Acetic acid side chains

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

Interposing an additional carbon atom between the indazole nucleus and the acetic acid side chain provides another compound that shows anti-inflammatory activity in model systems. Reduction of the carboxylic acid in the indazole (38-1) by means of hthium aluminum hydride leads to the carbinol (38-2). Alkylation of the enolate from the alcohol with methyl 2-bromo-2-methylpropionate leads to the corresponding ether. Saponification gives the free acid and thus bindarit (38-3) [40]. 

The methyl esters of keto acids (XLVI) and (XLVII) from both alio and epiallogibberic acids show positive Cotton effects so that the acetic acid side chain at C-8a must be -oriented. This means that the carboxyl group and ring D must be -oriented in alio- and epiallogibberic acids. 

The space group of the racemic compound was found to be Pbca, with cell constants of a = 8.60 A, b = 18.59 A, and c = 19.06 A. The stereoview of ( )-etodolac indicates that the oxygen of the pyrano ring and the acetic acid chain lie above the plane of the indole ring, and that the torsion angle aboiit the acetic acid side chain is 297.6°. The carbon atom of the carboxyl group is situated at 5.53 A from the center of the benzene ring, and lies in... 

Fig. 33. Outline of the biosynthesis of uroporphyrinogen III (abbreviated urogen III), Starting with glycine labelled at position 2. The label is distributed as indicated with filled circles. The carboxyl group of glycine is lost as carbon dioxide. A = acetic acid side chain P = propionic acid side chain.

Fig. 35. The structures of factors I (62), II (63, sirohydrochlorin) and III (64). A —acetic acid side chain P=propionic acid side chain.

Fig. 41. Proposed mechanism for the retentive decarboxylation of acetic acid side chain during haem biosynthesis.

Figure 4.14 Octaacetic acid porphyrin 17 is reversibly adsorbed on vesicle surfaces below pH 4.5. At pH 5, the porphyrin dissolves in water. It is now protonated at the pyrrolenine nitrogen atom, whereas the acetic acid side chains are half-deprotonated. At higher pH, the two-banded spectrum of the N-diprotonated porphyrin dication is again replaced by a four-banded spectrum of the neutral porphyrin base.

Attempts to co-crystallize amphiphilic porphyrins with micellar fibres failed completely. The van der Waals interactions between porphyrin planes ( stacking ) are so strong that unsubstituted porphin and (3-octamethylporphyrin are insoluble in practically all solvents. Porphyrins with larger substituents such as ethyl or acetic acid side chains allow face-to-face dimerization only, an action which occurs in all solvents and also probably in micelles down to a concentra-... 

Formation of coproporphyrinogen III from uroporphyrinogen III. Acetic acid side chains (Ac) are decarboxylated to methyl groups (M), sequentially, starting clockwise from ring D. P, -CH2CH2COOH. 

In the second reported synthesis IS) (Scheme 3) racemic A-benzoyl-meroquinene (42 R = H) was obtained from hexahydroisoquinolone 34. The cis vinyl and acetic acid side chains were formed by a sequence of reactions including stereoselective hydrogenation, Schmidt rearrangement, and pyrolytic JV-nitrosolactam fragmentation. 

Decarboxylation of the acetic acid side chain on ring C... 

Cobyrinic acid acts as the substrate for the first of two amidases, CbiA, which amidates the a and c acetic acid side chains (Figure 24). As with CobB, CbiA uses glutamine as its preferred amino donor and requires ATP as an energy source. Kinetic analysis has shown that the hydrolysis of glutamine and the synthesis of cobyrinic acid tf,c-diamide are uncoupled. It was also shown that the amino groups are transferred in the order of r first and then a, allowing a model to be proposed whereby phosphinylated intermediates are formed. ... 

In Chapter 27 we analysed the synthesis of bicyclic lactone (6). In his vitamine B12 synthesis Eschenmoser needed to lengthen the acetic acid side chain of (6) into the propionic side chain of (7). This he accomplished by the Arndt-Eistert procedure. 

Ziegler and co-workers (216, 217) have described a new approach to the quebrachamine skeleton involving internal cyclization of an acetic acid side chain to a 2-unsubstituted indole. The key intermediate is the disubstituted piperidine 466, which is treated with indolyl-3-acetyl chloride in aqueous sodium carbonate-methylene chloride to afford a lactam ester, 467. 

The most important properties in respect to protein structures (Richardson and Richardson, 1989) are, however, not so much related to chemical reactivity. Even more important is the variation in water solubility (Hutchens, 1976) and hydrophobicity (Sueki et al., 1984) of proteins. Table 9.2.3 gives the usual assignments of acidic, basic, and hydrophobic amino acids. Solubility in water turns out to be unpredictable from first principles. Amino acids with charged side groups R are, for example, not always more soluble than those with electroneutral hydrocarbon substituents. On the contrary, by far the most soluble amino acid (1.5 kg/L ) is proline, with three CH2 groups in a pyrrolidine unit as the only substituent. Aspartic acid with an acetic acid side chain is less soluble by a factor of 250 (6g/L). Cationic amino acids are, in general, much more soluble than their anionic counterparts the effect of hydrophobic substituents (e.g., isobutyl, sec-butyl, phenyl, or indole) is not very pronounced (Table 9.2.3). 

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