The 3‐(3‐Pyridine)propionyl Anchor Group for Protease‐Catalyzed Resolutions: <i>p</i>‐Toluenesulfinamide and Sterically Hindered Secondary Alcohols
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Bibliographic record
Abstract
Abstract Compared to an acetyl acyl group, the 3‐(3‐pyridine)propionyl group increases substrate binding to many proteases and substrate solubility in water, thereby increasing the rates of protease‐catalyzed reactions. For example, proteases reacted up to six hundred‐fold faster with the 3‐(3‐pyridine)propionyl ester of 1‐phenylethanol than with the corresponding acetate ester. In addition, the 3‐(3‐pyridine)propionyl group enables a simple, mild acid extraction to separate the remaining starting material and product. To demonstrate the synthetic usefulness of this strategy, we resolved multi‐gram quantities of ( R )‐ and ( S )‐ p ‐toluenesulfinamide with α‐chymotrypsin and gram quantities of ( R )‐ and ( S )‐2,2‐dimethylcyclopentanol with subtilisin Carlsberg. The 3‐(3‐pyridyl)propionyl group was better for these resolutions than the corresponding acetate or dihydrocinnamate because it decreased the reaction time due to increased reactivity, decreased the reaction volume due to increased substrate solubility and enabled purification without chromatography. Molecular modeling suggests the enantioselectivity of α‐chymotrypsin toward ( R )‐ p ‐toluenesulfinamide is high ( E =52) because of a favorable hydrophobic interaction between the p ‐tolyl group of the fast‐reacting ( R )‐enantiomer and leaving group pocket. The enantioselectivity of subtilisin Carlsberg toward ( S )‐2,2‐dimethylcyclopentanol is high ( E =43) because the large substituent (the 2,2‐dimethyl quaternary carbon) of the slow‐reacting ( R )‐enantiomer cannot fit in the S 1 ′ leaving group pocket.
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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 | 0.000 |
| Science and technology studies | 0.001 | 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