Tyrosine electrophilic aromatic substitution

Thyroxine has two aromatic rings, and you should be prepared to draw upon what you learned about aromatic chemistry in Chapters 22 and 23. It is also an amino acid and, in order to make the synthesis as cheap as possible, the chemists at Glaxo who developed the method used the amino acid tyrosine as a starting material. Nitration of tyrosine puts two nitro groups ortho to the OH group in an electrophilic aromatic substitution (make sure that you understand why ). 

Although the chemical modification of tyrosine residues has enjoyed a long history, this residue remains an underused target for bioconjugation reactions. It is typically modified through electrophilic aromatic substitutions (EAS), which makes its reactivity distinct from other amino acid side chains. This reaction... 

Although hydroxylation of phenylalanine to tyrosine looks like a typical electrophilic aromatic substitution, scientists at the U.S. National Institutes of Health discovered that the biochemical pathway combines epoxidation of the benzene ring followed by epoxide ring-opening with rearrangement. This rearrangement, which is the biochemical analog of the pinacol-type reactions described earlier, is known as the NIH shift. ... 

A noteworthy example of electrophilic aromatic substitution in nature, as mentioned in the introduction, is biosynthesis of the thyroid hormone thyroxine, where iodine is incorporated into benzene rings that are derived from tyrosine. 

Both agents are widely applied as auxiliary agents for radioiodination. The in situ formed Cl- I or Na I adds to activated phenyl residues by an electrophilic aromatic substitution reaction. Since tyrosine comprises an activated phenyl residue, the labeling of proteins and peptides is performed with this method vide infra). For smaller organic compounds like 2-hydroxy-6-methoxy-N- [(1 -ethyl-2-pyrrolidinyl)methyl]benzamide (BZM), Chloramine-T has also been applied for radioiodination (Kung et al. 1988). 

It is believed that thyroxine is formed in nature from the amino acid tyrosine (180) through the stage of diiodotyrosine, 181. When iodine is taken into the body, it is covalently bound to tyrosine residues in thyroglobulin molecules, and the enzyme thyroperoxidase converts the bound tyrosine to monoiodotyrosine (MIT, 181) and diiodotyrosine, 18. This transformation is clearly an enzyme-mediated electrophilic aromatic substitution reaction. Other enzymes convert 182 to 179. 

Thyroxine (see the model above ) is an aromatic compound and a key hormone that raises metabolic rate. Low levels of thyroxine (hypothyroidism) can lead to obesity, lethargy, and an enlarged thyroid gland (goiter). The thyroid gland makes thyroxine from iodine and tyrosine, which are two essential components of our diet. Most of us obtain iodine from iodized salt, but iodine is also found in products derived from seaweed, like the kelp shown above. An abnormal level of thyroxine is a relatively common malady, however. Fortunately, low levels of thyroxine are easily corrected by hormone supplements. After we study a new class of reaction in this chapter called electrophilic aromatic substitution, we shall return to see how that reaction is related to thyroxine in "The Chemistry of... Iodine Incorporation in Thyroxine Biosynthesis."... 

Reactions on tyrosine occur either at the oxygen atom of the phenol unit or at the aromatic ring through electrophilic aromatic substitution (EAS). Thus, the reactions can be divided into O-alkylated and C-alkylated products next to aromatic substitution products. 

Fig. 10.3-5 Tyrosine modification using a when proteins are treated alone with either three component Mannich-type reaction. component, (b) The reaction conversion is (a) Aldehydes and anilines condense to listed for a number of anilines and aliphatic form imines in situ, which react with tyrosine amines using a-chymotrypsinogen A as the residues through an electrophilic aromatic substrate and formaldehyde as the aldehyde substitution reaction. No reaction occurs component.

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

The naturally occurring aromatic amino acids phenylalanine, tryptophane and tyrosine (Fig. 1) have been labelled with fluorine-18 through similar electrophilic substitution methods [7]. Aromatic residues contained in peptides have been labelled with CH3C02[ F]F [105,106], an example of direct labelling of macromolecules. However, direct labelling of macromolecules is usually not the method of choice nowadays (see Section 6). 

Electrophilic substitution of aromatic nuclei in tyrosine and tryptophan side chains has frequently been reported in connection with acidolytic removal of blocking groups. C-Benzylation and tert.butylation of the tyrosine side chain and N-alkylation of the indole nucleus in tryptophan are often attributed to the alkyl cations generated in the reaction. This common side reaction is caused, however, mainly by the alkylating agents formed in the process, such as benzyl bromide or tert.butyl trifluoroacetate. The same is true for the S-alkylation of the methionine side chain. Conversion of the thioether to a sulfonium salt can... 

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