Divergent Asymmetric Synthesis of Four Pentacyclic Homoproaporphine Alkaloids via C–H Elaboration

Pentacyclic homoproaporphine alkaloids, which contain a [6/6/6/6/6]-spiro-bridged framework and multiple stereocenters, present synthetic challenges. Here, we report a divergent synthesis of four pentacyclic homoproaporphine alkaloids, (-)-robustamine, (-)-robustamine <i>cis</i>-<i>N</i>-oxide, (+)-regelinine, and (+)-regeline, through sequential C-H elaboration that proceeds via a two-stage cyclization-functionalization strategy. The first stage of the synthetic strategy is the efficient construction of the [6/6/6/6]-tetracyclic core framework via two sequential C<i>sp</i>²-H cyclizations. The second stage is precise regulation of the backbone stereochemical diversity through a series of C<i>sp</i>³-H functionalization steps, including a locally desymmetrizing spirocarbocyclic ketone transposition, tunable C<i>sp</i>³-H oxidation at C11, and stereoselective C<i>sp</i>³-H epimerization at C6a. This work establishes a practical C-H elaboration platform that enables concise access to structurally complex natural product architectures.