Nucleophilic displacement naturally occurring nucleophiles

A naturally occurring sulfonium salt, S-adenosylmethionine (SAM), is a key substance in certain biological processes. It is formed by a nucleophilic substitution in which the sulfur atom of methionine attacks the primary carbon of adenosine triphosphate, displacing the triphosphate leaving group as shown in Figure 16.7. 

Since the triazines obtained until 1995 have had mainly alkyl or aryl substituents, or been benzo-fused derivatives, reports concerning the reactivity of substituents have been relatively few. Gompper et al. reported that 4,5,6-trichlorotriazine (99) undergoes substitution reactions with amines and alcohols <79CB1535>. The first reaction site was the C-4 position, and successive displacement(s) occurred depending on the nature of the nucleophile (Scheme 17). 

Beyond simple displacement reactions in which an amine behaves as a nucleophile, there is a small group of specialized reactions of amines, each of which has a very specific use. The Hofmann elimination has heen more important in structure determination than anything else. It is frequently combined with the Mannich reaction, however, to make an important synthetic entry to cyclic carbonyl compounds with methylene groups next to the ctirbonyl (see Problem 19). Such structures are present in many naturally occurring (plant-derived) antitumor agents. 

The scarcity of unnatural D-amino acids makes these compounds attractive synthetic targets, especially when one considers the disparity of price relative to their naturally occurring partners. If the hydroxyl group of an L-lactate could be displaced by a nitrogen nucleophile with inversion of configuration, this would allow easy access to D-alanine derivatives. Such a transformation can be realized by the reaction of 2 with diphenyl phosphorylazide and DBU to produce the (R)-azidoester 96 (98% ee) [33]. The initial step of the reaction is the formation of phosphonate 95. The resulting liberated azide then completely displaces the phosphonate group, with nearly total inversion of the stereo center. 

Table 2.7 lists nucleophilicity constants in water for a number of naturally occurring nucleophiles, values of rate constants for nucleophilic substitution (ky) relative to H2O, and the calculated concentrations, [NucJso, at which the rate constant for the Sn2 displacement by the nucleophile of interest is equal to the rate of 8 2 displacement by H2O (kNuc[Nuc]5oivo = kn2o[H20]). It is readily apparent that as the magnitude for the value of n increases, the concentration of nucleophile needed to compete with hydrolysis decreases. 

Both electrophilic and nucleophilic reactions can generate halogenopur-ines with differences in regioselectivity dependent on substituents and on the nature of the substrate (anion, neutral molecule, or cation). In the neutral molecule nucleophilic displacements occur in the order 2 > 4 > 6 in the anion the imidazole ring may be sufficiently 7r-excessive for attack to occur at C-2, and the nucleophilic substitution order becomes 4 > 6 > 2. Strong electron donors are usually necessary to promote 2-halogenation by electrophilic halogen sources. 

One of the fascinating aspects of organophosphorus chemistry is the extent to which stereochemical and electronic factors control the rate and also the nature of the products of nucleophilic displacements at tetrahedral phosphorus. Our original goal in this work was to design a synthesis of diethylphosphonomethyl-alkenylphosphinates III. Unfortunately the condensation of I with aldehydes occurred primarily by path A (Scheme I) to give II... 

Instead, the displaced F- ion re-attacks the newly formed molecule within the complex, leading eventually to the products shown in (42). Although the lifetime of the F- ion/molecule complexes is not known, they must live sufficiently long to allow secondary reactions to occur. Depending upon the nature of the original nucleophile, the re-attack by the displaced F- ion can involve proton transfer, SN2 substitution and E2 elimination. Proton transfer to the displaced F" ions (43) is the dominant reaction if the neutral in the complex is more acidic than HF. This is the case when the primary... 

The essential reaction of halogen substituents at the tetrazole carbon atom is that of nucleophilic displacement. This readily occurs because of the tt-deficient deactivated nature... 

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