Electrophilic functional

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequentiy, an active site nucleophile in close proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via S 2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

To be eligible to living anionic polymerization a vinylic monomer should carry an electron attracting substituent to induce polarization of the unsaturation. But it should contain neither acidic hydrogen, nor strongly electrophilic function which could induce deactivation or side reactions. Typical examples of such monomers are p-aminostyrene, acrylic esters, chloroprene, hydroxyethyl methacrylate (HEMA), phenylacetylene, and many others. 

Sequential addition of monomers 6 7-26-27-114) is the most obvious procedure. Once the first monomer has been polymerized, the resulting living species is used as a polymeric initiator for the polymerization of the second one. The monomers are to be added in the order of increasing electron affinity to provide efficient and fast initiation 26 U4). This condition is rather restrictive, and the number of monomer systems that can be used is limited (Table 5). Moreover, when the second monomer contains an electrophilic function (e.g. ester) which could lead to side reactions, it is necessary to first lower the nucleophilicity of the living site. This is best done by intermediate addition of 1.1-diphenylethylene25). The stabilized diphenylmethyl anions do not get involved in side reactions with ester functions, while initiation is still quantitative and fast. 

The electrophilic functions most commonly used in grafting onto processes are ester 141 144), benzylic halide 145,146) and oxirane, 47). Other functions such as nitrile or anhydride could be used as well. The backbone is a homopolymer (such as PMMA) or a copolymer containing both functionalized and unfunctionalized units. Such species can be obtained either by free radical copolymerization (e.g. styrene-acrylonitrile copolymer) or by partial chemical modification of a homopolymer (e.g. 

An affinity label is a molecule that contains a functionality that is chemically reactive and will therefore form a covalent bond with other molecules containing a complementary functionality. Generally, affinity labels contain electrophilic functionalities that form covalent bonds with protein nucleophiles, leading to protein alkylation or protein acylation. In some cases affinity labels interact selectively with specific amino acid side chains, and this feature of the molecule can make them useful reagents for defining the importance of certain amino acid types in enzyme function. For example, iodoacetate and A-ethyl maleimide are two compounds that selectively modify the sulfur atom of cysteine side chains. These compounds can therefore be used to test the functional importance of cysteine residues for an enzyme s activity. This topic is covered in more detail below in Section 8.4. 

Anion-triggered reactions, as discussed earlier in Chapter 2, embody transformations in most cases, in which a nucleophile acts as the attacking species towards an electrophile. Since oxidation and reduction procedures are well established for providing nucleophilic or electrophilic functionalities, they can be combined with anionic process. 

Intramolecular nucleophilic attack of a pyridine or piperidine nitrogen atom onto an electrophilic function placed in the -position of a side chain is a common way to achieve quinolizidine compounds. These reactions are systematized below on the basis of the nature of the electrophile. 

We have also developed targeted library approaches towards cysteine proteases, which are important pharmaceutical targets due to their role in the pathogenesis of many diseases.1251 A common feature of virtually all cysteine protease inhibitors is an electrophilic functionality, such as a carbonyl or a Michael acceptor, which can react with the nucleophilic active site cysteine residue. We specifi-... 

Like the piperidones, a wide variety of TV-heterocyclic aromatic compounds show an ability to activate electrophilic functional groups. It is known that acetophenone is completely protonated in CF3SO3H, however in the presence of benzene there is no hydroxyalkylation (condensation) reaction.12 On the other... 

Trifluoromethyl)trimethylsilane has been prepared by a modification5 of the procedure originally published by Ruppert.4 The optimized yield is 75%. Other less convenient methods are also available for its preparation. (Trifluoromethyl)trimethylsilane acts as an in situ trifluoromethide equivalent under nucleophilic initiation and reacts with a variety of electrophilic functional groups. Carbonyl compounds such as aldehydes, ketones and lactones react rather readily5 7 with (trifluoromethyl)trimethylsilane under fluoride initiation. The reagent also reacts with oxalic esters,8 sulfonyl fluorides,9 a-keto esters,10 fluorinated ketones,11 and... 

Similar chemistry is possible starting from hydrazones bearing acidic a protons an initial diastereoselective enolization and electrophilic functionalization of the hydrazone can be followed by derivatization which is stereoselective in the planar sense . ... 

An interesting arylation of the silyl enolate of Ley s dioxanone 133 in the presence of a catalytic amount of Pd2(dba)3 (5 mol%) and P(/-Bu)3 (10 mol%) with 0.5 equiv of Znp2 or Zn(0-/-Bu)2 provides a single diastereoisomer of the coupled products 134 (dba = dibenz[ , ]anthracene). A variety of electronically and sterically distinct aryl halides, including those containing electrophilic functional groups, have been introduced (Equation 20) <2004JA5182>. 

Electrophilic functional groups in ortho-position to the carbon-magnesium bond allow two sequential alkylations. Starting from ort/io-iodobenzyl chloride 104, the benzannulated heterocycles 105 and 106 are obtained after the reaction with appropriate electrophiles (Scheme 8) . ... 

Anionic "living" polymerization can be carried out in polar as well as in non-polar solvents, provided they are aprotic, and contain no strongly electrophilic functions. The rate of chain growth is much faster in polar than in non-polar solvents. 

The above mechanism assigns an electrophilic function to the metal ion. During decarboxylation, an electron pair initially associated with the carboxylate ion group is transferred to the rest of the molecule. A metal ion, because of its positive charge, should assist this transfer (46). 

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