BOC-amino acid

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

H Kuroda, S Kubo, N Chino, T Kimura, S Sakakibara. Unexpected racemization of pro line and hydroxyproline phenacyl ester during coupling reactions with Boc-amino acids. Int J Pept Prot Res 40, 114, 1992. 

The next residues were attached successively by dicyclohexylcarbodiimide-mediated coupling of Boc-amino acids with the free amino groups. The use of excess Boc-amino acid eliminated the need for capping after coupling. The last Boc-group and the benzyl-based side chain and carboxy-terminal protectors were removed at the end of the synthesis by acidolysis with hydrogen bromide in trifluoroacetic acid the latter was used instead of acetic acid to avoid acetylation of hydroxymethyl side chains (see Section 6.6). Catalytic hydrogenolysis of the peptide removed the nitro... 

FIGURE 5.15 Synthesis of PAM (phenylacetamidomethyl) resin. (Merrifield et al., 1976). Use of PAM resin implies a Boc-amino acid anchored to oxymethylphenylacetamidomethyl-polystyrene through an ester linkage. The acetamido group renders the ester more stable to acid. 

Activated esters of A-alkoxycarbonylamino acids are prepared by two approaches, activation of the acid followed by reaction with the hydroxy compound, and trans-esterification. Most of the products are stable enough to be purified by washing a solution of the ester in an organic solvent with aqueous solutions. A few that are not crystalline are purified by passage through a column of silica. The commonly used method for their preparation is addition of dicyclohexylcarbodiimide to a cold mixture of the reactants in dimethylformamide or ethyl acetate. The first Boc-amino acid nitrophenyl esters were obtained using pyridine as solvent. Pyridine generates the nitrophenoxide ion that is more reactive. For one type of ester, 2-hydroxypyridino... 

A second method of activating the acid for esterification (see Section 7.6) is as the mixed anhydride. The mixed-anhydride reaction had been employed decades ago for preparing activated esters. However, it was never adopted because of its unreliability and the modest yields obtained. The method was fine-tuned (Figure 7.12), after reliable information on the properties of mixed anhydrides was acquired (see Section 2.8). Tertiary amine is required for esterification of the mixed anhydride to occur. The method is generally applicable, except for derivatives of asparagine, glutamine, and serine with unprotected side chains. The base also prevents decomposition that occurs when the activated derivative is a Boc-amino acid (see... 

LA Carpino, EME Mansour, A El-Faham. Bis(BOC) amino acid fluorides as reactive peptide coupling reagents. J Org Chem 58, 4162, 1993. 

RWilder, S Mobashery. The use of triphosgene in preparation of V-carboxy-a-amino acid anhydrides, (from Boc-amino acids) J Org Chem 57, 2755, 1992. 

FIGURE 7.23 Decomposition of a Boc-amino-acid /V-carboxyanhydnde by tertiary amine. Two molecules combine with the release of two molecules of C02 to form a pyrrolidine-2,4-dione. 

DECOMPOSITION DURING THE ACTIVATION OF BOC-AMINO ACIDS AND CONSEQUENT DIMERIZATION... 

NL Benoiton, FMF Chen. Unexpected dimerization in the reactions of activated Boc-amino acids with oxygen nucleophiles in the absence of tertiary amine, in JE Rivier, GR Marshall, eds. Peptides, Structure and Function. Proceedings of the 11th American Peptide Symposium, Escom, Leiden, 1990, pp 889-891. 

FMF Chen, NL Benoiton. Identification of the side-reaction of Boc-decomposition during the coupling of Boc-amino acids with amino acid ester salts, in JA Smith, JR Rivier, eds. Chemistry and Biology. Proceedings of the 12th American Peptide Symposium, Escom, Leiden, 1992, pp. 542-543. 

NL Benoiton, YC Lee, FMF Chen. Identification and suppression of decomposition during carbodiimide-mediated reactions of Boc-amino acids with phenols, hydroxy-lamines and amino acid esters. Ini J Pept Prot Res 41, 587, 1993. 

Pyridine (1) is a weak and good base and good solvent for effecting aminolysis of acyl fluorides (see Section 7.12) and for preparing Boc-amino-acid iV-carboxyanhydrides (see Section 7.14) and activated esters by the carbo-diimide method (see Section 7.7), especially the esters of Boc-amino acids, as it prevents decomposition of the activated residue (see Section 7.15). It is the preferred base for aminolysis of acyl fluorides in dichloromethane. 

FIGURE 8.16 Preparation of Cbz/Boc-/V-methylamino acids by methylation of Cbz/Boc-amino acids. [Benoiton et al., 1972]. Sodium hydride is added to substrate and methyl iodide in tetrahydrofuran, producing the sodium salt of the /V-methylated derivative. 

Another method was developed for the synthesis of 5,8-methano-3,l-benzoxazine-2,4-diones 157. The A-BOC amino acid 156 was prepared from the half ester 155 without purification of the intermediates. Thus, 155 was treated with ethyl chloroformate, and subsequently with sodium azide. 

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