Convenient Synthesis ofN-Methylamino Acids Compatible with Fmoc Solid-Phase Peptide Synthesis

Abstract

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.

Getting in Shape: Controlling Peptide Bioactivity and Bioavailability Using Conformational Constraints

“…Historically, N-methylation was applied in later stages, perhaps due to the difficulty of the chemistry involved, though thanks to the work of Kessler and others, synthesis of N-methylated peptides is more accessible than ever before. 26,50–52 The effects of cyclization, substitution and N-methylation are typically non-additive and highly cooperative, making it difficult to predict or rationalize the results of even simple series of analogues. Even so, these “scanning” methodologies have established that conformational control of peptide bioavailability is possible, and indeed may be possible in most cases in which a small, contiguous epitope is found to mediate bioactivity.…”

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

“…N-methyl derivatives of amino acids can be prepared through chemical synthesis [115]. Recently, Biron et al have described an improved synthesis of N-methylated amino acids, in solution [123] and on solid phase [124]. When only small quantities of N-methylated derivatives are required, site-selective N-methylation of the peptide on solid phase [124] and the introduction of larger alkyl groups is possible [125].…”

N‐(4‐Nitrophenylsulfonyl)‐ and N‐(Fluorenylmethoxycarbonyl)‐N‐ethyl Amino Acid Methyl Esters – A Practical Approach

“…an S N 2 dealkylation according to the efficient procedure described by Biron and Kessler. [25] Treatment of N-ethyl-NFmoc--isoleucine methyl ester (3d), chosen as a model system, with lithium iodide in refluxing ethyl acetate, afforded after 20 h the corresponding N-ethyl-N-Fmoc--isoleucine (4) in 94 % yield, which could be directly used without further purification. The cleavage reaction did not involve racemization as shown by 1 H NMR spectroscopic analysis of 4.…”