Calculations on the ruthenium-catalyzed diene and dienyne ring-closing metathesis reactions in the synthesis of taxol derivatives

Brooks, S., Charlton, G., Letort, A., Prunet, J. and Bucher, G. (2021) Calculations on the ruthenium-catalyzed diene and dienyne ring-closing metathesis reactions in the synthesis of taxol derivatives. Journal of Organic Chemistry, 86(18), pp. 13056-13070. (doi: 10.1021/acs.joc.1c01879) (PMID:34449228)

Abstract

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.

• Item Type: Articles
• Additional Information: Financial support for this work was provided by the University of Glasgow. We thank Dr. Brian Millward, Honorary Research Fellow, for a generous donation. GB, SB, and GC thank the EPSRC UK National Service for Computational Chemistry Software (NSCCS) for a CPU time grant.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Prunet, Dr Joelle and Bucher, Dr Goetz
• Authors: Brooks, S., Charlton, G., Letort, A., Prunet, J., and Bucher, G.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of Organic Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-3263
• ISSN (Online): 1520-6904
• Published Online: 27 August 2021
• Copyright Holders: Copyright © 2021 American Chemical Society
• First Published: First published in Journal of Organic Chemistry 86(18): 13056-13070
• Publisher Policy: Reproduced in accordance with the publisher copyright policy