Strategic 1,9-Proton-Transfer-Driven\nCycloaddition:\nSynthesis and Stereoselective Contraction of Nine-Membered Heterocycles

We introduce a phosphine-catalyzed cycloaddition involving\nunprecedented\nlong-range intramolecular proton transfer, facilitating the synthesis\nof nine-membered heterocycles, which are privileged structures in\nnatural products, as well as potent pharmacophores. Experimental and\ncomputational studies revealed that the enamide tether of the N-aromatic\nzwitterion directly enables long-range regioselective intramolecular\nproton transfer to proceed independently of outer-sphere proton shuttling.\nThis understanding of selective proton transfer has led to the improved\nefficiency and regioselectivity of the desired 1,9-proton transfer\nreaction under anhydrous conditions, thereby advancing the development\nof higher-order cycloaddition reactions. Further stereoselective contraction\nof the synthesized nine-membered cyclic compounds using 3-aza-Cope\nrearrangement demonstrates the synthetic versatility of our approach.\nThe findings of this study not only advance the general understanding\nof the long-range proton transfer mechanism but also broaden its practical\nutility in various chemical fields.