Nucleophile-Dependent Z/E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C–H Alkylation of 1,4-Dienes

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C–H alkylation is principally more atom- and step-economic than the classical allylic functionalizations and thus can be considered a transformat...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2019-04, Vol.141 (14), p.5824-5834
Main Authors: Lin, Hua-Chen, Xie, Pei-Pei, Dai, Zhen-Yao, Zhang, Shuo-Qing, Wang, Pu-Sheng, Chen, Yu-Gen, Wang, Tian-Ci, Hong, Xin, Gong, Liu-Zhu
Format: Article
Language:English
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Summary:The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C–H alkylation is principally more atom- and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C–H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E- and regioselectivities in the Pd-catalyzed asymmetric allylic C–H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C–H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C–H cleavage and reveal that the Z/E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.8b13582