Phthalimidomethyl esters

Phthalimidomethyl esters of Z-protected amino acids are easily accessible by their reaction with A-(chloromethyl)- or A-(bromomethyl)phthalimide followed by catalytic hydro-genolysis of the Z group. 1 1 N-Protected peptides can be esterified by the same procedure. Esterification via cesium saltsP is equally suitable for the preparation of this type of ester. 

These esters undergo acidolysis within 10-15 minutes by treatment with 2M HBr in acetic acid at room temperature. They are stable toward standard catalytic hydrogenation, but are cleaved by reduction with Zn/AcOH (12 h, rt)t l or by nucleophiles sodium ben-zenethiolate readily cleaves the phthalimidomethyl esters (DMF, rt, 30min).t Removal of the phthalimidomethyl group is also accomplished using 2 equivalents of sodium hydroxide in MeOH/HaO (1 1) or 2-4 equivalents of diethylanoine in MeOH at room temperature for... 

The phthalimidomethyl ester protectionO l has been used for the synthesis of poly-L-glutamic acid.f l This protecting group is cleaved by piperidine or sodium hydroxide, but it is also sensitive to acids and catalytic hydrogenation. The co-ester is prepared by reacting Z-Glu-OBzl with A-chloromethylphthalimide in the presence of DCHA. Owing to its characteristic absorption at 299 nm, the reaction can be monitored spectrometricaUy. 

N-Chloromethylphthalimide (ClMPI), N-chloromethyl-4-nitrophthalimide (ClMNPl) and N-chloromethylisatin (ClMIS) react quantitatively with fatty acids, dicarboxylic acids and barbiturates (Figure 11) [105]. The reactivity of these labels is due to the high mobility of the chlorine atom. This reaction is similar to those with phenacyl bromide. For a complete reaction it is necessary to convert the acids to alkali metal or ammonium salts. Triethylamine or a crown ether is used as catalyst. Aprotic solvents such as acetonitrile, methanol and diethyl ether are suitable reaction media. The reaction is complete within 30—40 min at 60 °C. The disadvantage of these labels is reactivity to alcohols and primary and secondary amines, and as a result the selectivity is limited. HPLC separation of phthalimidomethyl esters was performed on a reversed phase column (Cg) with acetonitrile/water in various proportions as the mobile phase. Detection was at 254 nm. 

Reagent for formation of phthalimidomethyl esters. Uv-sensitive derivatisation reagent for hplc. Mp 132°. 

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