A Concise and Modular Three-Step Synthesis of (S)-Verapamil using an Enantioselective Rhodium-Catalyzed Allylic Alkylation Reaction
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Bibliographic record
Abstract
A concise and modular asymmetric synthesis of the calcium channel blocker (S)-verapamil is described. This approach employs an enantioselective rhodium-catalyzed allylic alkylation reaction between an α-isopropyl-substituted benzylic nitrile and allyl benzoate to construct the challenging acyclic quaternary stereocenter. The terminal olefin then serves as a convenient synthetic handle for a hydroamination to introduce the phenethylamine moiety, furnishing (S)-verapamil in three steps and 55% overall yield, thus providing the most efficient synthesis of this important pharmaceutical reported to date. Furthermore, given the modular nature of the synthesis, it can be readily modified to prepare structurally related bioactive agents.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 it