Nucleophiles carbon chain branching

Sharkey, W. H. Polymerizations Through the Carbon-Sulphur Double Bond. VoL 17, pp. 73-103. Shimidzu, T. Cooperative Actions in the Nucleophile-Containing Polymers. Vol. 23, pp. 55-102. Slichter, W. P. The Study of High Polymers by Nuclear Magnetic Resonance. VoL 1, pp. 35-74. Small, P. A. Long-Chain Branching in Polymers. VoL 18,pp. 1-64. 

The compound dimethylallyl diphosphate provides an excellent example of a natural product with a diphosphate leaving group that can be displaced in a nucleophilic substitution reaction. Suitable nucleophiles are hydroxyl groups, e.g. a phenol, though frequently an electron-rich nucleophilic carbon is employed. Dimethylallyl diphosphate is a precursor of many natural products that contain in their structures branched-chain C5 subunits termed isoprene units. 

Kinetics demonstrate that in the epoxidation of the n-hexyl jS-alkylvinyl ketones 54 the possibility of nucleophilic attack decreases as the carbon chain in group R becomes longer or more branched. The Hammett correlation has been studied in the reaction of 55. ... 

The structural features responsible for the genotoxicity are a double bond in the necine base between C-1 and C-2, presence of hydroxy groups at C-1 and C-9, and esterification of at least one of these hydroxy groups with a branched carbon chain (Frei et al., 1992). In most vertebrates and insect herbivores, the alkaloid A -oxides are reduced in the gut to their free bases. The reduced alkaloids are then taken up and bioactivated by cytochrome P450-dependent monooxygenases of the liver to highly reactive dehydropyrrolizidine alkaloids that react with nucleophilic groups of proteins and DNA (Roder, 1995). 

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

Since its introduction in carbohydrate chemistry by Hicks and Fraser-Reid in 1975 [22], applications of the opening of epoxide with carbon nucleophiles abound in the literature. Just a few seminal examples will be mentioned here, other examples will be found in combination with other branching-chain methods. 

The 1,3-disconnection we met in Chapter 6 is also effective for carbon nucleophiles (21). The reaction is the Michael addition of carbanions to a,d-unsaturated carbonyl compounds and we may expect Grignard reagents or RLi to do this reaction. We shall look for this disconnection when there is a branch point at the /3 or 7 carbon atoms, and particularly when the bond to be disconnected joins a ring to a chain. Ketone (22) can clearly be made this way. 

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