Benzoylation: of alanine

No compound other than the methyl ester of N-benzoyl-Lphenylalanine, 33, is an obvious choice for an open-chain analog of the locked substrate 25 but D-24, on the other hand, may be a locked analog of either N-benzoyl-D-alanine methyl ester 34 or of N-formyl-D-phenylalanine methyl ester 35 (75). If 24 is an analog of 34 rather than 35, the comparison of the two locked analogs made in Section V.B. is not valid the phenyl of 24 would then correspond to the benzoyl phenyl of 34. 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

FIGURE 10.11 Adsorption isotherms of A-benzoyl-L-alanine (1) and iV-benzoyl-D-alanine (2). Experimental data fitted to the Bilangmuir model. (Reproduced from Jacobson, S. et al., J. Am. Chem. Soc., 112, 6492, 1990. With permission from American Chemical Society.)... 

A 3-amino-/V-[2-chloro-4 [(3-hydroxyphenyl)methyl]aminocarbonyl benzoyl-L-alanine substituted Wang resin was /V-acylated with 2-methoxy-11-oxo-l l/7-pyrido[2,l-Z>]-quinazoline-8-carboxylic acid in A-methylpyrro-lidone in the presence of l-hydroxy-7-azabenzotriazole and diisopropylcar-bodiimide (00MIP2). The product was cleaved from the resin by treatment with 50% TFA in a mixture of CH2C12 and MeOH. 

Experiment 5.221 RESOLUTION OF dl-ALANINE Benzoyl DL-alanine. Dissolve lOOg (1.1 mol) of DL-alanine (Expt 5.180) in 400 ml of water containing 44.5 g (1.1 mol) of sodium hydroxide and cool the solution in an ice bath. Add 175g (1.2 mol) of benzoyl chloride and a solution of 49 g (1.2 mol) of sodium hydroxide in 200 ml of water to the stirred, cooled, amino acid solution, alternately and in portions during 2 hours continue to stir for a further 2-hour period. Boil the reaction mixture with 10 g of decolourising charcoal, filter, cool the clear yellow filtrate to 0 °C and acidify carefully to Congo red with concentrated hydrochloric acid. Triturate a portion of the oil which separates with water to induce crystallisation and then seed the bulk of the acidified solution with crystals and leave in an ice bath to complete the crystallisation process. Filter off the product, wash the filter cake with 500 ml of ice-cold water and recrystallise from about 3.5 litres of boiling water. The yield of benzoyl-DL-alanine, m.p. 162-164 °C, is 194.5 g (90%). 

Other Oxazolidine as well as Thiazolidine Derivatives for Branching Amino Acids. The cyclic derivative of alanine and other amino acids employed most frequently for a-allq lation is not (1) but rather the benzaldehyde acetal (5), either with a benzoyl or with a Cbz group on nitrogen. These compounds were used for the preparation of 2-methyl-2-aminobutanoic acid, a-methylphenylalanine, a-methyllysine, 2-methylaspartic acid, and 2-methylglutamic acid. Bicyclic compounds containing oxazolidinone rings such as (6) (from alanine, leucine, and phenylalanine) and (7) (from azetidinecaiboxylic acid, proline, " hydroxyproline, and cysteine ) have also been applied to the synthesis of branched amino acids. 

Binding of X-Phenyl, N-Benzoyl-L-alaninates to a-Chymotrypsin in Phosphate Buffer, pH 7.4 (203), 35... 

Figure 3.33 Effect of temperature on adsorption isotherms, (a) Adsorption of p-cresol on ODS silica. Column dimensions 1.2 x 50 mm. Temperature 1, 25°C 2, 40°C 3, 60°C. Reproduced with permission from J. Jacobson, J. Frmz and Cs. Horvath, ]. Chromatogr., 316 (1984) 53 (Fig. 9). (b) Adsorption of N-Benzoyl-D-alanine on immobilized bovine serum albumin. Reproduced with permission from S. Jacobson and G. Guiochon, J. Chromatogr., 522 (1992) 23 (Fig. 2).

Table 12.5-8. Clostripain-catalyzed coupling of 4-guanidinophenyl esters of 4-phenylbutyric acid (Pbu-OGp) and benzoyl-fi-alanine (Bz-(S-Ala-OGp), respectively, with various amino acid amides and peptides according to Gunther et al.[,99 .

TPL also catalyzes the reverse reaction and may perform other 0 ,/3-elimination and /3-replacement reactions. In addition to L-tyrosine, L- and D-serine, 5-methyl-L-cysteine,. S-ethyl-L-cysteine, 5-(o-nitrophenyl)-L-cysteine, 0-benzoyl-L-serine, ° and /3-chloro-L-alanine also act as substrates for /3-elimination. TPL also catalyzes racemization of alanine. ... 

V-Benzoyl-L-alanine was reacted with oxalyl chloride in CH2Cl2/benzene at room temperature. The solvents were replaced by toluene and triethylamine was added, followed by methanol. Workup by chromatography gave 51% of a product A. 

In cases such as that outlined, the enantiomer that forms the less soluble salt is usually obtained in an optically pure state. The other enantiomer is usually obtained in an impure state, because some of the less soluble salt invariably remains in solution. In the case diagrammed, the impure N-benzoyl-L-alanine may be treated with strychnine to give the insoluble strychnine salt. In this way, both enantiomers may be obtained in an optically pure state. 

Filter off the crude product, wash the filter-cake with about 60 ml of chilled water. The yield of crude N-benzoyl-P-alanine (mp 131-133°C) is approximately 20.2 g. 

T Recrystallization. Recrystallize 20 g of the crude product from 350 ml of boiling water. About 1 g of decolourising charcoal may be added, if the solution has a pale-yellowish colouration. The yield of pure N-benzoyl-P-alanine (mp 132-132.5°C) is 18.2 g. 

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