Convenient synthesis of N-methylamino acids compatible with Fmoc solid-phase peptide synthesis.
N(alpha)-Methylamino acid containing peptides exhibit interesting therapeutic profiles and are increasingly recognized as potentially useful therapeutics. Unfortunately, their synthesis is hampered by the high price and unavaibility of many N(alpha)-methylamino acids. An efficient and practical preparation of N(alpha)-methyl-N(alpha)-(o-nitrobenzenesulfonyl)-alpha-amino acids without extensive purification is described. The procedure is based on the well-known N-alkylation of N(alpha)-arylsulfonylamino esters which was improved by using dimethyl sulfate and DBU as base. Ester cleavage is efficiently achieved by using an S(N)2-type saponification with lithium iodide, avoiding racemization observed with lithium hydroxide hydrolysis. Compatibility of the synthesized N(alpha)-methylamino acids with Fmoc solid-phase peptide synthesis is demonstrated by using normal coupling conditions to efficiently prepare N-methyl dipeptides. The described procedure allows the preparation of N(alpha)-methylamino acids in a very short period of time and a rapid synthesis of N-methyl peptides using Fmoc solid-phase peptide synthesis.
Biron
Eric
E
Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstrasse 4, Garching D-85747, Germany.
Kessler
Horst
H
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D005449:Fluorenes / Q000737:chemistry; D007202:Indicators and Reagents; D015394:Molecular Structure; D010452:Peptide Biosynthesis; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
C496789:9-fluorenylmethoxycarbonyl; D000596:Amino Acids; D005449:Fluorenes; D007202:Indicators and Reagents; D010455:Peptides