7-Elimination and replacement

P-Elimination and then replacement reaction of an a-amino acid with a nucleophile is very attractive from the viewpoint of synthetic organic chemistry because various P-substituted alanines may be prepared from a simple a-amino acid, such as serine, and nucleophiles. A reaction catalyzed by tryptophan synthase - the formation of tryptophan from serine and indole - is one of the most well-known P-elimination and replacement reactions (Scheme 2.7). Here, an aldimine Schiff base is derived from reaction of the enzyme-bound PLP with serine, which then dehydrates to give the Schiff base of PLP with 2-aminoacrylate. Indole then adds to the vinyl Schiff base, generating tryptophan after lysine aminolysis of the Schiff base product. 

Several PLP-dependent enzymes catalyze elimination and replacement reactions at the y-carbon of substrates, an unusual process which provides novel routes for mechanism-based inactivation. An example of this class of enzymes is cystathionine y-synthase [0-succinylhomoserine (thiol)-lyase], which converts (7-succinyl-L-homoserine and L-cysteine to cystathionine and succinate as part of the bacterial methionine biosynthetic pathway (Walsh, 1979, p. 823). Formation of a PLP-stabilized o-carbanion intermediate activates the )8-hydrogen for abstraction, yielding j8-carbanion equivalents and allowing elimination of the y-substituent. The resulting j8,y-unsaturated intermediate serves as an electrophilic acceptor for the replacement nucleophile. Suitable manipulation of the j8-carbanion intermediate allows strategies for the design of inactivators which do not affect enzymes which abstract only the a-hydrogen. 

Sulfur removal is accomplished directly by a hydrogenolysis mechanism or indirectly by prior hydrogenation. Figure 7.9 shows the two possible pathways for dibenzothiophene HDS. In the direct route, the S-atom is eliminated and replaced by hydrogen. The other mechanism requires saturation of one aromatic ring before sulfur removal. The sulfur-free products may undergo further hydrogenation until the molecule is completely saturated. 

The nitro groups in Eqs. 7.88-7.90 are readily replaced by hydrogen with tin hydride under radical conditions as discussed already. However, the nitro groups in the a-nitrosulfides or (3-nitrosulfides are not replaced by hydrogen on treatment with tin hydride but the reaction affords desulfonated products (Eq. 7.51) and alkenes (Eq. 7.97) such radical elimination reactions are discussed in Section 7.3.1. (see Eqs. 7.91 and 7.92).138... 

In mammals the epimerase (Eq. 20-7, step a) probably utilizes a similar chemical mechanism but eliminates UDP and replaces it with HO" to give free N-acetylmannosamine, which is then phosphor-ylated on the 6-hydroxyl (Eq. 20-7, step b). ManNAc may also be formed from free GlcNAc by another 2-epimerase (step a").47C/d... 

As shown in Figure 17.9, esters of sulfuric acid exist in which either one or both of the ionizable H atoms are replaced by hydrocarbon substituents, such as the methyl group. Replacement of one H yields an acid ester, and replacement of both yields an ester. Metabolically, acid ester sulfates are synthesized in phase II reactions to produce water-soluble products of xenobiotic compounds (such as phenol) that are readily eliminated from the body (see Section 7.4). 

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