Strategic 1,9-Proton-Transfer-Driven Cycloaddition: Synthesis and Stereoselective Contraction of Nine-Membered Heterocycles

Abstract

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