Alanine ester

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

Figure 5.1. Fast acylation of alanine ester via host-guest complexation (from Chemistry and Engineering News, 1983, p. 33).

Finally, as a specific example, the regioselective esterification of ribavirin (24) deserves to be discussed (Figure 6.6) [83]. This compound is a powerful antiviral agent used to treat hepatitis C. In order to overcome some significant side effects, it has been suggested that its administration in the form of a prodrug might improve its pharmacokinetic profile. Indeed a series of predinical evaluations showed that the alanine ester 24a possesses improved bioavailability. In... 

Scheme 7.18 Regioselective acylation to synthesize the alanine ester of ribavirin, an antiviral agent.

Under oxidative conditions, a side chain alkyl group is sometimes removed from a coordinated amino group. This has been observed in the case of the complexes of the Schiff base of salicylaldehyde with alanine esters (Equation 30) (60, 61). 

It is of interest that the alanine ester groups in the membrane teichoic... 

The teichoic acid which had not been subjected to ion-exchange chromatography contained D-alanine in characteristic, labile, ester linkage. It contained insufficient glucose to accommodate all of the alanine ester residues (alanine phosphorus ratio, 0.89 1), and the kinetics of the reaction with hydroxylamine indicated that all of the alanine is attached to the available hydroxyl groups at C-2 of glycerol residues. 

The 2-amino-2-deoxy-D-glucosyl phosphate linkage is very labile to acid consequently, the teichoic acid is hydrolyzed under mild conditions to a fragment which is apparently44 (43) or (44). Study of this compound should establish which hydroxyl group of the 2-acetamido-2- deoxy-D-glucose residue bears the phosphodiester group. The alanine ester residues (84a) Unpublished work of the authors with Mr. D. Button. 

All of the ribitol teichoic acids so far examined are composed of chains of ribitol residues joined through phosphodiester groups at C-l and C-5. Each chain is terminated by a phosphomonoester residue, and the ribitol residues bear glycosyl and D-alanine ester substituents. Detailed structures have been proposed for the polymers from Bacillus aubtilis and Lactobacillus arabinosus, and from two strains of Staphylococcus aureus. The structure of the teichoic acid from Bacillus subtilis was the first to be established in detail the other polymers differ mainly in the nature of the glycosyl substituents. 

The teichoic acid shows an infrared absorption band at 1751 cm.-1, characteristic of carboxylic ester groups, which is not observed in samples from which the D-alanine residues have been removed. Removal of the u-alanine was readily effected with ammonia or hydroxylamine, when D-alaninamide or D-alanine hydroxamate were formed. The kinetics of the reaction with hydroxylamine reveal the high reactivity of its D-alanine ester linkages, which, like those in most other teichoic acids, are activated by the presence of a neighboring phosphate group. That the D-alanine residue is attached directly to the ribitol residues, instead of to the d-glucosyl substituents, was also shown by oxidation with periodate under controlled conditions of pH, when it was found that the D-alanine residues protect the ribitol residues from oxidation. Under the same conditions, all of the ribitol residues were oxidized in a sample of teichoic acid from which the D-alanine had been removed, and it is concluded that the ester groups are attached to C-2 or C-3 of the ribitol residues. 

The incorporation of the D-alanine ester groups is, presumably, the last stage in the biosynthesis of teichoic acids. Several organisms possess enzymes which activate D-alanine, that is, which form a D-alanyl-adenosine 5-phosphate-enzyme complex but, so far, there has been no demonstration of incorporation, in cell-free systems, of D-alanine into teichoic acid or any... 

The united ethereal solutions, which are brown in colour, are shaken for 5 minutes with potassium carbonate, then poured off, and dried for 12 hours over anhydrous sodium sulphate. When the greater part of the ether has been evaporated at ordinary pressure on a water bath, the distillation is continued under a pressure 10—12 mms. At ordinary temperature, ether first passes over. The distilling vessel is now warmed in warm water, when a first fraction is obtained, which still contains alcohol and ether, and also some glycocoll ester and alanine ester. When the temperature of the bath has risen to 55°, the main part of the alanine ester begins to boil. The operation is discontinued when, at a bath temperature of 80°, nothing more distils over. In this way 110—125 gms. distillate are obtained, consisting for the most part of alanine ester. 

To obtain free alanine the alanine ester is heated for about 6 hours with 5 times its weight of water on a water bath, until the alkaline reaction has disappeared. The solution is evaporated on a water bath till crystallisation begins. The liquid is allowed to stand at 0°, when about 30 gms. alanine separate optical examination shows this to consist of almost pure d-compound. From the mother liquor a second crop of 20—25 gms. may be obtained, and this still consists of fairly pure active amino-acid, so that the total yields amount to 50—55 gms. The last mother liquor still contains a fair amount of active alanine, but it is mixed with so much racemic substance that it cannot be separated from it by mere recrystallisation from water. The first two crops are dissolved once more in hot water, and the liquid evaporated on the water bath till it begins to crystallise. At 0° a large quantity of the pure, active amino-acid separates out. 

N-TFA-alanine ester Recovery (%) after exposure to the stream of gas for Retention time (min)... 

An interesting version of this concept was published recently [18]. After reaction of the alanine ester 5 with borane, the mixture of the diastereo-mers 6 and 7 could be separated (Scheme 1). The chiral nitrogen atom directs the attack of the electrophile at the enolate. The direction of the attack can be explained by the Felkin - Anh model, because the electrophile approaches anti to the largest (benzyl) substituent. The enolate shown... 

One of the main questions in the cobalt(III)-promoted hydrolysis of activated amino acid esters is whether the ratedetermining step is addition of hydroxide to the carbonyl carbon, or loss of the alkoxide from the intermediate. Work with /3-alanine ester showed that below pH 8.5 the ratedetermining step was the elimination of alkoxide. At pH 10 and above, the rate-determining step changes and the addition of hydroxide to the activated ester becomes the rate-controlling step. This is due to the fact that above pH 10 the hydroxyl group of the intermediate becomes deprotonated (equation 7). The deprotonation of the hydroxyl group accelerates the loss of alkoxide by 10 times. ... 

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