Some Aromatic Side-Chain Compounds

Natural Occurrence and Uses of Some Aromatic Side-Chain Compounds... 

NATURAL OCCURRENCE AND USES OF SOME AROMATIC SIDE-CHAIN COMPOUNDS... 

Aromatic side chains of amino acids such as phenylalanine, tryptophan, and tyrosine are found in general in the interior of proteins, in hydrophobic regions. In some proteins they mediate helix-helix contacts. It is to be expected that agents containing aromatic groups could interact with proteins via aromatic-aromatic interactions, as for instance, proven by X-ray studies of biphenyl compounds which inhibit sickle-cell hemoglobin gelation. 

The 3-D artemisinin analogue database was created with Sybyl 6.2 (Tripos Assoc., St. Louis, MO)154 using the reported crystal structure for artemisinin as a template. The structures were minimized using the Tripos force field in Sybyl 6.2, producing structures close to that of artemisinin. To best describe the aromatic side chains of some analogues, as well as the aliphatic nature of the artemisinin backbone, Gasteiger-Htickel charges were calculated for each of the compounds. 

N-Tfa- and iV-Fmoc-a-amino ketones have been synthesized56 by reaction of some N -heterocycles or benzene with chiral AM Tfa- and Fmoc-a-aminoacyl)benzotriazoles [e.g. (49)] in the presence of aluminium trichloride. Full preservation of chirality was reported. Aromatic side-chains in some of the (a-amineacyl)benzotriazole compounds gave a competitive intramolecular cyclization, again with retention of chirality [e.g. (49) to (50)]. A full report57 on the intramolecular acylation of aromatics with Meldrum s acid derivatives catalysed by metal trifluoromethanesulfonates under mild reaction conditions has appeared [e.g. (51) to (52)]. The method tolerates many functional groups and was extended to the synthesis of 1-tetralones, 1-benzosuberones and donepezil (53). 

Intramolecular Excimer Fluorescence Studies in Polymers Carrying Aromatic Side Chains. Some years ago, it was shown that certain excited aromatic molecules may form a complex with a similar molecule in the ground state, which is characterized by a structureless emission band red-shifted relative to the emission spectrum of the monomer. The formation of such complexes, called "exclmers", requires the two chromophores to lie almost parallel to one another at a distance not exceeding about 3.5A° (11). Later, it was found that Intramolecular excimer formation is also possible. In a series of compounds of the type C5H (CH2)jiC H5, excimer fluorescence, with a maximum at 340nm, was observed only for n 3 -all the other compounds had emission spectra similar to toluene, with a maximum at about 280nm (12). Similar behavior was observed in polystyrene solutions, where the phenyl groups are also separated from one another by three carbon atoms (13). 

The female of mammalian species secretes a series of steroid hormones characterized by an aromatic A ring and the lack of a side chain at the 17 position. These compounds serve as regulators in the reproductive processes of the species. The name (estrogens) comes from the fact that in some lower animals the elaboration of this type of compound is directly involved with the phe-... 

It appeared to the author some years ago that, irrespective of the mechanism of the toxic action of DDT, there might be a correlation of structure and toxicity in analogous compounds. Hammett (13) has shown that the rate and equilibrium constants of over 50 side-chain reactions of meta and para substituted aromatic compounds may be correlated with the so-called substituent constant a, according to the equation log k — log k0 = pa, where k and k0 are rate (or equilibrium) constants for substituted and unsubstituted compounds, respectively, p is the reaction constant giving the slope of the linear relationship, and a is the substituent constant, which is determined by the nature and... 

Derivatives of phenylethanolamine substituted by a phenolic hydroxyl on the para position have been known for some time to exhibit 0-adrenergic agonist activity. As a consequence of this property, the compounds have proven useful as bronchodilators for the treatment of asthma (see Chapter 3). Since such sympathomimetic drugs tend to have undesired activity on the cardiovascular system in addition to the desired activity on the bronchii, considerable work has been devoted to the preparation of compounds that would show selectivity for the adrenergic receptors (02> that predominate in the lung. Attachment of the side chain to a heterocyclic aromatic phenol has been one avenue that has shown promise for achieving this selectivity. 

In Table IV some physical data and spectral characteristics of 6,7-secoberbines are listed. Only methyl corydalate (55) is optically active. Formula 55 presents the spatial structure of this compound, deduced by Nonaka et al. (65) and confirmed by Cushman et al. by both correlation with (+)-mesotetrahydrocorysamine (72) (<5S) and total synthesis (69). It is difficult to find common characteristic features in both the mass and H-NMR spectra of these alkaloids because they differ significantly from each other in their structures. On one hand, corydalic acid methyl ester (55) incorporates a saturated nitrogen heterocycle, while the three aromatic bases (56-58) differ in the character of the side chain nitrogen. For example, in mass fragmentation, ions of the following structures may be ascribed to the most intensive bands in the spectrum of 55 ... 

Many secondary phenolic compounds are derived from the amino acids phenylalanine and tyrosine and therefore contain an aromatic ring and a three-carbon side chain (see Fig. 3.3). Phenylalanine is the primary substrate for phenylpropanoid synthesis in most higher vascular plants, with tyrosine being used to a lesser extent in some plants. Because of their common structure, compounds derived from these amino acids are collectively called phenylpropanoids. 

Compounds showing vitamin K activity are substituted naphthoquinones. The parent compound, 2-methyl-1,4-naphthoquinone, does show some biological activity as do other similar but synthetic compounds. The production of the complete naturally active forms is thought to depend upon the addition of an isoprene chain at position 3 on the aromatic ring. Differences in this side chain produce the various K vitamins (Figure 12.10). A most important physiological role of vitamin K is in the synthesis of the blood clotting factors, II (prothrombin), VII, IX and X. 

Activity in these tricyclic compounds is restricted to compounds having a two- or three-carbon side chain and methyl-substituted or unsubstituted amino groups in the side chain. Some compounds with substituents on the aromatic ring are active. Finally, the two-carbon bridge linking the aromatic rings may be -CH2—CH2— or -CH=CH—. Amitriptyline is recommended for the treatment of mental depression, with improvement in mood seen in two to three weeks after the start of medication. Imipramine is used in similar cases. 

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