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Strategies for total synthesis have advanced alongside the development of new methodologies, thereby enabling access to structurally intricate molecules that were previously difficult to obtain. Here, we present a strategy for the synthesis of bis(cyclotryptamine) alkaloids inspired by methods for single-atom insertion/deletion. To implement our plan, we first pursued the synthesis of tetrahydropsychotriadine (4), an isomer of calycanthine (1), which was achieved in 9 steps and set the stage for the preparation of calycanthine (1), chimonanthine (2), and psychotriadine (6). Our studies, driven by calculations, also provide the first access to a natural product bearing the pyrrolidinoquinoline scaffold, CPC-2 (29). Finally, we resolve a long-standing misassignment of the structure of the natural product dubbed isocalycanthine. En route to our synthesis of 4, we establish a methodology for the construction of unprecedented diaryl-substituted cis- and trans-fused 5,5-bicycles using a photodecarbonylation. The mechanism for the trans-selective formation of 5,5-bicycles is investigated by using DFT calculations.

Traditionally, a retrosynthesis aims to disconnect a molecular target into simpler precursors as quickly as possible, prioritizing the early deconstruction of primary contributors to the molecule’s overall structural complexity (i.e., primary complexity elements). The complementary approach, which rapidly constructs complexity early in the forward synthesis, is much less common. Herein, we report a 14-step protective group-free total synthesis of the polycyclic sesquiterpenoid alkaloid hispidospermidin, which exploits an early-stage complexity-generating bicycle formation to forge the carbon skeleton, followed by subsequent peripheral functionalizations. Specifically, a key Giese conjugate addition of a bridgehead radical established the quaternary center, and a novel isomerization was discovered, which enabled a one-pot protocol to establish the trans-hydrindane moiety, and application of a C–H desaturation/etherification sequence constructed the tetrahydrofuran moiety at a late stage. Uniquely, our strategy generates the primary complexity element, the bicyclo[3.3.1]nonane core, in the first step of the synthesis, whereas the three previous syntheses feature mid- to late-stage bicycle construction (total of 23–31 steps). Analysis of the structural complexity landscape of the four syntheses of hispidospermidin suggests that building a molecule from the “Inside-Out”, as described here, may be a broadly applicable strategy to expedite the total synthesis of topologically complex molecules.