Some Biological Nucleophilic Addition Reactions

We ll see in Chapter 29 that living organisms use many of the same tions that chemists use in the laboratory. This is particularly true of i bonyl-group reactions, where nucleophilic addition steps play a critical ruie in the biological synthesis of many vital molecules. For example, one of the pathways by which amino acids are made involves nucleophilic addition of an amine to w-keto acids. To choo.se a specific example, the bacterium Bari/ lus subtilis synthesizes the amino acid alanine from pyruvic acid. 

The key step in this biological transformation is the nucleophilic addi tion of an amine to the ketone carbonyl group of pyruvic acid. The tetrahedral intermediate loses water to yield an imine, which is further reduced in a second nucleophilic addition step to yield alanine. 

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The next section explores the mechanism of nucleophilic addition to aldehydes and ketones There we 11 discuss their hydration a reaction m which water adds to the C=0 group After we use this reaction to develop some general principles we 11 then survey a number of related reactions of synthetic mechanistic or biological interest... 

The Michael reaction involves conjugate addition of a nucleophile onto an a,P-unsaturated carbonyl compound, or similar system. Such reactions take place in nature as well, and some can be potentially dangerous to us. For example, the a,P-unsaturated ester ethyl acrylate is a cancer suspect agent. This electrophile can react with biological nucleophiles and, in so doing, bind irreversibly to the nucleophile, rendering it unable to carry out its normal functions. A particularly important enzyme that can act as a nucleophile is DNA polymerase, which is responsible for the synthesis of strands of DNA, especially as part of a DNA repair mechanism (see Section 14.2.2). The nucleophilic centre is a thiol grouping, and this may react with ethyl acrylate as shown. 

The conversion of 5,5,5-trifluoro-4-trifluoromethylpent-3-en-2-one with methyl acetoacetate in the presence of sodium hydride opens a new reaction pathway for the preparation of molecules which might show some biological and medical activities. The first step of this reaction is the anti-Michael addition of the nucleophile (a-metallated ester) to the 3-position of 5,5,5-trifluoro-4-trifluoromethylpent-3-en-2-one. In the next step metallation in the /-position yields the enolate which attacks nucleophilically the olefinic CF2-carbon forming 4-acetyl-2-fluoro-6-methyl-5-methoxy-carbonyl-3-trifluoromethylpyran by fluoride elimination. 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

In addition, although most abiotic processes are nonenantioselective, not aU are indeed the case. Nucleophilic 5 jv2-substitution reactions at a chiral center will result in chiral inversion to the antipodal enantiomer. While such processes are often biologically mediated, as for the nonsteroidal anti-inflammatory drugs [328], they can also be abiotic. Appropriate sterile controls should be used for experiments with such compounds, as was done in the demonstration of microbial chiral inversion of ibuprofen in Swiss lake water [329]. Photolysis of a-HCH [114], /3-PCCH [114], and chlordane compounds [116] was demonstrated not to be enantioselective, as expected for an abiotic process. However, this may not be the case for some pyrethroids, known to isomerize photolytically. 

You shouldn t need us to tell you the mechanism of this reaction even without looking at the mechanism we gave for the formation of the oxime it should come as no surprise to you by now. But as the reaction is very important in chemistry and biology, we ll discuss it in some depth. First, the amine attacks the aldehyde and the intermediate known as a hemiacetal is formed. Amines are good nucleophiles for carbonyl groups, and aldehydes and ketones are electrophilic. There is no need for any catalysis in this step. Indeed, addition of acid would slow the reaction down as the nucleophilic amine would be removed as a salt. 

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