Chemical acylation

Under natural conditions various strains of Penicillium fungi produce either penicillin G or free 6-aminopenicillanic add ( = 6-APA). The techniques used to prepare analogues such as the ones given above have been (i) fermentation in the presence of an excess of appropriate adds which may be incorporated as side-chain (ii) chemical acylation of 6-APA with activated acid derivatives. 

Semisynthetic Derivatives. No significant improvements in activity have resulted from modifications of the 3-, 9-, 2and/01 4"-hydioxyl groups (314). 3 -0-Acyl derivatives have not been found via fermentation, but chemical acylation of the 3 -hydroxyl group yields products having good antibiotic activity and better pharmacokinetics than the patent macroHdes. Two such compounds have been developed (315,316) ... 

Also the scope of the acylase method is limited in practice because chemical acylation of amino adds is difficult, and some N-acylamino adds are unsusceptible to the enzyme. 

Initial attempts at introducing unnatural amino acids into proteins in mammalian cells involved the transfection of an amber suppressor tRNA that is chemically acylated with an unnatural amino acid in vitro This approach limits the amount of overall protein that can be produced since the acylated suppressor tRNA is consumed stoichiometrically and cannot be regenerated inside cells. It is also technically demanding to prepare the chemically acylated tRNA. 

Biosynthetic site-specific incorporation of photocaging amino acids into proteins by amber suppressor tRNA, chemically acylated by the photocaging amino acid, was used to... 

Chemical acylation of tylosin subsequently yielded a larger series of esters from which 4"-0-(4-methoxyphenylacetyl)tylosin (15) Figure 5.6) has emerged to the stage of preclinical studies due to its activity against certain resistant organisms and its improved metabolic stability [78-80], Several tylosin-related factors have also been acylated by chemical and biochemical methods [81-84], In addition to esters, 4"-0-alkyl and 4"-deoxy derivatives of tylosin have been prepared, but none was superior to compound (15) [85],... 

PC and PX of this type are best prepared from GPC obtained by chemical hydrolysis of natural PC (e) and subsequent chemical acylation. From this kind of PC, PX are obtained by PLD catalyzed transesterification. PLAj or PLA2 hydrolysis of these compounds and chemical reacylation allows one to obtain PL with different acyl chains. Since in Zyso-PL the acyl chain in sn2 position tends to migrate to the snl position, PLA2 hydrolysis gives a more suitable substrate for further acylation. 

Some groups have reported on their search for less reactive acylating agents, to suppress noncatalyzed chemical acylation and increase product enantiomeric excess. Irimescu and Kato carried out an enantioselective lipase catalyzed acylation of 1 phenylethylamine and 2 phenyl 1 propylamine by reacting the amines with carbox ylic acids in a nonsolvent system or in ionic liquids (Figure 14.9). The reaction equilibrium was shifted toward amide synthesis by the continuous removal of the... 

A lipoprotein lipase from Pseudomonas sp. effected not only regioselective acetylation of the orthoester 95 without observing the acylation of the axial hydroxyl groups but also enantioselective butyroylation (>95% ee) of symmetrical 4,6-dibenzoate 203 which was derived from the acetate 202 by benzoylation and acidic methanolysis (Scheme 4-10). 79 Regioselective chemical acylation of the equatorial hydroxyl group in 95 was also reported using benzoyl (64% yield) and p-nitrobenzoyl chlorides (51%).79... 

Chirazyme L2-C2 (CAL-B) proved to be a very useful enzyme for the development of an acylation process for the large-scale production of vitamin A (retinol, 91) at Roche (Scheme 27) [90,91]. In the plant process of vitamin A, intermediate 88 is partially acylated and then subjected to acid-catalyzed dehydration and isomerization to yield the vitamin A ester 90 via acetate 89. Contrary to the chemical acylation, an enzymatic approach allowed for a highly selective monoacylation of 88, and Chirazyme L2-C2 showed a very high conversion rate at 30% (w/w) substrate concentration. A first continuous process on the laboratory scale was set up with a 15 ml fixed-bed reactor containing 5.0-8.0 g of immobilized biocatalyst 4.9 kg of 89 was synthesized within 100 days in 99% yield and with 97% selectivity for the primary hydroxyl group. The laboratory process was implemented in a miniplant (120 g of biocatalyst), which could convert 1.4 kg of 88 into 1.6 kg 89 per day. After 74 days the conversion efficiency was still 99.4%. Further development of this transformation led to a modified process, which uses Thermomyces lanuginosus lipase immobilized on Accurel MPlOOl for the continuous production of 89 [92]. 

Primary amines and hydrazines are acetylated by cytosolic polymorphic A-acetyltransferases (NATs) that utilize acetyl-CoA as a cofactor (Sim et al., 2008 Makarova, 2008). Some carboxylic acid drugs acylate amino acids through the formation of adenosine 5 -monophosphate (AMP) intermediates that subsequently form acyl CoA intermediates that react with amino acid A-acyltransferases to yield amides (Pearson and Wienkers, 2008 Testa and Kramer, 2008). A few chemical acylations can occur. 

The quantative aspect of hydroxyl determination is illustrated in Table 3.4 for the analysis of hydroxyl in some polymeric materials. In most cases, the fluorine resonance from -butyl trifluoroacetate (at 7463 Hz in Figure 3.1) was used as internal standard to calibrate the spectral integral. From the data shown in Table 3.4 it seems that the adduct formation is quantitative for primary and secondary hydroxyls. The reaction normally requires less than 20 minutes at room temperature. However, as with the chemical acylation methods, tertiary hydroxyl was found to react only partially, and the reaction for ter -butanol required about 24 hours to reach equilibrium. The method can be used for the determination of hydroxyl groups in polymers of unknown structure. 

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