Alkyl from amino acids

Mass spectral fragmentation patterns of alkyl and phenyl hydantoins have been investigated by means of labeling techniques (28—30), and similar studies have also been carried out for thiohydantoins (31,32). In all cases, breakdown of the hydantoin ring occurs by a-ftssion at C-4 with concomitant loss of carbon monoxide and an isocyanate molecule. In the case of aryl derivatives, the ease of formation of Ar—NCO is related to the electronic properties of the aryl ring substituents (33). Mass spectrometry has been used for identification of the phenylthiohydantoin derivatives formed from amino acids during peptide sequence determination by the Edman method (34). 

The Fcm derivative is prepared from amino acids on treatment with formylferro-cene and Pd-phthalocyanine by reductive alkylation (60-89% yield). It is cleaved with 2-thionaphthol/CF3COOH. Its primary advantage is its color, making it easily detected. ... 

Diastereoselective preparation of a-alkyl-a-amino acids is also possible using chiral Schiff base nickel(II) complexes of a-amino acids as Michael donors. The synthetic route to glutamic acid derivatives consists of the addition of the nickel(II) complex of the imine derived from (.S )-,V-[2-(phenylcarbonyl)phenyl]-l-benzyl-2-pyrrolidinecarboxamide and glycine to various activated olefins, i.e., 2-propenal, 3-phenyl-2-propenal and a,(f-unsaturated esters93- A... 

Alkylation of Schiff bases, derived from amino acid and non-optically active aromatic aldehydes by phase-transfer catalysis in the presence of cinchona alkaloid derived quaternary ammonium salts, gave ce values of up to 50% l42. 

Using the same principle as that described for l,3-dioxolan-4-ones, it is possible to a-alkylate 2-amino acids without racemization76,78. An A. O-acetal is formed from an (7 )-amino acid 1, e.g., with trimethylacetaldehyde (R2 = -Bu) the l,3-oxazolidin-5-ones 2 and 3 are furnished with a defined diastereoselectivity, which is the first stage in the process of self-reproduction of chirality 82. Formation of the enolate 4 from 2 and attack of an electrophile in the second step gives the product 6 with retention of configuration in the a-position, and 7 with inversion of configuration, again with a defined diastereoselectivity. Hydrolysis yields the a-alkylated amino acids 10 and 11. 

Since the chirality of the center undergoing electrophilic attack is destroyed on enolate formation, the enantiomerically pure civ-isomer of the 5-alkyl-2-/cr -butyl-4-imidazolidinone 8, after alkylation and hydrolysis, gives the enantiomer of the a-alkyl-a-amino acid obtained on alkylation of the trans-isomer 8 provided that the cis- and trans-isomers have been prepared from the same enantiomer of the starting amino acid3. 

Schollkopf et al.187) synthesized a-alkyl-a-amino acids (186) by the alkylation of chiral 1-substituted 2-imidazolin-5-ones (185), which can be prepared from a-amino acid (S)-phenylethylamides and orthoformic esters. The optical yields of the products (186) were in many cases higher than 95 %. 

Later, this reaction sequence was further optimized [42], and also shown to be useful for the synthesis of other N-alkylated sulfoximines, including those (such as 57) prepared from amino acids (Scheme 2.1.1.16). 

Hinds et al.[26 used a helicogenic Ca-alkylproline derivative 271 in the peptide Ac-Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala-OH, which is derived from an immunogenic sequence in influenza hemagglutinin, specifically replacing the first Pro residue in the sequence. They found increased binding to a pair of monoclonal antibodies which recognize this site. 26 The insertion of C -alkyl a-amino acids into peptide systems is discussed in Section 10.3. 

These products (4) can be used to effect a-alkylation of amino acids with retention or inversion of configuration. Thus either (S)- or (R)-a-methyldopa (6) can be prepared from (S)-alanine, as shown in equations (I) and (II). 

Tertiary amines do not react with nitrous acid, acetyl chloride, benzoyl chloride, benzenesulfonyl chloride, but react with alkyl halides to form quaternary ammonium halides, which are converted by silver hydroxide to quaternary ammonium hydroxides. Quaternary ammonium hydroxides upon heating yield (1) tertiary amine pins alcohol (or, for higher members, olefin plus water). Tertiary amines may also be formed (2) by alkylation of secondary amines, e.g., by dimethyl sulfate, (3) from amino acids by living organisms, e g, decomposition of fish in the case of trimethylamine. 

