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 cis-N-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 Csp2-H cyclizations. The second stage is precise regulation of the backbone stereochemical diversity through a series of Csp3-H functionalization steps, including a locally desymmetrizing spirocarbocyclic ketone transposition, tunable Csp3-H oxidation at C11, and stereoselective Csp3-H epimerization at C6a. This work establishes a practical C–H elaboration platform that enables concise access to structurally complex natural product architectures.