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.

Automated summary

Density-functional and semiempirical calculations on intermediates in ring-closing metathesis reactions in the synthesis of Taxol derivatives show excellent agreement with previous experimental results. The role of steric overloading in determining the outcome is highlighted, with rigidity of the Taxol skeleton playing a key role. Transition states in the final metathesis reaction stage are sensitive to steric effects. Predictions suggest preference for one diastereomer with a compact cyclic carbonate moiety, while a bulkier benzoate-protecting group results in prohibitive activation barriers. The orientation of the pseudoaxial methyl group on the cyclohexene ring likely determines the cascade formation pathway.