Methyl esters, to protect carboxyl groups

Dithianyl-2-methyl esters, to protect carboxyl groups, 243... 

Di-t-butyl[9-(10,10-dioxo-l0,10,10,10-tet-rahydrothioxanthyl)]methyl carbamates, to protect amines, 320 Di-f-butylmethylsilyl esters, to protect carboxyl groups, 263... 

Methyl carbonates to protect alcohols, 104 to protect phenols, 165-166 a-Methylcinnamyl esters, to protect carboxyl groups, 249... 

Two chemical methods have been devised to avoid formation of the nonsweet (Z)-P-aspartyl compound. The first of these entails the use of an activated precursor in which the P-carboxyl group is protected [11]. In this method, the approach described in Scheme 1 is used. This route gives an overall aspartame yield of about 55%. The rate of formation of the product depends on the degree of hydrolysis of the intermediate aspartyl P-methyl ester to the diacid (not shown), before entering the esterification medium (steps 3 and 4). 

The synthesis starts with the coupling of two more amino acids aspartic acid and phenylalanine. As you would expect, the carboxylic acid group of phenylalanine is protected, this time as a methyl ester, and the NH2 group of aspartic acid is protected as a Cbz-derivative. Since aspartic acid has two carboxylic acid groups, one of these also has to be protected. Here is the method—first the Cbz-group is put on then both acids are protected as benzyl esters. Then just one of the benzyl esters is hydrolysed. It may seem surprising to you that this chemoselective hydrolysis is possible, and you could not have predicted that it would work, without trying it out in the lab. 

The reaction is limited by the equilibrium position, and so products have to be removed from the mixture in order to a chieve high yields. In excess of phenylalanine methyl ester the protected aspartame forms a poorly soluble carboxylate anion which precipitates from the reaction mixture. This makes it easy to remove by fihra tion. The last step of the process is the removal of protecting group by conventional... 

An alternative reagent, trimethylsilyldiazomethane in hexane, is commercially available and appears useful for preparation of bile acid methyl esters [62], Like carboxylic acid groups, hydroxyl groups also require protection prior to GC-MS analysis. A common and mild method to prepare trimethylsilyl (TMS) ethers is to react the sample with a mixture of dry pyridine, hexamethyldisilazane (HMDS), and trimethylchlorosilane (TMCS), 3 2 1 or 9 3 1 (by volume) with, or without heating [32], However, if 0X0 groups are present in the bile acid, this reaction can yield enol-TMS ethers and multiple products. This artifact can be avoided by converting the 0X0 group into an oxime, usually a methyloxime (MO). To do this, the sample is dissolved in 50 pL pyridine with 5 mg methoxyammonium chloride and heated for 30 min at 60°C [32]. 

For protecting carboxyl groups, methyl esters (OMe), ethyl esters (OEt), benzyl esters (OBZL), p-nitrobenzyl esters (ONB), /-butyl esters (OBut) or substituted hydrazides (e.g., —N2H2—Z) are used. Coupling occurs according to the azide method. 

The blocking and deblocking of carboxyl groups occurs by reactions similar to those described for hydroxyl and amino groups. The most important protected derivatives are /-butyl, benzyl, and methyl esters. These may be cleaved in this order by trifluoroacetic acid, hydrogenolysis, and strong acid or base (J.F.W. McOmie, 1973). 2,2,2-Trihaloethyl esters are cleaved electro-lytically (M.F. Semmelhack, 1972) or by zinc in acetic acid like the Tbeoc- and Tceoc-protected hydroxyl and amino groups. 

Section 27 16 Carboxyl groups are normally protected as benzyl methyl or ethyl esters Hydrolysis m dilute base is normally used to deprotect methyl and ethyl esters Benzyl protecting groups are removed by hydrogenolysis... 

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. 

In a penicillin synthesis, the carboxyl group was protected as a / -bromophenacyl ester that was cleaved by nucleophilic displacement (PhSK, DMF, 20°, 30 min, 64% yield). Hydrogenolysis of a benzyl ester was difficult (perhaps because of catalyst poisoning by sulfur) basic hydrolysis of methyl or ethyl esters led to attack at the /3-lactam ring. ... 

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