Chemical reactions acyl transfer

This chapter describes the various ways that the rates of acyl transfer reactions can be enhanced in supramolecular complexes or by supramolecular catalysts in which the crucial ingredients are such simple and relatively featureless chemical species as alkaline-earth metal ions, mainly Sr and Bi ions, and occasionally Ci . ... 

As in the case of DNA synthesis, discussed in Section n, the quantity kf is the product of the usual chemical forward reaction rate constant and the monomer concentration. Again we are treating here only the special case in which it is assumed that all monomer concentrations, as well as all forward rate constants, are equal and invariant. An analogous comment applies to the quantity kb, utilized below for the back reaction. In this case of protein synthesis, which probably involves 60-different types of monomer unit (amino-acyl transfer-RNA species), some of which may be present in only minor amounts, this restriction may be a very severe one. 

Asymmetric Alkylation. 4-Pseudoephedrine ([IS, 2S]-(+)) is a commodity chemical employed in over-the-counter medications with annual worldwide production in excess of 300 metric tons. The enantiomer, /-pseudoephedrine, is also readily available in bulk and is inexpensive. Pseudoephedrine has been shown to be highly effective as a chiral auxiliary in asymmetric alkylation reactions. Treatment of either enantiomer of pseudoephedrine with carboxylic acid chlorides and anhydrides leads to efficient and selective iV-acylation to form the corresponding tertiary amide derivatives (Table 1). Typically, the only by-product in the acylation reactions is a small amount (<5%) of the A,0-diacylated product, which is easily removed by crystallization or flash column chromatography. Because intramolecular 0- -N acyl transfer within pseudoephedrine 3-amino esters occurs rapidly, and because the A-acyl form is strongly favored under neutral or basic conditions, products arising from (mono)acylation on oxygen rather than nitrogen are not observed. 

Alkylation products of pseudoephedrine amides are readily transformed in a single operation into highly enantiomerically enriched carboxylic acids, aldehydes, ketones, lactones or primary alcohols. Alkylated pseudoephedrine amides can be hydrolyzed under acidic or basic conditions to form carboxylic acids. Simply heating a pseudoephedrine amide at reflux in a 1 1 mixture of sulfuric acid (9-18 N) and dioxane affords the corresponding carboxylic acid in excellent chemical yield with little or no epimerization (eq 7). Under these conditions, the substrate initially undergoes a rapid N— -0 acyl transfer reaction followed by rate-limiting hydrolysis of the resulting (3-ammonium ester intermediate to form the carboxylic acid. ... 

A stable chemical analog that mimics the transition state of a chemical reaction was the first approach used to elicit catalytic antibodies (Fig. 4) (3-5). Acyl transfer reactions are the most studied type of catalytic antibody reaction, and a wealth of knowledge about this reaction has been garnered through... 

Based on an extensive theoretical treatment of equilibrium positions,P l an interesting approach of solid-to-solid conversion catalyzed by proteases has been developed. According to this, a favorable equilibrium shift toward the peptide product is given when the starting reactants are largely undissolved in the reaction medium and the product precipitates. The use of solid-phase substrate pools combines the equimolar or nearly equimolar supply of reactants with high obtainable yields, easy workup procedures and, in principle, compatibility with conventional chemical peptide synthesis standard procedures. Both the advantage of solid-phase substrate pools mainly in equilibrium-controlled synthesisl " and the extension of this approach to protease-catalyzed acyl-transfer reactionst have been successfully demonstrated. 

