Calculations on the Ruthenium-Catalyzed Diene and Dienyne Ring-Closing Metathesis Reactions in the Synthesis of Taxol Derivatives

Density-functional
and semiempirical calculations (M06, M06L, and
PM6) on intermediates in the ring-closing metathesis (RCM) reactions
in the synthesis of Taxol derivatives give results in excellent agreement
with the results of previous experimental work. The results suggest
that the degree of steric overloading plays a decisive role in determining
the outcome (ene–ene or ene–yne–ene metathesis).
Due to the rigidity of the Taxol skeleton being formed in the ene–yne–ene
cascade reaction, the transition states in its final ene–ene
metathesis reaction stage are particularly sensitive to steric effects.
Thus, the reaction is predicted to be preferred for one diastereomer
of the precursor in which the diol functionality is protected with
a compact cyclic carbonate moiety, whereas the use of a bulkier benzoate-protecting
group results in activation barriers for Taxol formation that are
prohibitive. The reason why one diastereomer of the carbonate-protected
precursor undergoes formation of a tricycle via an ene–yne–ene
RCM cascade, whereas the other diastereomer undergoes cyclooctene
formation via an ene–ene RCM, likely lies in the orientation
of the pseudoaxial methyl group on the cyclohexene ring, which in
the latter case would unfavorably point toward the reactive center
of the Ru-complex, leading to Taxol formation.