Reactions with Naturally Occurring Nucleophiles

Haag WR, Mill T. 1988. Some reactions of naturally occurring nucleophiles with haloalkanes in water. Environ Toxicol Chem 7 917-924. 

The most commonly employed dienophiles in DA reactions with normal electron demand are maleimide derivatives. These electron-poor alkenes react smoothly with various conjugated dienes to form the respective bicyclic cycloadducts under mild conditions (Fig. 14a). One drawback of maleimides that limits their widespread use in bioconjugation is their ability to react with naturally occurring nucleophiles,... 

UGT-catalyzed glucuronidation of the carboxylic acid group in drugs results in the formation of acyl glucuronides, which are intrinsically electrophilic in nature. Protein modification can occur via a simple transacylation reaction with a protein nucleophile(s) or by acyl migration within the f3-0-glucuronide unit to a reactive aldehyde intermediate. Detailed mechanistic discussion on this issue is provided with the NSAIDs ibufenac and ibuprofen in the following section. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

Sulfoxides (R1—SO—R2), which are tricoordinate sulfur compounds, are chiral when R1 and R2 are different, and a-sulfmyl carbanions derived from optically active sulfoxides are known to retain the chirality. Therefore, these chiral carbanions usually give products which are rich in one diastereomer upon treatment with some prochiral reagents. Thus, optically active sulfoxides have been used as versatile reagents for asymmetric syntheses of many naturally occurring products116, since optically active a-sulfinyl carbanions can cause asymmetric induction in the C—C bond formation due to their close vicinity. In the following four subsections various reactions of a-sulfinyl carbanions are described (A) alkylation and acylation, (B) addition to unsaturated bonds such as C=0, C=N or C= N, (C) nucleophilic addition to a, /5-unsaturated sulfoxides, and (D) reactions of allylic sulfoxides. 

The electrode reaction of an organic substance that does not occur through electrocatalysis begins with the acceptance of a single electron (for reduction) or the loss of an electron (for oxidation). However, the substance need not react in the form predominating in solution, but, for example, in a protonated form. The radical formed can further accept or lose another electron or can react with the solvent, with the base electrolyte (this term is used here rather than the term indifferent electrolyte) or with another molecule of the electroactive substance or a radical product. These processes include substitution, addition, elimination, or dimerization reactions. In the reactions of the intermediates in an anodic process, the reaction partner is usually nucleophilic in nature, while the intermediate in a cathodic process reacts with an electrophilic partner. 

The kg value was determined to be about 6.9 x 10" s independent of the nature of L in 50°C decalin (AH - 31.8 kcal mol-1 AS - +20.2 cal mol 1 K l). Competition ratios k.g/ky equal to 3 and 5 were determined for L - P(OPh3)3 and PPI13, respectively under the same conditions. The second order pathway was proposed to occur via nucleophilic attack of L on the cluster, and an intermediate with a formulation the same as II/ was suggested, without supporting evidence of its existence, as a possible initial product of this nucleophilic attack. However, since fragmentation was only a minor side reaction of the substitution reactions with L - PPI13, it is quite unlikely that the photofragmentation and second order thermal substitution reactions occur via a common intermediate. 

Most syntheses of naturally occurring phenazines, though, are based on a two-step elaboration of the central heterocycle of the phenazine [78]. The first key step involves the generation of orf/zo-monosubstituted 88 or orf/zo, ortho -disubstituted diphenylamines 89-91 via nucleophilic aromatic substitution. Ring formation is then achieved by means of reductive or oxidative cyclization, for which a number of efficient methods are available. The main flaw of this approach is the synthesis of the substituted diphenylamines via nucleophilic aromatic substitution, as this reaction often can only be performed under strongly basic reaction conditions and at high temperatures. In addition, the diphenylamines required may only be achieved with certain substitution patterns with high yields. 

Substituted binaphthyl compounds can be synthesized in high optical yields using nucleophilic aromatic substitution reactions in which the chiral leaving groups are alkoxy moieties derived from naturally occurring alcohols28-29. For example, the condensation of 2-(l-alkoxynaphth-2-yl)-4.5-dihydro-4,4-dimethyl-l,3-oxazole with 1-naphthyllithium or 2-methoxy-l-naphthyl 2-magnesium bromide leads to (ft)- or (.S)-(l,T-binaphthyl-2-yl)-4,5-dihydro-4,4-dimethyl-l,3-oxazole derivatives. 

---