Alkylation of Schiff Bases Derived from a-Alkyl-a-Amino Acids... 

An ion-pair derived from the substrate and solid NaOH forms a cation-assisted dimeric hydrophobic complex with catalyst 39c, and the deprotonated substrate occupies the apical coordination site of one of the Cu(II) ions of the complexes. Alkylation proceeds preferentially on the re-face of the enolate to produce amino acid derivatives with high enantioselectivity. However, amino ester enolates derived from amino acids other than glycine and alanine with R1 side chains are likely to hinder the re-face of enolate, resulting in a diminishing reaction rate and enantioselectivity (Table 7.5). The salen-Cu(II) complex helps to transfer the ion-pair in organic solvents, and at the same time fixes the orientation of the coordinated carbanion in the transition state which, on alkylation, releases the catalyst to continue the cycle. 

For substrates derived from amino acids other than glycine or alanine, the side chain of the amino acid also needs to be considered. Rotation around the Ca-Cp bond of the enolate could locate the side chain over the re-face (as shown in Figure 8.3) or over the si-face. It is likely that the side chain will prefer to be on the sterically less-hindered re-face of the enolate, so it will hinder the approach of the electrophile to this face and this will result in a lower enantioselectivity during the alkylation. The overall rate of reaction will also decrease as the size of the side chain increases. Thus, the model shown in Figure 8.3 correctly predicts both the absolute configuration of the product and the dependence of the enantioselectivity on the size of the amino acid side chain. Substrate 39g derived from phenylglycine provides a way to probe the... 

Table 4.5 Phase-transfer-catalyzed enantioselective benzylation of aldimine Schiff bases derived from a-alkyl-a-amino acids.3) (For experimental details see Chapter 14.15.1).

Poly(amino acids) are insoluble in common solvents, are difficult to fabricate due to high melting point, and absorb a significant amount of water when their acid content reaches over 50 mol%. To solve these problems, polyesters derived from amino acids and lactic acids [e.g., poly (lactic acid-co-lysine) PLAL] are developed. The PLAL system is further modified by reaction with lysine A-carboxyanhydride derivatives. Another modification of poly(amino acids) includes poly(iminocarbon-ates), which are derived from the polymerization of desaminotyrosyl tyrosine alkyl esters. These polymers are easily processable and can be used as support materials for cell growth due to a high tissue compatibility. Mechanical properties of tyrosine-derived poly(carbonates) are in between those of poly(orthoesters) and poly(lactic acid) or poly(gly-colic acid). The rate of degradation of poly(iminocarbonates) is similar to that of poly (lactic acid). 

In an attempt to develop a PEG-supported version of a chiral phase-transfer catalyst the Cinchona alkaloid-derived ammonium salt 15 used by Corey and Lygo in the stereoselective alkylation of amino acid precursors was immobilized on a modified PEG similar to that used in the case of 13. The behaviour of the catalyst obtained 16, however, fell short of the expectations (Danelli et al. 2003). Indeed, while this catalyst (10 mol%) showed good catalytic activity promoting the benzy-lation of the benzophenone imine derived from tert-butyl glycinate in 92% yield (solid CsOH, DCM, -78 to 23 °C, 22 h), the observed ee was only 30%. Even if this was increased to 64% by maintaining the reac-... 

Alkylation of amino acids has also been achieved by first forming heterocyclic derivatives. For example, the oxazolidinone from CBZ-phenylalanine and formaldehyde reacts with potassium hexa-methyldisilazide followed by allyl bromide to give the expected product in 76% yield.Chiral tetrahy-dro-l,4-oxazin-2-ones have been used in a similar manner to give amino acids with a degree of diastereoselectivity. 23. >... 

Methylation of diamines with formaldehyde and formic acid yields the tetramethyl derivatives, e.g., tetramethyldiaminobutane (92%). In most instances, alkylation of amino acids by this same combination gives complex products, although a-dimethylaminobutyric acid can be made from the corresponding a-amino acid in 80% yield. Reaction of the readily available amino alcohols like N-raethylethanolamine and 2-isopropylamino-ethanol gives the N,N-dialkyl derivatives. ... 

N-alkylated a-amino acids, whereby the side chains typical of coded residues are transferred from the C - to the N-atom 4) fS-amino acids, the subclass of residues investigated most extensively in which the amino and carboxyl functionalities are separated by more than one carbon atom and 5) short-range, backbone-to-backbone cyclizations that generate small-ring, monolactam or dilactam building blocks. 

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