Carboxy group activation esterification

Another alternative for incorporation of the first protected amino acid onto hydroxymethyl base resins without activation of the carboxy group is by a Mitsunobu reac-tion.f l The esterification of 4-hydroxymethylphenoxy-type resins by Fmoc-protected amino acids using this method was first reported by Sieber,P l who observed the presence of an unidentified hydrophobic impurity in the amino acids cleaved from the resin however, independent studies by the groups of Krchnak and Spatola l have shown that the esterification of 4-hydroxymethylphenoxy-type PSty and PEG-PS resins using this procedure proceeds rapidly with acceptable to good yields, with practically no racemization and without the presence of additional contaminants in the final product. On the other hand, this method did not provide satisfactory results for cellulose supports.P l... 

Of great importance in peptide chemistry are the f-butyl, benzyl and substituted benzyl es-ters. 226 They are more stable to acids than the corresponding urethanes. Benzyl and substituted benzyl esters can be prepared by azeotropic esterification with the respective benzyl alcohol, by activating the carboxy group, e.g. with dicyclohexylcarbodiimide (DCC) or by reacting a carboxylate with a benzyl halide (Scheme 65). The latter 5N2-type ester formation is particularly efficient if cesium carbox-ylates are employed. Under the conditions required for this reaction the racemization of a-chiral car-... 

Actinoplanic acids A and B exhibited IC50 values of 230 and 50 nM, respectively, against rHFPTase. Both compounds are competitive with FPP and displayed Kj values of 98 and 8 nM, respectively. The inhibition profile of these compounds was uncompetitive with respective to the Ras peptide substrate. The inhibition of FPTase by actinoplanic acids is selective and reversible and these compounds did not inhibit the human squalene synthase and bovine brain GGPTase (ICso s > 1 jjM) [87,88]. Similar to other examples of inhibitors that are competitive with respect to FPP, esterification of the carboxy groups of actinoplanic acids completely eliminated inhibitory activity. The increased potency of actinoplanic acid B is associated with the increased number of negative charges when compared with acid A [87,88]. 

Photolysis of ammonium salts of prochiral acids 255 and 256 may lead to a mixture of two diastereoisomers. When photolyzed in acetone solution, the optically active salts of 255 or 258 with proline tert-butylester provide only racemic products. However, photolysis of the chiral crystals, followed by esterification of the carboxylic group with diazomethane after acidification, affords the chiral photoproducts 257 and 259, respectively, in over 95% ee [196]. From the absolute configuration of the new asymmetric centers and X-ray analysis of the starting salts, it became apparent that both salts reacted in such a way that interaction between the carboxy substituents was minimized in the benzo-vinyl bridging transition state. 

On the other hand, with less basic nucleophiles, especially under acidic conditions, the ready reversibility of carboxylate formation may permit nucleophilic addition to compete and ultimately lead to substitution through the addition-elimination mechanism. A typical example is the esterification of a carboxylic acid (Section 9-4), in which an alcohol and a carboxylic acid react to yield an ester and water. The nucleophile, an alcohol, is a weak base, and acid is present to protonate both the carbonyl oxygen, activating it toward nucleophilic addition, and the carboxy OH, converting it into a better leaving group, water. 

Gas-chromatographic methods are widely used to analyze amino acids in the hydrolyzates of small protein samples. The method s sensitivity is the major reason for these applications. In addition, GC-based techniques provide opportunities to distinguish and quantitate amino acids (and several other compound types) as different optical isomers. The most popular procedure to separate R and S isomers employs an optically active (chiral) stationary phase. Because of the zwitterionic nature of amino acids, a two-step derivatization is necessary prior to GC. As the first step, the acid (carboxy) function is blocked through esterification. During the second treatment, the amino groups are acylated. Figure 16 demonstrates... 

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