N-Methylamino acids

MONOMETHYLATIONOFAMINO GROUPS AND THE SYNTHESIS OF N-ALKOXYCARBONYL-N-METHYLAMINO ACIDS... 

THE DISTINCT CHIRAL SENSITIVITY OF N-METHYLAMINO ACID RESIDUES AND SENSITIVITY TO ACID OF ADJACENT PEPTIDE BONDS... 

When treated with formaldehyde, esters of AAs form immonium ions which undergo reaction with cyclopentadiene to give 2-azanorbornenes 58. Decomposition of 58 afforded esters of N-methylamino acids without racemization (87JOC5746). 

C-Alkylation of polypeptides. Seebach et al.1 report that selective C-alkylation of a sarcosine (N-methylglycine) unit in a tri- or hexapeptide with an N-protected terminal group is possible if polylithiation is eifected with excess LDA in THF with addition of LiCl (5-6 equiv.) to provide a homogeneous mixture. In some cases, addition of an aprotic dipolar solvent (DMPU) or of BuLi can improve the yield. Under these conditions, epimerization and N-alkylation are slight. The new center introduced by alkylation of Sar tends to have the (R)-configuration when the configuration at the other centers is (S). In the methylation of the tripeptide formulated in equation (I), the yield is particularly high because the Sar unit is flanked by an N-methylamino acid. In this case, aldehydes can also serve as electrophiles. Alkylation and benzylation are also possible in the presence of added DMPU. 

L-amino acids, and in many cases also non-proteinogenic amino acids such as D-amino acids, oc-aminoisobutyric acid, isovaline, (3-alanine, and N-methylamino acids, serve as the raw materials for the production of peptides. The formation of the peptide linkage between the amino acids takes place in the following ways ... 

W. Konig, I. Benecke, et al., Isocyanates as reagents for enantiomer separation application to amino acids, N-methylamino acids and 3-hydroxy acids, J. Chromatogr., 279 555-562 (1983). 

N-Methylamino acids. N-Methylation of amino acids can be effected with minimal racemization by alkylation of the amidine ester (8, 191) with methyl triflate. Methylation with dimethyl sulfate replts in extensive racemization. 

N-Methyhtmino acid derivatives.1 CbO- and Boc-amino acids are converted into the corresponding N-methylamino acid derivatives in excellent yield by methyl iodide and silver oxide in DMF. An unprotected carboxyl group is also converted into the methyl ester by this procedure. 

N-Methylamino acid derivatives, 202 Methyl[ 18]annulene, 111 Methyl[18]annulenecarboxylate, 193 Methylation, 126, 201-202... 

The ninhydrin reaction is not restricted to a-amino acids, however. It is well known that imino acids, notably proline, but also for example pipecolic acid, in solution produce a different color with an absorption maximum at 440 nm. Primary aliphatic amines react likewise with ninhydrin to give Ruhe-man s purple but the color yield is lower than for a-amino acids. Peptides, amino acids with secondary amino groups, mainly N-methylamino acids, and secondary amines also react with ninhydrin, although often more slowly and with smaller yield than the a-amino acids. Tertiary amines and all aromatic amines do not react with ninhydrin. Ammonia itself reacts to give a color with ninhydrin, although with a rather low yield. 

In these syntheses, the corresponding N-methylamino acids are prepared as described by Cheung and Benoiton (9). 

Okamoto, K., and Quastel, J. H., 1977, Effects of N-methylamino acids and convulsants on spontaneous action potentials in guinea-pig cerebellar slices, Br.J. Pharmacol. 59 551 -560. 

Of particular interest is the fact that a number of amino acids present in the actinomycins are not constituents of cellular proteins. These include D-amino acids, e.g., D-valine and D-alloisoleucine N-methylamino acids, e.g., sarcosine, N-methylvahne, N-methylalanine and the imino acid, 4-oxo-L-proline. Although the chemical differences between actinomycins are generally small, there are significant quantitative differences in their biological activity (Table 1). 

Biron E, Kessler H (2005) Convenient synthesis of N-methylamino acids compatible with Fmoc solid-phase peptide synthesis. J Org Chem 70 5183-5189... 

Akaji, K., Hayashi, Y, Kiso, Y, and Kuriyama, N. (1999) Convergent synthesis of dolastatin 15 by solid phase coupling of N-methylamino acid. Pept. Sci., 35, 9-12. 

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