Think sp³ Rich!
Top notch medchem building blocks got unlocked.
Chemists from Enamine Ltd. published a robust route to saturated azabicyclic scaffolds (Angewandte Chemie):
“𝘉𝘪𝘤𝘺𝘤𝘭𝘪𝘤 𝘐𝘴𝘰𝘴𝘵𝘦𝘳𝘦𝘴 𝘰𝘧 𝘗𝘺𝘳𝘪𝘥𝘪𝘯𝘦/𝘗𝘪𝘱𝘦𝘳𝘪𝘥𝘪𝘯𝘦: 𝘍𝘳𝘰𝘮 𝘚𝘺𝘯𝘵𝘩𝘦𝘴𝘪𝘴 𝘵𝘰 𝘈𝘱𝘱𝘭𝘪𝘤𝘢𝘵𝘪𝘰𝘯𝘴”
Key innovation
KOtBu/I₂/CO₂-mediated cyclization of cyclic alkenyl amines, delivering:
✔️ 2-azabicyclo[2.2.2]octanes (35-73% yield)
✔️ 2-azabicyclo[3.2.1]octane (69% yield)
✔️ 2-azabicyclo[2.2.1]heptanes (75-85% yield)
✔️ 7-azabicyclo[2.2.1]heptane (70% yield)
✔️ 2-azabicyclo[3.1.1]heptanes (62-73% yield)
✔️ 2-azabicyclo[2.1.1]hexanes (52-90% yield)
✅ 52–90% yield
✅ Scales up to 20 g
✅ Simple procedure ,no photochemistry or propellanes required
✅ High functional group tolerance, with even aliphatic C-Cl bonds
Additional highlights
✔️ 2-Azabicyclo[2.2.2]octanes serve as bioisosteres of pyridine/piperidine, 2nd and 3rd most popular medchem moieties ❗
✔️ The method showed high functional group tolerance, with even aliphatic C-Cl bonds
✔️ Authors demonstrate the first scalable synthesis of 1,2-disubstituted bicyclo[1.1.1]pentanes (from 2-azabicyclo[2.1.1]hexane)
✔️ Unlocks patentable chemical space
Synthetic utility
The authors demonstrated various modifications of the 2-azabicyclo[2.2.2]octane core at the bridgehead position using radical chemistry approaches. These included:
✔️ Decarboxylative reduction (54% yield)
✔️ C(sp3)-C(sp2) cross-coupling with aryl bromides (48% yield)
✔️ Coupling with vinyl bromides (33% yield)
✔️ Minisci-type reactions (59% yield)
Biological evaluation of isosteres
Pyridine ➡️ 2-Azabicyclo[2.2.2]octane:
✅ Saturated analogue of psychoactive drug Pyberaline showing similar water solubility (397-399 μM).
Piperidine ➡️ 2-azabicyclo[2.2.1]heptane:
✅Analogue of FDA-approved Bupivacaine (Compound 74)
✅Equipotent anesthetic activity (in mice)
✅Improved metabolic stability: CLint 8 vs 39 μL min⁻¹ mg⁻¹
✅Reduced lipophilicity: logD 1.6 vs 2.6
I believe that these building blocks will become common moieties in medchem and agrochemicals, allowing us to better balance ADMET, potency, solubility and other parameters.
What is your opinion on sp3 rich scaffolds and “Escape from Flatland” paradigm❓
Full manuscript: https://doi.org/10.1002/anie.202517814
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