Active esters transesterification

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). 

Besides allylic substitution reactions it was also shown that [Fe(CO)3(NO)] 76 is catalytically active in transesterification reactions under neutral conditions (Scheme 24) [70]. Various activated acyl donors 97 can be used to give rise to the corresponding carboxylic esters 100 in good to excellent yields. This reaction proceeds in the absence of additional ligands in nonpolar solvents, for example, hexane. Mechanistically, the reaction is assumed to proceed via a Fe-acyl-complex 98 (Scheme 24). 

The aminolysis of activated esters generally occurs more readily in polar solvents and is catalyzed by mild acid (see Section 7.6) or 1-hydroxybenzotriazole. Transesterification and through mixed anhydrides are other methods by which activated esters can be obtained (see Section 7.8).20-27... 

The alternative method for making activated esters is base-catalyzed transesterification. Fmoc-amino acids are esterified in excellent yields by reaction with pentafluorophenyl trifluoroacetate at 40°C in the presence of pyridine (Figure 7.13). A mixed anhydride is formed initially, and the anhydride is then attacked by the pentafluorophenoxy anion that is generated by the pyridine. Succinimido, chlorophe-nyl, and nitrophenyl esters were made by this method when it was introduced decades ago. A unique variant of this approach is the use of mixed carbonates that contain an isopropenyl group [Cf C CfyO-COjR]. These react with hydroxy compounds in the presence of triethylamine or 4-dimethylaminopyridine (see Section 4.19) to give the esters and acetone.30 35... 

Ir-catalyzed allylic substitutions employing allylic alcohols as substrates and diethyl malonate as pronucleophile were first reported by Takeuchi and coworkers [11]. Here, the substitution step was found to be preceded by OH activation via transesterification to a malonic ester derivative. The asymmetric alkylation of cinnamic alcohol was similarly accomplished by Helmchen and colleagues, using a PHOX ligand and the procedure described in Section 9.2.3 [19]. 

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

Many catalysts do not use metals in their pure reduced metallic forms. Anchored organometallic complexes are often analogs of homogenous catalysts fixed on a solid support. In particular, titanate complexes both in solution and in supported form have been found to be especially active in transesterifications of simple esters.It was proposed that titanates catalyze the transesterification reaction through a Lewis acid mechanism where the reactant ester and metal form a Lewis complex activating the carbonyl groups for a nucleophilic attack by the reactant alcohol. The tetrahedral intermediate that is formed breaks down into the product alcohol and an ester-metal Lewis... 

Transesterification of sugars and derivatives with such active esters as the acetate, butanoate, decanoate, or dodecanoate of 2,2,2-trichlorethanol allowed selective acylation. In this first way, D-glucose, D-galactose, and D-mannose, in multigram quantities, gave the primary acylate in fair yield,110 in pyridine solution, in the presence of PPL (70,000 U). This type of reaction was also selective with di- and tri-saccharides thus, in... 

The selective enzyme-catalyzed acylation of carbohydrates is of great interest, as of carbohydrates fatty acid esters of carbohydrates have important applications in detergents, cosmetics, foodstuff, and pharmaceuticals because of their surface-active properties. Monoacylated sugars have been synthesized by lipase-catalyzed transesterifications of activated esters in pyridine and by protease-catalyzed esterifications in DMF. A most remarkable new development... 

Other metals which catalyze PET polycondensation are proposed to coordinate with and activate ester carbonyl groups similarly. That different metals are optimal for activating the ester carbonyls of DMT and of BHET (i.e., catalyzing transesterification and polycondensation, respectively) has been well explained by accounting for differences in carbonyl oxygen basicity between methyl esters and hydroxyethyl/alkoxyethyl esters. The optimum catalysts for each step maximize electronic interactions with the reacting esters [29, 30]. 

Peptide synthesis. Vinyl esters of amino acids, prepared by transesterification with vinyl acetate, have been used as activated esters in peptide synthesis. The coupling reaction is best carried out in ethyl cyanoacetate, for this solvent suppresses the formation of colored products derived from liberated acetaldehyde. Racemization appears to be slight. 

The addition of a higher molecular weight acid such as capric acid, is beneficial, and under these conditions high yields of propionates are obtained, presumably via a transesterification mechanism. Using this enzymatic technique it is possible to carry out relatively large scale preparative syntheses of natural flavor-active esters, using natural raw materials as substrates. 

