TY - JOUR
T1 - An acid‐labile anchoring linkage for solid‐phase synthesis of C‐terminal peptide amides under mild conditions
AU - ALBERICIO, FERNANDO
AU - BARANY, GEORGE
N1 - Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 1987/8
Y1 - 1987/8
N2 - A series of polymer‐supported benzylamides substituted with one to three alkoxy groups in the ring positions were prepared and shown to give carboxamides upon treatment with acid. Based on the initial screening, the bis(o‐methoxy)‐p‐alkoxybenzylamide anchoring linkage was selected for a detailed evaluation of its suitability for solid‐phase synthesis of C‐terminal peptide amides. The handle derivative 5‐[(2′ or 4′)‐Fmoc‐aminomethyl‐3′,5′‐dimethoxyphenoxy]valeric acid (1) was prepared in seven facile steps [purification of intermediates unnecessary; overall yield 15% for crystalline product, which is a mixture of positional isomers], and was quantitatively coupled onto amino group‐containing supports by use of N,N'‐dicyclohexylcarbodiimide plus 1‐hydroxybenzotriazole in N,N‐dimethylformamide. Stepwise elaboration of peptide chains proceeded smoothly with both Nα‐9‐fluorenyl‐methyloxycarbonyl (Fmoc) and Nα‐dithiasuccinoyl (Dts) amino acids, and final cleavage of tert.‐butyl side‐chain protecting groups and of the anchoring linkage occurred readily in trifluoroacetic acid–dichloromethane (7:3) at 25°. The methodology was demonstrated by the syntheses of H‐Trp‐Asp‐Met‐Phe‐NH2 (tetragastrin) and H‐Tyr‐Gly‐Gly‐Phe‐Met‐NH2 (methionine‐enkephalinamide), both with high yields and purities.
AB - A series of polymer‐supported benzylamides substituted with one to three alkoxy groups in the ring positions were prepared and shown to give carboxamides upon treatment with acid. Based on the initial screening, the bis(o‐methoxy)‐p‐alkoxybenzylamide anchoring linkage was selected for a detailed evaluation of its suitability for solid‐phase synthesis of C‐terminal peptide amides. The handle derivative 5‐[(2′ or 4′)‐Fmoc‐aminomethyl‐3′,5′‐dimethoxyphenoxy]valeric acid (1) was prepared in seven facile steps [purification of intermediates unnecessary; overall yield 15% for crystalline product, which is a mixture of positional isomers], and was quantitatively coupled onto amino group‐containing supports by use of N,N'‐dicyclohexylcarbodiimide plus 1‐hydroxybenzotriazole in N,N‐dimethylformamide. Stepwise elaboration of peptide chains proceeded smoothly with both Nα‐9‐fluorenyl‐methyloxycarbonyl (Fmoc) and Nα‐dithiasuccinoyl (Dts) amino acids, and final cleavage of tert.‐butyl side‐chain protecting groups and of the anchoring linkage occurred readily in trifluoroacetic acid–dichloromethane (7:3) at 25°. The methodology was demonstrated by the syntheses of H‐Trp‐Asp‐Met‐Phe‐NH2 (tetragastrin) and H‐Tyr‐Gly‐Gly‐Phe‐Met‐NH2 (methionine‐enkephalinamide), both with high yields and purities.
KW - 5‐[(2′ or 4′)‐aminomethyl‐3′,5′‐dimethoxyphenoxy]valerate handle
KW - N‐9‐fluorenylmethyloxycarbonylamino acids
KW - N‐dithiasuccinoylamino acids
KW - methionine‐enkephalinamide
KW - solid‐phase peptide synthesis
KW - tetragastrin
KW - tris(alkoxy)benzylamides
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U2 - 10.1111/j.1399-3011.1987.tb03328.x
DO - 10.1111/j.1399-3011.1987.tb03328.x
M3 - Article
C2 - 3679670
AN - SCOPUS:0023391680
SN - 0367-8377
VL - 30
SP - 206
EP - 216
JO - International Journal of Peptide and Protein Research
JF - International Journal of Peptide and Protein Research
IS - 2
ER -