Influence of the β-Alkoxy Group on the Diastereoselectivity of\nAldol Reactions of Tetrahydro-4<i>H</i>-thiopyran-4-one with\n4-Alkoxytetrahydro-2<i>H</i>-thiopyran-3-carboxaldehydes
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Bibliographic record
Abstract
The diastereoselectivity of the aldol reaction of tetrahydro-4<i>H</i>-thiopyran-4-one (<b>3</b>) with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (<b>9a</b>) under a variety of conditions is examined. Under\noptimized conditions, three of the four possible diastereomers from this aldol reaction can be obtained\nselectively (3−16:1). Reactions of <b>9a</b> with the Li, B, Mg(II), and Ti(IV) enolates of <b>3</b> and with the\ncorresponding trimethylsilyl enol ether <b>4b </b>in the presence of BF<sub>3</sub>·OEt<sub>2</sub>, SnCl<sub>4</sub>, or TiCl<sub>4</sub> as promoters\ngave the Felkin adducts exclusively (>95%) as mixtures of syn (<b>11a</b>) and anti (<b>12a</b>) diastereomers.\nUse of the “amine-free” Li enolate of <b>3</b> gave <b>12a</b> with a much higher diastereoselectivity (9:1) and\nyield (70%) than that obtained using the lithium diisopropylamide-generated Li enolate of <b>3</b> (2−3:1; 15−40%). The TiCl<sub>4</sub>-promoted reaction of <b>4b</b> with <b>9a</b> gave <b>11a</b> with excellent selectivity (16:1). In contrast, the MgBr<sub>2</sub>·OEt<sub>2</sub>-promoted reaction of <b>4b</b> with <b>9a</b> gave the anti-Felkin adducts\nexclusively as a 3:1 mixture of syn (<b>13a</b>)/anti (<b>14a</b>) diastereomers. Similar aldol reactions of <b>3</b> with\nthe cis and trans isomers of 4-(methoxy)methoxytetrahydro-2<i>H</i>-thiopyran-3-carboxaldehyde (<b>9b</b>\nand <b>9c</b>) were examined to probe the influence of the ketal protecting group in <b>9a</b> on the observed\naldol diastereoselectivity. The results are rationalized by applying Evans' stereochemical model\nfor merged 1,2- and 1,3-asymmetric induction (nonchelation), with the exception of the MgBr<sub>2</sub>·OEt<sub>2</sub>-promoted reactions of <b>4b</b> with <b>9a</b>, <b>9b</b>, and <b>9c</b>, which are accommodated by assuming chelation\ncontrol. Comparison of the reactions of <b>9a</b>, <b>9b</b>, and <b>9c</b> suggests that the ketal group in <b>9a</b> uniquely\nallows high levels of either Felkin or anti-Felkin selectivity to be achieved.
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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 | 0.001 | 0.011 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.003 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.032 | 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