biostudies-literatureZhang LZNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)930https://www.ebi.ac.uk/biostudies/studies/S-EPMC11754474biostudies-literatureUnknown16(1)The enantioselective domino Heck/cross-coupling has emerged as a powerful tool in modern chemical synthesis for decades. Despite significant progress in relative rigid skeleton substrates, the implementation of asymmetric Heck/cross-coupling cascades of highly flexible haloalkene substrates remains a challenging and and long-standing goal. Here we report an efficient asymmetric domino Heck/Tsuji-Trost reaction of highly flexible vinylic halides with 1,3-dienes enabled by palladium catalysis. Specifically, the Heck insertion as stereodetermining step to form ƞ³ allyl palladium complex and in situ trapping with nucleophiles enable efficient Heck/etherification in a formal (4 + 2) cycloaddition manner. Engineering the Sadphos bearing androgynous non-C₂-symmetric chiral sNature communicationsEnantioselective Heck/Tsuji-Trost reaction of flexible vinylic halides with 1,3-dienes.PMC1175447421921003Zhou MZhang PCWang QZhang JZhang LZfalseEnantioselective Heck/Tsuji-Trost reaction of flexible vinylic halides with 1,3-dienes.The enantioselective domino Heck/cross-coupling has emerged as a powerful tool in modern chemical synthesis for decades. Despite significant progress in relative rigid skeleton substrates, the implementation of asymmetric Heck/cross-coupling cascades of highly flexible haloalkene substrates remains a challenging and and long-standing goal. Here we report an efficient asymmetric domino Heck/Tsuji-Trost reaction of highly flexible vinylic halides with 1,3-dienes enabled by palladium catalysis. Specifically, the Heck insertion as stereodetermining step to form ƞ³ allyl palladium complex and in situ trapping with nucleophiles enable efficient Heck/etherification in a formal (4 + 2) cycloaddition manner. Engineering the Sadphos bearing androgynous non-C₂-symmetric chiral s2025-01-01T00:00:00Z2025 Jan2025-04-18T14:27:17.539Z2025-04-07T00:36:30.131ZS-EPMC117544743984342610.1038/s41467-025-56142-z