Nucleophilic metabolites, conjugation reactions

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Glutathione and sulfatation conjugations are important pathways for generally detoxifying endogenous substrates and xenobiotics (Commanndeur et al. 1995). However, some produced metabolites (ie mercapturic acids, O-sulfo conjugates) are toxic by different mechanisms, often by reaction with DNA and other cellular nucleophiles. 

Electrophiles not only complex with macromolecular nucleophilic sites, but also complex with those of small molecules. The most important of these is the -SH group of GSH. Conjugation of electrophiles with GSH is an important detoxication reaction catalyzed by GSH transferases (see Chapter 12). Although GSH concentration in hepatocytes is high relative to other tissues (4-8mM), depletion of GSH can occur upon acute exposure to protoxicants whose electrophilic metabolites... 

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