A General Approach for Strained Ring Functionalization via Nucleophilic Catalysis
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Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide Nucleophilic addition to strained rings offers an efficient route to small aliphatic rings, which serve as valuable bioisosteres in drug development. However, these reactions often require external stoichiometric bases, additives, or strong nucleophiles, limiting their practicality, compatibility, and scope. Moreover, achieving diastereocontrol in these reactions remains challenging, and direct addition of sp 3 C–H bonds continues to be difficult owing to their lack of electron lone pairs and weak acidity. Here, we present, for the first time, a nucleophilic catalysis strategy that addresses these challenges, enabling not only the direct and diastereoselective addition of a wide range of sp 3 C–H bonds, but also diverse heteroatom-based nucleophiles, including carboxylic acids, amides, phosphine oxides, and thiols, to strained rings without the need for external bases or additives. Mechanistic studies suggest the involvement of a covalent intermediate, generated through the nucleophilic addition of the catalyst to the strained ring substrate.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
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Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
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