 18 by a mthenium catalyst (Scheme 5.11) was combined with transesterification using various acyl donors and catalyzed by C.antarctica B Hpase. From aU the acyl donors studied, 4-chlorophenyl acetate was found to be the best. The desired product 19 was obtained in 80% yield and over 99% ee. 

Scheme 5.11 Dynamic kinetic resolution of alcohol 18 by combination of enzymatic transesterification and ruthenium-catalyzed racemization.

In addition to the catalytic action served by the snRNAs in the formation of mRNA, several other enzymatic functions have been attributed to RNA. Ribozymes are RNA molecules with catalytic activity. These generally involve transesterification reactions, and most are concerned with RNA metabofism (spfic-ing and endoribonuclease). Recently, a ribosomal RNA component was noted to hydrolyze an aminoacyl ester and thus to play a central role in peptide bond function (peptidyl transferases see Chapter 38). These observations, made in organelles from plants, yeast, viruses, and higher eukaryotic cells, show that RNA can act as an enzyme. This has revolutionized thinking about enzyme action and the origin of life itself. 

Ester-thioester copolymers were enzymatically synthesized (Scheme 7). ° The lipase CA-catalyzed copolymerization of e-caprolactone with 11-mercaptoundecanoic acid or 3-mercaptopropionic acid under reduced pressure produced the polymer with molecular weight higher than 2 x 10". The thioester unit of the resulting polymer was lower than the feed ratio. The transesterification between poly(8-caprolactone) and 11-mercaptoundecanoic acid or 3-mercaptopropionic acid also took place by lipase CA catalyst. Recently, aliphatic polythioesters were synthesized by lipase CA-catalyzed polycondensation of diesters with 1,6-hexanedithiol. ... 

Chemoenzymatic synthesis of alkyds (oil-based polyester resins) was demonstrated. PPL-catalyzed transesterification of triglycerides with an excess of 1,4-cyclohexanedimethanol mainly produced 2-monoglycerides, followed by thermal polymerization with phthalic anhydride to give the alkyd resins with molecular weight of several thousands. The reaction of the enzymatically obtained alcoholysis product with toluene diisocyanate produced the alkyd-urethane. 

Fatty acid esters of sugars are also very important biodegradable and biocompatible surfactants that are prepared either by transesterification of methyl ester with sugar on basic catalysts or by esterification of fatty acids with sugar on acidic catalysts. Liquid acids and bases have been replaced by enzymatic catalysis with lipase, giving a higher yield of monoester [43, 44], but solid catalysts have not been used extensively so far. 

In contrast to Mori s synthesis, Pawar and Chattapadhyay used enzymatically controlled enantiomeric separation as the final step [300]. Butanone H was converted into 3-methylpent-l-en-3-ol I. Reaction with trimethyl orthoacetate and subsequent Claisen-orthoester rearrangement yielded ethyl (E)-5-methyl-hept-4-enoate K. Transformation of K into the aldehyde L, followed by reaction with ethylmagnesium bromide furnished racemic ( )-7-methylnon-6-ene-3-ol M. Its enzyme-catalysed enantioselective transesterification using vinylacetate and lipase from Penicillium or Pseudomonas directly afforded 157, while its enantiomer was obtained from the separated alcohol by standard acetylation. 

The transesterification of cocaine to cocaethylene is an enzymatic reaction catalyzed by microsomal carboxylesterases and blocked by inhibitors of serine hydrolases [124][125], In Chapt. 3, we have discussed the mechanism of serine hydrolases, showing how a H20 molecule enters the catalytic cycle to hydrolyze the acylated serine residue in the active site of the enzyme. In the case of cocaine, the acyl group is the benzoylecgoninyl moiety (Fig. 7.9,d ), which undergoes esterification with ethanol according to Steps e and/ (Fig. 7.9). 

One of the best examples of the utility of enzymatic synthesis in catalyzing reactions that cannot be accomplished by any other route is the synthesis of substituted oxazolidine diesters. The oxazolidine ring is extremely water sensitive, the oxazolidine rapidly reverting back to the alkanolamine and aldehyde in the presence of water. Bis-oxazolidines have been used as hardeners for polymer coatings but the diester based on the hydroxyethyl oxazolidine and adipic acid cannot be synthesized directly with chemical catalysis because of the rapid rate of reaction of the oxazolidine ring with either the water from the esterification or the alcohol from transesterification. ... 

The dimethyl ester of adipic acid, rather than adipic acid, was used as a transesterification substrate. Reaction rate studies had shown that the transesterification would be much faster than the esterification reaction. It was considered that the rate of attack on the oxazolidine ring by methanol would be slower than the rate of attack by water and that the ring opening would not be catalysed by the enzyme, whereas the rate of the transesterification would be increased significantly, particularly at the low temperature of the enzymatic esterification. 

In a succeeding publication, the same authors reported on an enantiose-lective approach to diquinane enones 6 and ent-6 by combining the above-described synthesis with an enzymatic kinetic resolution (Scheme 4) [12]. After lipase-catalyzed enantioselective transesterification of diol rac-12. 

The enzymatic resolution of racemic substrates now is a well-established approach for the synthesis of single enantiomers [1, 2]. A representative example is the kinetic resoluhon of secondary alcohols via lipase-catalyzed transesterification for the preparation of enantiomericaUy enriched alcohols and esters [3], The enzymatic resolution in general is straightforward and satisfactory in terms of optical purity, but it has an intrinsic Hmitation in that the theoretical maximum yield of a desirable enantiomer cannot exceed 50%. Accordingly, additional processes such as isolation, racemization and recycling of unwanted isomers are required to obtain the desirable isomer in a higher yield (Scheme 1.1). 

There are basically two approaches to the synthesis of enantiomerically pure alcohols (i) kinetic resolution of the racemic alcohol using a hydrolase (lipase, esterase or protease) or (ii) reduction mediated by a ketoreductase (KRED). Both of these processes can be performed as a cascade process. The first approach can be performed as a dynamic kinetic resolution (DKR) by conducting an enzymatic transesterification in the presence of a redox metal [e.g. a Ru(ll) complex] to catalyze in situ racemization of the unreacted alcohol isomer [11] (Scheme 6.1). We shall not discuss this type of process in any detail here since it forms the subject of Chapter 1. 

Scheme 10.9 Synthesis of optically active formoterol using an enzymatic transesterification step.

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