Modifiers nucleophiles

To achieve the desired asymmetric induction, chirality must be introduced. There are essentially three ways to do this. One can employ (i) chirally modified substrates (ii) chirally modified nucleophiles or (iii) a chiral reaction medium (chiral coordinating cosolvents, ligands or catalysts). This chapter is organized according to these three approaches. 

Song et al. [72] synthesized fluorinated poly(phthalazinone ether)s (FPPEs) via a modified nucleophilic aromatic substitution using mild reaction conditions. Potassium fluoride and calcium hydride were used as the catalyst and base in preparing highly... 

Purified enzyme from Escherichia coli has been studied for its reactivity tvith homologous five-carbon phosphosugars to yield KDO derivatives, and tvith modified nucleophiles. Thus, the stereochemically distinct fiuoro-analogs of PEP (Z)- and ( )-31 could be separately condensed vith D-erythrose 4-phosphate to yield, stereospecifically, the corresponding (3S)-and (3R)-configured, fiuoro-substituted DAHP derivatives 32 and 33, respectively (Figure 5.18) [127]. This provides direct evidence that the enzyme catalyzes si face addition of the C-3 of PEP to the rc face of the acceptor aldehyde. 

Some Hammett values for reactions in thiazole and in nucleophile are reported in Table V-3. The observed p values for normal substitution processes (methoxy and thiophenoxysubstitution) are high and positive, indicating that the substituent plays an important role in modifying the stability of the intermediate anion. 

Two modified sigma constants have been formulated for situations in which the substituent enters into resonance with the reaction center in an electron-demanding transition state (cr+) or for an electron-rich transition state (cr ). cr constants give better correlations in reactions involving phenols, anilines, and pyridines and in nucleophilic substitutions. Values of some modified sigma constants are given in Table 9.4. 

Another useful reagent for the 3-aLkylation of indole is the /V,/V-dimethy1foTma1 diminium ion, which forms the useful intermediate gramine [87-52-5] (9). The C-3 substituent can subsequendy be modified by displacement of the dimethylarnino group by a nucleophile. Alternatively, gramine can be converted to its quaternary salt prior to substitution. A variety of carbanions can function as the nucleophile. 

The effect of a substituent may be substantially modified by fast, concurrent, reversible addition of the nucleophile to an electrophilic center in the substituent. Ortho- and para-CS.0 and pam-CN groups have been found by Miller and co-workers to have a much reduced activating effect on the displacement of halogen in 2-nitrohaloben-zenes with methoxide ion [reversible formation of hemiacetal (143) and imido ester anions (144)] than with azide ion (less interaction) or thiocyanate (little, if any, interaction). Formation of 0-acyl derivatives of 0x0 derivatives or of A-oxides, hydrogen bonding to these moieties, and ionization of substituents are other examples of reversible and often relatively complete modifications under reaction conditions. If the interaction is irreversible, such as hydrolysis of a... 

The two isomeric possibilities are 1,2- and 2,1-benzisoxazole. Both are preferentially halogenated by electrophilic halogen in the homocyclic ring, initially in the 5-position, although substituents can modify this behavior [67AHC(8)277]. Nucleophiles attack the heteroring (84MI26). 

An optically active sulfoxide may often be transformed into another optically active sulfoxide without racemization. This is often accomplished by formation of a new bond to the a-carbon atom, e.g. to the methyl carbon of methyl p-tolyl sulfoxide. To accomplish this, an a-metallated carbanion is first formed at low temperature after which this species may be treated with a large variety of electrophiles to give a structurally modified sulfoxide. Alternatively, nucleophilic reagents may be added to a homochiral vinylic sulfoxide. Structurally more complex compounds formed in these ways may be further modified in subsequent steps. Such transformations are the basis of many asymmetric syntheses and are discussed in the chapter by Posner and in earlier reviews7-11. 

Perhaps the most important single function of the solution environment is to control the mode of decomposition of reaction intermediates and hence the final products. This is particiflarly true in the case of electrode reactions producing carbonium ion intermediates since the major products normally arise from their reaction with the solvent. It is, however, possible to modify the product by carrying out the electrolysis in the presence of a species which is a stronger nucleophile than the solvent and, in certain non-nucleophilic solvents, products may be formed by loss of a proton or attack by the intermediate on further starting material if it is unsaturated. The major reactions of carbonium ions are summarized in Fig. 6. 

In principle, numerous reports have detailed the possibility to modify an enzyme to carry out a different type of reaction than that of its attributed function, and the possibility to modify the cofactor of the enzyme has been well explored [8,10]. Recently, the possibility to directly observe reactions, normally not catalyzed by an enzyme when choosing a modified substrate, has been reported under the concept of catalytic promiscuity [9], a phenomenon that is believed to be involved in the appearance of new enzyme functions during the course of evolution [23]. A recent example of catalytic promiscuity of possible interest for novel biotransformations concerns the discovery that mutation of the nucleophilic serine residue in the active site of Candida antarctica lipase B produces a mutant (SerlOSAla) capable of efficiently catalyzing the Michael addition of acetyl acetone to methyl vinyl ketone [24]. The oxyanion hole is believed to be complex and activate the carbonyl group of the electrophile, while the histidine nucleophile takes care of generating the acetyl acetonate anion by deprotonation of the carbon (Figure 3.5). 

To conclude, a strong correlation was found to exist between the net charge of the proteins in solution, the net charge of the SUM surface, and the extent of protein adsorption, which was expressed in terms of flux losses measured after filtration of the different protein solutions. Moreover, in the case of charge-neutral SUMs, flux losses increased with the hydrophobicity of the nucleophiles bound to the S-layer lattice. All proteins caused higher flux losses on SUMs modified with HDA than on those modified with GME or... 

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