Carboxylic acid derivatives enzymic

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

Bergeron S, Chaplin D, Edwards JH, Ellis BS, Hill CL, Holt-Tiffin K, Knight JR, Mahoney T, Osborne AP, Ruecroft G (2006) Nitrilase-catalyzed desym-metrization of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org Proc Res Dev 10 661-665 Burns M, Weaver J, Wong J (2005) Stereoselective enzymic bioconversion of aliphatic dinitriles into cyano carboxylic acids. WO 2005100580 DeSantis G, Zhu Z, Greenberg W, Wong K, Chaplin J, Hanson SR, Farwell B, Nicholson LW, Rand CL, Weiner DP, Robertson D, Burk MJ (2002) An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives. J Am Chem Soc 124 9024-9025... 

Matsumura and Bousch (1966) isolated carboxy lest erase (s) enzymes from the soil fungus Trichoderma viride und a bacterium Pseudomonas sp., obtained from Ohio soil samples, that were capable of degrading malathion. Compounds identified included diethyl maleate, desmethyl malathion, carboxylesterase products, other hydrolysis products, and unidentified metabolites. The authors found that these microbial populations did not have the capability to oxidize malathion due to the absence of malaoxon. However, the major degradative pathway appeared to be desmethylation and the formation of carboxylic acid derivatives. 

Structures 24 are conveniently thought of as derivatives of carboxylic acids, and include acids, esters, anhydrides, acyl halides, and amides. These structures (and others less commonly encountered) can be readily interconverted, either directly or indirectly the number of different reactions is therefore large.109 Because these processes occupy an important place in organic chemistry and because carboxylic acid derivatives are of central importance in biochemical systems and therefore of considerable interest in the study of enzyme action, they have been the subject of intensive investigation.110 We shall outline briefly the main features, and in order to give an idea of the kinds of mechanistic questions involved, we consider ester hydrolysis in somewhat greater detail. 

J. 2002. An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives./. Am. Chem. Soc.,124(31), 9024-9025. 

The catalysis of hydrolysis of carboxylic acid derivatives by weak bases has not been carefully studied until relatively recently. Koshland reported in 1952 the catalysis of acetyl phosphate hydrolysis by pyridine Bafna and Gold (1953) reported the pyridine-catalyzed hydrolysis of acetic anhydride. A short time later the catalysis of aromatic ester hydrolysis by imidazole was demonstrated (Bender and Turnquest, 1957 a, b Bruice and Schmir, 1957). Since that time a large amount of work has been devoted to the understanding of catalyzed ester reactions. Much of the work in this area has been carried out with the purpose of inquiry into the mode of action of hydrolytic enzymes. These enzymes contain on their backbone weak potential catalytic bases or acids, such as imidazole in the form of histidine, carboxylate in the form of aspartate and glutamate, etc. As a result of the enormous effort put into the study of nucleophilic displacements at the carbonyl carbon, a fair understanding of these reactions has resulted. An excellent review is available for work up to 1960 (Bender, 1960). In addition, this subject has been... 

However, the in vivo reduction of aldehydes by this enzyme is not normally a quantitatively important reaction because aldehydes are rapidly oxidized to their corresponding carboxylic acid derivatives by aldehyde dehydrogenase. Alcohol dehydrogenase is a very important enzyme for the metabolism of ethanol. 

In addition to in situ racemization of a-substituted carboxylic acid derivatives by deprotonation/reprotonation, a procedure involving halide exchange has been developed135, 361. Whilst the a-halo esters undergo racemization at a reasonable rate, the corresponding carboxylates are almost inert to racemization under the reaction conditions. Using immobilized phosphonium halide and CLEC (cross-linked enzyme crystals), a dynamic resolution procedure has been developed for the hydrolysis of a-bromo and a-chloro esters (Fig. 9-17). The enantiomeric excess in each case was similar to that achieved for simple kinetic resolution reactions using the same enzyme/substrate combinations. 

For the hydrogenation of pyrroles, palladium and rhodium catalysts can be used besides platinum, under 3 to 4 atm of hydrogen. Electron-deficient pyrroles can even be hydrogenated at atmospheric pressure. Multiply-substituted pyrroles are hydrogenated by use of platinum or rhodium catalysts to give the cis product only [34]. This method has, for example, been used in the synthesis of a pyrroli-dizine carboxylic acid derivative (Scheme 3), a possible agent of the angiotensinconverting enzyme [35], and in the synthesis of Anatoxin a [36]. 

Amidation, the formation of amides. Amino acid and peptide amides are synthesized by reaction of the appropriate esters or activated carboxylic acid derivatives with ammonia. Amidation of bioactive peptides is performed using the bifunctional enzyme peptidylglycine a-amidating monooxygenase (PAM) by N-oxidative cleavage of a glycine-extended precursor [S. T. Prigge et al.. Science 1997, 278, 1300]. 

Base catalysed racemisation is a straightforward approach because enzymes typically operate at pH close to 7. Clearly the relevant substrates must possess a stereogenic center with an acidic proton, such as a-substituted carboxylic acid derivatives [53-55]. 

L"Cysteine derivatives Coenzyme A (D 11) Cosubstrate of carboxylic acid activating enzymes pantothenic acid, a constituent of coenzyme A, is a vitamin for animals... 

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