Rapid and Modular Access to All‐Carbon Quaternary Center‐Containing 2,2‐Disubstituted Bicyclo[1.1.1]pentanes via Cyanocarbene Addition to Bicyclo[1.1.0]butanes
Bibliographic record
Abstract
Abstract While 1,3‐disubstituted bicyclo[1.1.1]pentanes (BCPs) have garnered considerable interest in medicinal chemistry as bioisosteres of para ‐substituted benzenes, the utilization of bridge‐functionalized BCPs, especially those containing all‐carbon quaternary centers at the bridge‐positions, in drug design has lagged behind. This is primarily due to the synthetic challenges associated with these scaffolds. Herein, we report the insertion of diazo‐free donor‐acceptor carbenes into the C─C bond of bicyclo[1.1.0]butanes (BCBs), enabling the rapid and modular synthesis of 1,2,2,3‐tetrasubstituted bicyclo[1.1.1]pentanes (BCPs) bearing three all‐carbon quaternary centers in up to 83% yield. This transformation is metal‐free, one‐pot, operationally simple, and accomodates to a wide range of substrates. The decoration of bioactive molecules with 2,2‐disubstituted BCP exhibits superior antitumor activity compared to the anticancer drug Sonidegib, rendering this method highly practical and appealing. Density functional theory (DFT) calculations combined with control experiments reveal that the reaction proceeds through a stepwise nucleophilic ring‐opening/recyclization pathway, involving the reaction between the singlet carbene species and the BCB skeleton.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".