Abstract
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 tandem Heck/Tsuji−Trost reaction of highly flexible vinylic halides with 1,3-dienes enabled by palladium catalysis. A variety of functional cyclic isoprenoids, which are key structural motifs of numerous natural products family, were delivered in good yields with excellent regio-, diastereo- and enantioselectivity. Specifically, the Heck insertion of stereodetermining step to form ƞ3 π-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 sulfinamide phosphine ligands were vital component in achieving excellent catalytic reactivity and enantioselectivity. This strategy offers a general, modular and divergent platform for rapidly upgrading feedstock flexible vinylic halides and dienes to various value-added molecules and is expected to inspire the development of other challenging enantioselective domino Heck/cross-couplings.