Evolution of a Synthetic Strategy toward the Syntheses of Bis-tetrahydroisoquinoline Alkaloids

The bis-tetrahydroisoquinoline (bis-THIQ) natural products represent a medicinally important class of isoquinoline alkaloids that exhibit broad biological activities with particularly potent antitumor properties, as exemplified by the two U.S. FDA approved molecules trabectidin and lurbinectedin. Accordingly, other members within the bis-THIQ family have emerged as prime targets for synthetic chemists, aiming to innovate an orthogonal chemical production of these compounds. With the ability of these complementary strategies to reliably and predictably manipulate molecular structures with atomic precision, this should allow the preparation of synthetic derivatives not existing in nature as new drug leads in the development of novel medicines with desired biological functions.

Beyond the biological perspective, bis-THIQ natural products also possess intricate and unique structures, serving as a source of intellectual stimulation for synthetic organic chemists. Within our laboratory, we have developed an integrated program that combines reaction development and target-directed synthesis, leveraging the architecturally complex molecular framework of bis-THIQ natural products as a driving force for the advancement of novel reaction methodologies. In this Account, we unveil our synthetic efforts in a comprehensive story, describing how our synthetic strategy toward bis-THIQ natural products, specifically jorunnamycin A and jorumycin, has evolved over the course of our studies through our key transformations comprising (a) the direct functionalization of isoquinoline N-oxide to prepare the bis-isoquinoline (bis-IQ) intermediate, (b) the diastereoselective and enantioselective isoquinoline hydrogenation to forge the pentacyclic skeleton of the natural product, and (c) the late-stage oxygenation chemistry to adjust the oxidation states of the A- and E-rings. First, we detail our plan in utilizing the aryne annulation strategy to prepare isoquinoline fragments for the bis-THIQ molecules. Faced with unpromising results in the direct C–H functionalization of isoquinoline N-oxide, we lay out in this Account our rationale behind the design of each isoquinoline coupling partner to overcome these challenges. Additionally, we reveal the inspiration for our hydrogenation system, the setup of our pseudo-high-throughput screening, and the extension of the developed hydrogenation protocols to other simplified isoquinolines.

In the context of non-natural bis-THIQ molecules, we have successfully adapted this tandem coupling/hydrogenation approach in the preparation of perfluorinated bis-THIQs, representing the first set of electron-deficient non-natural analogues. Finally, we include our unsuccessful late-stage oxygenation attempts prior to the discovery of the Pd-catalyzed C–O cross-coupling reaction. With this full disclosure of the chemistry developed for the syntheses of bis-THIQs, we hope our orthogonal synthetic tactics will provide useful information and serve as an inspiration for the future development of bis-THIQ pharmaceuticals.