Although cephalosporin C is divisable into a-aminoadipic acid, cysteine, and valine, the actual mechanism whereby Cephalosporium sp. incorporates the three amino acids into cephalosporin C has not been established, Arnstein and Morris isolated 8 (a-aminoadipyl) cysteinyl valine from mycelia of Penicillium chrysogenum and suggested that the tripeptide is a precursor in all penicillin biosynthesis.. This same tripeptide also appears to be found in the intracellular pool of Cephalosporium sp.- The final postulated step in the biosynthesis of penicillin is an acyl transfer reaction, or the production of 6-aminopeni-cillanic acid if precursor is not added. Cephalosporium sp. apparently do not produce sidechain amidases or acyl transferases, and no 7-ACA has been reported found in the fermentation. Thus, to obtain clinically useful antibiotics, chemical manipulation of cephalosporin C is necessary. Synthesis of many 7-acyl derivatives was possible once a practical cleavage reaction made available large amounts of 7-ACA from cephalosporin C. of these derivatives, sodium cephalothin was the first... 

For other applications of the Brpnsted equation to SN2 reactions, see Smith, G. F. J. Chem. Soc. 1943, 521-523. Hudson, R. F. Klopman, G. J. Chem. Soc. 1962, 1062-1067. Hudson, R. F. Chemical Reactivity and Reaction Paths Klopman, G., Ed. Wiley-Interscience New York, 1974 Chapter 5. For applications of the Brpnsted equation to acyl transfer and other reactions, see Hammett (2) and Jencks, W. P. Catalysis in Chemistry and Enzymology McGraw-Hill New York, 1969. 

The enzymatic nucleophile is similar in kind and reactivity to the ultimate solution acceptor. Examples of this class include the serine proteases and the alkahne phosphatase. The serine hydroxyl group is similar in chemical reactivity to the hydroxyl group of water, the final acceptor in these group transfer reactions (Fersht, 1985). For example, the active site Ser200 and His444 of cholinesterase are involved in a putative catalytic triad to effect acyl transfer (Taylor, 1991) ... 

Kim MG, Lee SB (1996) Penicillin acylase-catalyzed synthesis of P-lactam antibiotics in water-methanol mixtures effect of cosolvent content and chemical nature of substrate on reaction rates and yields. J Mol Catal B Enzym 1 201-211 Kohsaka M, Domain AL (1976) Conversion of penicDlin N to cephalosporin(s) by ceU-free extracts of Cephalosporium acremonium. Biochem Biophys Res Commun 70(2) 465-473 Koreishi M, Tani K, Ise Y et al. (2007) Enzymatic synthesis of P-lactam antibiotics and /V-fatty-acylated amino compounds by the acyl transfer reaction catalyzed by peniciUin V acylase from Streptomyces mobaraensis. Biosci Biotechnol Biochem 71(6) 1582-1586 Kupka JY, Shen, YQ, Wolfe S et al. (1983) Partial purification and properties of the alpha-ketoglutarate-linked ring expansion enzyme of beta-lactam biosynthesis of Cephalosporium acremonium. FEMS Microbiol Lett 16 1-6... 

Figure 2. A schematic acylation reaction carried out by the DMAP poplymer as an acyl-transfer support in the "Shadchan" system. Reproduced with permission from reference 14. Copyright 1985 American Chemical Society.

As mentioned in the Introduction, imidazole is found in biologic systems and, as mentioned, is quite robust chemically. For example, the imidazole ring system is not readily oxidized Y-oxidation does not readily occur. Very powerful oxidizing agents are required to oxidize the imidazole ring. Chemically, this was recently reported by the use of trimethylsilyl fluorosulfonyldifluoroacetate (TFDA). Mechanistically, this proceeds similar to the acyl transfer reaction described earlier. 

With the access to diverse and stable biocatalysts, more and more conventional chemical processes (first generation) in pharmaceutical manufacturing have been replaced by second-generation biocatalysis processes with substantial impact on the pharmaceutical industry. In this chapter, some commonly used biocatalytic reactions for chiral preparation, including hydrolytic reactions, acyl and glycosyl transfer reactions, asymmetric reduction/ oxidation reactions, and asymmetric formation of C-C bonds, are introduced and exemplified by the research achievements developed by the authors laboratory as well as other research groups. Some of the bioprocesses described herein have been successfully applied on pilot or even industrial scale. ... 

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