Active esters

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

Fig. 8. Rephcation. The amino adenosine X and the pentafluorophenyl ester Y form a hydrogen-bonded dimer XY, prior to reaction between the amine and the activated ester groups (shown in the circle). The reaction product is a <7 -amide conformer cis-Z that isomeri2es to the more stable trans- acnide Z. The rephcative process is cataly2ed by the reaction product Z (also referred to as the template). First, a termolecular complex XYZ is formed from X, Y, and Z.

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). 

Optically Active Acids and Esters. Enantioselective hydrolysis of esters of simple alcohols is a common method for the production of pure enantiomers of esters or the corresponding acids. Several representative examples are summarized ia Table 4. Lipases, esterases, and proteases accept a wide variety of esters and convert them to the corresponding acids, often ia a highly enantioselective manner. For example, the hydrolysis of (R)-methyl hydratropate [34083-55-1] (40) catalyzed by Hpase P from Amano results ia the corresponding acid ia 50% yield and 95% ee (56). Various substituents on the a-carbon (41—44) are readily tolerated by both Upases and proteases without reduction ia selectivity (57—60). The enantioselectivity of many Upases is not significantly affected by changes ia the alcohol component. As a result, activated esters may be used as a means of enhancing the reaction rate. 

Unprotected racemic amines can be resolved by enantioselective acylations with activated esters (110,111). This approach is based on the discovery that enantioselectivity of some enzymes strongly depends on the nature of the reaction medium. For example, the enantioselectivity factor (defined as the ratio of the initial rates for (3)- and (R)-isomers) of subtiHsin in the acylation of CX-methyl-ben zyl amine with tritiuoroethyl butyrate varies from 0.95 in toluene to 7.7 in 3-methyl-3-pentanol (110). The latter solvent has been used for enantioselective resolutions of a number of racemic amines (110). 

Optically active 2-arylaIkanoic acid esters have been prepared by Eriedel-Crafts alkylation of arenes with optically active esters, such as methyl 3 -2-(chlorosulfonoxy)- or 3 -2-(mesyloxy)propionate, in the presence of aluminum chloride (54,55). 

Finally the preformed 2-formyl-3-aminoquinoxaline (448) gave the pyrido[2,3-f ]quin-oxalin-2-one (449) with activated esters/sodium alkoxide (79ZC422). 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information for this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful... 

The / -(methylmercapto)phenyl ester has been prepared from an /-protected amino acid and 4-tH3SC6H40H (DCC, CH2CI2, 0°, 1 h 20°, 12 h, 60-70% yield). The p-(methylmercapto)phenyl ester serves as an unactivated ester that is activated on oxidation to the sulfone (H2O2, AcOH, 20°, 12 h, 60-80% yield) which then serves as an activated ester in peptide synthesis. ... 

A polymer-supported sulfonamide, prepared from an amino acid activated ester and a polystyrene-sulfonamide, is stable to acidic hydrolysis (CF3COOH HBr/ HOAc). It is cleaved by the safety-catch method shown below. ... 

Under Barbier conditions, trifluoromethyl bromide reacts with electrophiles, such as aldehydes, Orkelo esters, activated esters, and anhydrides in the presence of pyridine to give trifluoromethylated compounds [35, 45 46] (equations 34 37)... 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

This active ester was used for carboxyl protection of Fmoc-serine and Fmoc-threonine during glycosylation. The esters are then used as active esters in peptide synthesis. 

Cleavage is achieved with H2O, IPA, or MeOH. These derivatives also serve as active esters in peptide bond formation. ... 

A polymer-supported sulfonamide, prepared from an amino acid activated ester... 

In the previous review (91YGK205, 99H1157), we reported that l-hydroxy-4-nitroindole forms active ester derivatives by reaction with carboxylic acids, which can be applied to acylation of various nucleophiles. To expand the scope of the reaction and obtain novel fungicidal compounds, an attempt has been made to prepare derivatives of wasabi phytoalexin 109 (98P1959). 

In the presence of DCC, 140 is allowed to react with both l-hydroxy-5-nitroindole (36) and 1-hydroxy-1,2,3-benzotriazole (141). Interestingly, their corresponding active esters, 142 and 143, are obtained in excellent yields as stable crystalline compounds. Both compounds are found to react with variety of nucleophiles, such as alcohols and amines, to produce 144 and 145 in good to excellent yields, as can be seen from the typical examples shown in Scheme 22 (2001H2361). As aresult, it becomes possible to produce various kinds of derivatives of wasabi phytoalexin utilizing 142 and 143. 

Possessing a side chain at C-7 reminiscent of that of amoxacillin and a more typical sulfur containing C-3 moiety, cefatri zi ne (44) can be synthesized by the active ester... 

Structurally rather similar to cefatrizine is cefaparole ). It is prepared in quite an analogous manner by active ester condensation of and 7-aminocephalosporanic acid analogue The blocking group is removed with trifluoro-... 

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