Highly Selective and Modular Assembly of Densely Substituted Tetrahydrofurans

-Heterocycles bearing multiple vicinal stereocenters are especially critical targets due to their challenging construction under precise stereocontrol. The multisubstituted tetrahydrofuran (THF) family, for example, represents a privileged structural motif. Yet, syntheses of THFs are often step-intensive and tailored to a single target structure, as generalized and robust methods that rapidly introduce multiple substituents from simple precursors remain underdeveloped. Herein, we present a distinct approach featuring two core advantages: modular assembly from abundant building blocks, and precise chemo-, regio-, diastereo-, and enantioselectivity. Pivotal to the success of this methodology is synergistic metallaphotoredox-Lewis acid catalysis, which rapidly constructs four bonds in THFs bearing up to four stereocenters. Experimental and computational studies deliver further insight into the mechanism. High-throughput experimentation (HTE) highlights the potential for efficient generation of THF-based libraries.