A Revised Photo-Flow Protocol to Cubane-1,4-Dicarboxylate for Reliable Access to Cuneane Acids

Rigid, saturated benzene bioisosteres are increasingly popular in medicinal chemistry, yet even cubane remains underused because key precursors are difficult to access at scale. We report the first photosensitizer-free LED-based, scalable route to cubane-1,4-dicarboxylates, replacing mercury lamps used in all prior methods. The limiting [2+2] cycloaddition operates at 365 nm in continuous flow on commercially available hardware, delivering 54 g h-1. The seven-step sequence provides cubane-1,4-dicarboxylic acid monomethyl ester in 25% yield on a multi-hundred-gram scale. Recognizing carboxylic acids and acid-esters as the most versatile handles for cage compound derivatization, we systematically optimized cubane-to-cuneane rearrangements to produce both 2,6- and 1,3-cuneane acid-esters and, for the first time, all three cuneane monocarboxylic acids at a preparative scale. These advances establish accessible cubane synthesis and unlock cuneanes as practical sp3-rich benzene bioisosteres for drug discovery.