N-methylated amino acids

The importance of proper immobilization of enzymes can be shown in the kinetic resolution of racemic a-acetoxyamides. This group of compounds is an important class of chemicals since they can be readily transformed into a-amino acids [17], N-methylated amino acids, and tripeptide mimetics [18], amino alcohols [19], 1,2-diols [20], 1,2-diamines [21], and enantiopure l,4-dihydro-4-phenyl isoquinolinones [22]. 

FormylMet-tRNA Formate I < S-Formylglutathione Formaldehyde methyl amino acids... 

J Coste, E Frerot, P Jouin, B Castro. Oxybenzotriazole free peptide coupling reagents for N-methylated amino acids. Tetrahedron Lett 32, 1967, 1991. 

In addition to the 20 amino acids described, there are also a few amino acids quite frequently encountered that are not encoded by DNA. These are mainly found in peptides, and are typically slightly modified versions of the common amino acids, such as N-methyl amino acids. These components are represented by an appropriate variation of the normal abbreviation, e.g. N-methyl amino acids such as Tyr(Me) or Leu(Me), though A-methylglycine is often referred to as sarcosine (Sar). 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

One precaution should be kept in mind for n -methyl amino acids. N-methylatlon of the peptide linkage results in the energy of the usual trans amide becoming comparable to that of the cis ( ). The trans to cis transformation at a point in the peptide backbone results in a significMt conformational change. This possibility must be considered in interpreting results based on incorporation of N -methyl amino acids. 

This hypothetical intermediate is supported by the observation that AT-acyl protected N-methyl amino acids have a higher propensity for epimerization than the corresponding N-carbamoyl protected analogues. Once again the theme of tertiary amine leading to epimerization is demonstrated. 

The above method could be extended to the synthesis of N-methyl amino acids by using anhydrous MeNH2 instead of ammonia for the cyclization to the piperazine derivative. 

Bisebromoamide is cytotoxic linear peptide isolated from the marine cyanobacterium Lyngbya sp. (Teruya et al., 2009). Structure of bisebromoamide contains rich unusual amino acid derivatives with D-amino acids, N-methylated amino acids, a brominated tyrosine, a modified 4-methylpro-line, a 2-substituted thiazoline-4-methyl-4-carboxylic acid unit, and a rare... 

Tables 10 and 11 summarize the solution and sohd-phase synthesis, respectively, of many peptides that contain at least two consecutive N-methyl amino acid residues.

An alternative approach to improve the catalyst design was taken by Maikov and Kocovslcy [80], who employed acyclic N-methyl amino acids in the core of the catalyst structure, as illustrated by catalysts 85 and 86 (Table 7.8). (For experimental details see Chapter 14.21.3). Intrinsic rotational flexibility of the bond linking the stereogenic center with the formamide nitrogen allowed the molecule to adopt the most favorable conformation in the transition state. As a result,... 

CsA is a cyclic undecapeptide consisting completely of hydrophobic amino acids, as shown in Figure 1.8 [37]. Additional structural features are a threonine-derived butenyl-containing amino acid derivative as well as six N-methylated amino acid residues. In addition to reducing the proteolytic degradation rate and increasing the... 

Supporting evidence for this proposal was obtained from amino acid analyses which demonstrated that glycine was the only typical or non N-methylated amino acid present in 4ab and Sab. Marfey analysis of the acid hydrolysates of 4ab, Sab and majusculamide C (6) confirmed that 4ab and Sab differed from majusculamide C (6) in possessing an N-methyl-L-alanine residue rather than an L-alanine residue. Moreover, 4ab and Sab contained an N-methyl-L-leucine residue rather than an N-methyl-L-isoleucine residue,... 

Proline and Heterochiral N-methyl Amino Acids as Turn Inducers... 

However, some other depsipeptides require additional tools. Many depsipep-tides of natural origin possess complex architectures such a cyclic or a bicyclic skeleton and may include unnatural or N-methylated amino acids in their structure. In these cases, a manual synthesis combined with careful optimization of each step is required. In this regard, syntheses of callipeltin B [171] and oxathio-coraline [172] have recently been described. 

Fig. 8. Structure of (a) valinomycin and (5) and enniatins and beauvericin. Hov = a-hydroxy-isovaleric acid and Lac = lactic acid. The N-methyl amino acid for enniatin A is isoleucine enniatin B, valine enniatin C, leucine and beauvericin, phenylalanine.

Nigeglapine, 56-57 Nigeglaquine, 56-57 Nitrabirine W-oxide, 41, Alt, 65 Nitraramine, 145 Nitrocadambine A, 60-63 Nitroimidazole, 108-109 N-methyl amino acids, 431-432 N methyl angustilobine, 17-20 N-methyl anthraniloyl-CoA, 149-150 N-Methylcoclaurine, 386/ N-methyldibromois( hakellin, 267-269, 267/... 

Various analogues (10, 11, 12), in which L-alanine is replaced by a N-methyl-amino acid, were prepared with the aim of protecting the compounds against possible enzymatic degradation 47). 

Figure 6 The type II, or N-methyl-amino acid-activating, domain. As in Figure 4, the amino acid-activating domain is shown with aJenylating and thioester modules, the ATP-binding region, and the six conserved core sequences. The SAM-dependent N-methyltransferase module i also shown.

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