Stereoselective Reductions of 3-Substituted Cyclobutanones: A Comparison between Experiment and Theory

Xavier Deraet, Lauren Voets, Ruben Van Lommel, Guido Verniest, Frank De Proft, Wim De Borggraeve, Mercedes Alonso Giner

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The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach. On the experimental side, the hydride reduction of 3-substituted cyclobutanones was proven to be highly selective for the formation of cis alcohol (>90%), irrespective of the size of the hydride reagent. The pronounced selectivity can be further enhanced by lowering the reaction temperature or decreasing the solvent polarity. On the computational side, density functional theory and noncovalent interaction analysis reveal that torsional strain plays a major role in the preference for the antifacial hydride approach, consistent with the Felkin-Anh model. In the presence of the benzyloxy substituent, the high selectivity for the cis isomer is also driven by repulsive electrostatic interactions in the case of a syn-facial hydride attack. The computed cis/trans ratios are in good agreement with the experimental ones and thus show the potential of computational chemistry for predicting and rationalizing the stereoselectivity of hydride reductions of cyclobutanones.

Original languageEnglish
Pages (from-to)7803-7816
Number of pages14
JournalJournal of Organic Chemistry
Issue number12
Publication statusPublished - 19 Jun 2020

Bibliographical note

Funding Information:
The authors wish to thank the Fund for Scientific Research—Flanders (FWO) and the Vrije Universiteit Brussel (VUB)––for their continuous support. F.D.P. acknowledges VUB for a Strategic Research Program awarded to his research group. M.A. thanks FWO for a postdoctoral fellowship (12F4416N) and VUB for financial support. R.V.L. acknowledges FWO for a predoctoral fellowship received (1185219N). Computational resources and services were provided by the Shared ICT Services Centre funded by the Vrije Universiteit Brussel, the Flemish Supercomputer Center (VSC), and FWO. The graphical representations of the geometries were obtained using the freely available CYLview software. a

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Copyright 2020 Elsevier B.V., All rights reserved.


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