An “Inside-Out” Strategy Enables a 14-Step Total Synthesis of Hispidospermidin

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 <i>trans</i>-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.