Synthesis of the Side Chain by Coupling Reactions

The approaches to the taxol side chain described so far have used either a cycloaddition reaction to form a / -lactam, or have installed functional groups on a preexisting carbon skeleton. Another possible approach is to couple two halves of the side chain in some sort of stereo-controlled coupling reaction, and several examples of this chemistry have been published. 

Recently, Ueno et al used the chiral zirconium catalyst 7.4.4 for asymmetric induction. Thus, reaction of imine 7.4.5 and silyl enol ether 7.4.6 in the presence of 10 mol% S-IAA gave the desired phenyl isoserine derivative 7.4.7 in 94% ee and 95% yield. The a-hydroxy-phenylamine which was required for the catalytic asymmetric induction was then cleaved oxidatively using CAN after being converted to an a-methoxy-phenylamine derivative. Aqueous hydrolysis of the resulting aminoester 7.4.8 yielded the amino acid quantitatively, which was benzoylated to give the taxol side chain (269). 

Greene et al used a chiral camphor sulfonamide to achieve diastereoselective condensation of imine 7.4.9 and enolate of 7.4.10 to give 7.4.11. This gave the C-2 benzoyl protected docetaxel side chain 7.4.12 in greater than 99% enantiomeric excess and 45% chemical yield (270). A p-methylbenzylidene acetal protected taxol side chain was also synthesized in a similar way in 99% enantiomeric excess and 45% yield (277). 

An enolate-imine coupling reaction has been used to give the side chain in 59% yield in the key step (272). In this approach the imine 7.4.13 was coupled with the enol 7.4.14 in the presence of MgBr2 to give the adduct 7.4.15 this compound was converted to side chain methyl ester in three steps. 

In another approach, lithiated allene 7.4.16 was coupled with aldehyde 7.4.17 to give adduct 7.4.18, which could be ozonized to give side chain methyl ester in 28% overall yield (273), 

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