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Suppression of Racemization in Coupling Reactions between Amino Acids

IP.com Disclosure Number: IPCOM000222177D
Publication Date: 2012-Sep-23
Document File: 2 page(s) / 94K

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Suppression of Racemization in Coupling Reactions between Amino Acids

It was reported at Int. J. Peptide Protein Res., 39, 1992, 237-244 that additives like Copper salts are efficient racemization-suppressing in peptide synthesis.

The suppression of racemization was observed for both natural and non-natural a-amino acids, as shown in the following scheme:

Z= protected amino acid, PG (protecting group), COR3

R1, R2, R3= H (except R1), substituted or unsubstituted branched or linear alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; wherein R2 and NH2 may form a ring

Y= alkyl, substituted or unsubstituted amine, amino acid, OPG, OR3,

Coupling agent: carbodiimide (e.g. DCC (N,N'-Dicyclohexylcarbodiimide), EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), acylchloride (e.g. ethylchloroformate, pivaloyl chloride, isobutylchloroformate), CDI (1,1'-Carbonyldiimidazole)

Additive: Lead, Cobalt, Nickel, Copper and Zink salts

Base: organic bases (e.g. triethylamine, tributylamine, diisopropylethylamine), inorganic bases (e.g. carbonate)

Example 1 with DCC:

The reactor is charged with A in MTBE (8-15 volumes). B (1.05 eq., as HCl salt), CuCl2 (0.9-1.1eq.) and saturated solution of NaHCO3 (2.1 eq.) are added. The mixture is stirred at 10-40°C and DCC (1.2eq.) is added. The reaction is monitored and completed after few hours. The mixture is filtrated (for removing DCU (1,3-Dicyclohexylurea)). The r...