Pd-Catalyzed Asymmetric Allylic Alkylation of Cyclobutenes: From Double Inversion to Double Retention

The Pd-catalyzed allylic alkylation of 3,4-disubstituted, racemic cyclobutene electrophiles exhibits a highly unusual stereoselectivity that allows for controlling diastereo- and enantioselectivity only by the choice of ligand and independent of the configuration of the substrate. In order to shed l...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2023-07, Vol.145 (29), p.15912-15923
Main Authors: Primozic, Johann J., Ilgen, Julian, Maibach, Patrick, Brauser, Matthias, Kind, Jonas, Thiele, Christina M.
Format: Article
Language:English
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Summary:The Pd-catalyzed allylic alkylation of 3,4-disubstituted, racemic cyclobutene electrophiles exhibits a highly unusual stereoselectivity that allows for controlling diastereo- and enantioselectivity only by the choice of ligand and independent of the configuration of the substrate. In order to shed light on the origin of stereoinduction, we performed a systematic mechanistic investigation, including preparation of various putative Pd-allyl intermediates, 1H/31P NMR reaction monitoring, 2H-labeling studies, ESI–HRMS and 31P NMR analysis of reaction mixtures, and DFT structural computations. The mechanism disclosed exhibits several steps with stereospecificities deviating from the commonly accepted “double inversion rule”: oxidative addition was found to follow a stereoconvergent course, giving anti-configured η1-Pd-cyclobutene species as detectable on-cycle intermediates irrespective of the configuration of starting material, while the subsequent nucleophilic attack features a stereodivergent behavior. In stark contrast to their highly reactive anti-analogues, syn-Pd-cyclobutene complexes that can be formed as side products are rendered entirely unreactive by strong internal Pd–O chelation, preventing the formation of undesired product diastereomers.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.3c03590