Much of the current interest in making simple derivatives of (+ )-castanospermine (239) can be traced to a seminal publication in 1989, which showed that the alkaloid s anti-HIV activity could be increased by as much as twenty times upon esterification (216). Positionally selective acylation procedures usually involve sequential protection, acylation, and deprotection steps e.g. the preparation of esters at the C-6 and C-7 (217) or the C-8 hydroxy groups (218). Also of interest are procedures that take advantage of enzyme-catalyzed transesterification with activated esters, e.g. the use of subtilisin for ester formation at C-1, pancreatic porcine lipase for preferential reaction at C-6 and C-7 (219-221), and cross-linked enzyme crystals (CLECs) of subtilisin for making the potentially valuable antitumor agent 1-0-butanoylcastanospermine (222). A cautionary note was sounded, however, when it was observed that 6-0-acyl castanospermine esters could equilibrate to a mixture of... 

A 42-residue polypeptide that folded into a helix-loop-helix motif and dimerized to form a four-helix bundle was shown to catalyze the hydrolysis and transesterification reactions of active esters. Scheme 5.3 [6, 11, 12). The solution structure and reaction mechanism were extensively studied, see Section 5.2, and the rate en-... 

Crown ethers also enhance the activity of enzymes in organic solvents.100 The enzyme is lyophilized in the presence of the crown ether before use. a-Chymotrypsin treated in this way with 18-crown-6 was 640 times as active in transesterification of amino acid esters as the untreated enzyme. However, the rate was still 50 times lower than in water. The use of surfactants to improve activity in organic solvents seems preferable because of a greater rate increase. They also avoid the toxicity and expense of the crown ethers. The cross-linked enzyme crystals also offer a way to obtain reasonable rates in organic solvents. 

Transesterifications of (Reversion of hydrolytic reactions) (racemic) alcohols with nonactivated esters (racemic) alcohols with activated esters irreversible transesterification with vinyl-carboxyl ates esterases, lipases, proteases CCL, PPL, lipase from Pc PPL, pancreatin CCL, PFL, PPL, lipase PS and SAM II, lipase from Pf... 

Chemical modification of polymer-bound active ester groups is also subject to strong solvent effects. In copolyfAOTcp-styrere), both aminolysis and transesterification with primary alcohols are positively influenced by solvents in the order of dimethylformamide (DMF) > dioxan > diloroform > chlorobenzene > dimethylsulfoxide (DMSO). However, trans-esterification with phenols proceeds in dioxan, but not in DMF. The last-nan d solvent effect is probably related to inactivation of the phenolate ion in DMF, as observed ako for the acylation of polymer-bound phenolic groups by soluble trichlorophenyl esters [64]. 

Similar to the reaction course of the allylic substitution, which involves formation of tr-allyl moieties followed by subsequent nucleophilic addition across the Jt-bond, the mononitrosyl iron(—II) complex was expected to be active in transesterifications involving activation of carbonyl group and nucleophilic addition to the electrophilic carbon atom [100]. This assumption could be verified by experimental tests. Under neutral conditions without addition of a ligand co-catalyst, the iron complex 31 exhibited high activity in the transesterification of vinyl acetate. Good to excellent yields were obtained affording a new ester bond, as depicted in Scheme 39. 

Hedrick and Waymouth also used 1,3-dimethylimidazolylidene as a nucleophile to activate esters for transesterification reactions [73]. Here, the NHC first adds into the carbonyl, eliminating l.Oequiv. of alcohol, and is then displaced by... 

A three-step process (Scheme 2) was carried out to covalently attach a-chymotrypsin to functionalized polystyrene (PS) fibers (11). PS was functionalized by reacting with 4-nitro-phenyl chloroformate to yield nitrophenyl ending PS (PS-NPh) which was electrospun into fibers, then coupled with a-chymotrypsin. The fiber bound a-chjnnotrypsin refined 65% of the activity of free enzyme in aqueous solutions, and exhibited nearly three order of magnitude higher activity in transesterification of n-acetyl-L-phenylalanine ethyl ester in hexane and isooctane. Also, the half life of the bound a-chymotr3q)sin was 18 fold longer than that of free fonn in methanol... 

Cambou, B. and Klibanov, A. M. (1984) Preparative production of optically active esters and alcohols using esterase-catalyzed stereospecific transesterification in organic media J. Am. Chem Soc. 106,2687-2692... 

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