Rational Design of Aldol Reactions That Proceed via Kinetic Resolution with Switchable Enantioselectivity
Bibliographic record
Abstract
The stereoselectivity of aldol reactions of chiral reactants can be factorized into to three stereocontrol elements: the diastereoface selectivities of the ketone enol(ate) and aldehyde and the relative topicity of the coupling. Application of the multiplicativity rule to these elements leads to the prediction that kinetic resolution (KR) should be possible if all three stereocontrol elements are strongly biased. As a corollary, the enantioselectivity of the kinetic resolution should be switchable by a change in the sense of selectivity of any of the stereocontrol elements. This hypothesis was tested using aldehyde and ketone reactants with high diastereoface selectivities and developing reaction conditions that strongly favor either syn or anti relative topicity. The aldehyde 2 undergoes aldol reactions with near-exclusive Felkin diastereoface selectivity, and hydroxy-protected derivatives of ketone 1 (R = MOM, Et(3)Si, or Ac) undergo aldol reactions with high diastereoface selectivity to give 3,5-trans adducts. High levels of anti and syn relative topicity were obtained with dicyclohexylboron enolates and Ti(O(i)Pr)(4)Li "ate" enolates, respectively. Using these enolates, aldol reactions of (+/-)-2 with (+/-)-1 gave two of the eight possible diastereomeric adducts (3 from a diastereoselective like combination of reactant enantiomers and 4 from a diastereoselective unlike combination) predominantly (>95% of the adducts) in ratios of 0.05-20:1; boron enolates favored the like reaction (3:4, 15-20:1) and Ti "ate" enolates favored the unlike reaction (3:4, 1:10-20). Under these conditions, the ratio of like and unlike products is a measure of the mutual kinetic enantioselection (MKE) and reflects the ratio of the rate constants for the competing like and unlike reactions. For each of the four diastereomers of 1, the reactions with the highest MKEs in favor of the like (3) or unlike products (4) were repeated using highly enantioenriched ketone. These reactions occurred with the expected KR (s = 10-20) allowing selective access to enantioenriched diastereomers of 3 or 4 from (+/-)-2. These adducts are useful for polypropionate synthesis, and this design strategy for KR should be applicable to related processes.
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How this classification was reachedexpand
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 | 0.001 | 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 teacher head, 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".