Three-site cycloadditions within one reaction intermediate with site-selectivity controlled by electronic and size bias.

In homogeneous catalysis, a reaction intermediate typically possesses only one reactive site to ensure chemoselectivity. However, such a design limits efficiency and requires multiple independent steps to achieve divergent synthesis. What if a single intermediate could act as a "master key" featuring multiple, differentiated sites that each respond selectively to distinct partners? This concept has remained largely unexplored due to the long-standing challenge of controlling site selectivity. Here, we report the design of a remarkable three-site intermediate (Int-1) that serves as a selective, programmable hub for complex molecular synthesis. Using a gold catalyst and 1,6-allenynes, we generate an intermediate containing three sterically and electronically distinct cycloaddition sites (A, B, and C). The power of this intermediate lies in its intelligent site recognition: site-A reacts exclusively with bulky dipolarophiles, site-B selectively traps nucleophilic partners, and site-C engages electrophilic aldehydes. This precise multi-site control, rationalized by DFT calculations, enables three divergent cycloaddition pathways to proceed from a common intermediate. The discovery of three-site intermediate Int-1 establishes a new paradigm for multi-site divergent synthesis, providing a one-step platform for the efficient generation of structurally diverse benzoxepines-the core scaffolds of numerous bioactive molecules and pharmaceuticals.