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.

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.

Single-atom skeletal editing has recently emerged as a powerful strategy for the direct diversification of the heterocyclic cores of various compounds. Yet, methods that enable monocycle-to-bicycle tr...

Reported herein is a total synthesis of the peptide-polyketide natural product dahurelmusin A along with its C10 epimer (epi-dahurelmusin A). The syntheses benefited from well-established aldol and macrocyclization technologies. Access to the natural product and its C10 epimer provided opportunities to test the importance of the C10 stereocenter in the biological activity of the natural product.

Since the beginning of time, humanity has searched for drugs that can relieve pain without sparking addiction or the other devastating problems tied to opioids. It’s still very early, but a UC Berkele...

By putting a carbon atom in place of a core oxygen, chemists constructed an opioid that blocks pain with less respiratory depression in mice

Morphine is a µ-opioid receptor (MOR) agonist and potent analgesic. However, it displays several side effects including respiratory depression and ...

Reactions that alter organic scaffolds by a single atom are already proving useful, but time will tell if they’ll fundamentally change how molecules are made

Herein, we report an investigation of several synthetic strategies to access the aphidicolin family of natural products. Some unsuccessful approaches include strategies featuring Diels–Alder cycloaddi...

The molecule, coined “carbamorphine,”was built through total synthesis.

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ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have the potential to streamline and accelerate organic synthesis by enabling conceptually simp...

Late-stage functional group switching in dibenzofurans will aid drug discovery chemistry

Saturated heterocycles are commonly adorned with groups that influence their biological properties. Synthetic methods that transpose existing substituents on saturated heterocycles to multiple peripheral positions are therefore highly valuable. In this ...

Saturated heterocycles are commonly adorned with groups that influence their biological properties. Synthetic methods that transpose existing substituents on saturated heterocycles to multiple periphe...

The new members from Berkeley have spent decades researching gene editing, materials science, very young children, the depths of the universe and more.

WASHINGTON — The National Academy of Sciences announced today the election of 120 members and 30 international members in recognition of their distinguished and continuing achievements in original res...