Diastereoselective Synthesis of alpha-Fluoro-gamma-Lactams via Difluorocarbene-Triggered Cyclization and Rearrangement
Bibliographic record
Abstract
We report a difluorocarbene-enabled, diastereoselective synthesis of α-fluoro-γ-lactams from readily accessible β-aminoketones and inexpensive, commercially available ethyl bromodifluoroacetate (EBDFA). Compared to established routes to this medicinally relevant motif, our strategy avoids the use of costly electrophilic fluorinating or deoxyfluorinating reagents, highlighting difluorocarbene as a versatile C1 and F building block. Density functional theory (DFT) calculations reveal that cyclization is the stereodetermining step, with observed diastereomeric ratios governed by Curtin-Hammett kinetics. In addition to activating EBDFA, the K2CO3 base enables the favourable formation of a transient hemiaminal epoxide intermediate, with subsequent C–F bond formation proceeding through a nucleophilic fluoride ring-opening pathway. Overall, this work not only delivers a direct and modular route to stereodefined α-fluoro-γ-lactams but more broadly expands our mechanistic understanding of difluorocarbene-mediated amine-carbonyl coupling reactions.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".