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

• Published in: Journal of the American Chemical Society Vol. 141; no. 14; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.04.2019; Amer Chemical Soc
• Subjects: alkaloids; alkylation; amino acids; catalytic activity; Chemistry; Chemistry, Multidisciplinary; enantioselectivity; geometry; Lewis bases; palladium; Physical Sciences; reaction mechanisms; regioselectivity; Science & Technology; FUNCTIONALIZATION; AZLACTONES; OXIDATION; ALCOHOLS; DIASTEREOSELECTIVITY; STRATEGY; ALLYLATION; BOND ACTIVATION; MARINE ALKALOIDS; LEPADIFORMINE
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.8b13582

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.