Biomimetic Transannular Oxa-Conjugate Addition Approach to the 2,6-Disubstituted Dihydropyran of Laulimalide Yields an Unprecedented Transannular Oxetane
Bibliographic record
Abstract
2,6-Disubstituted dihydropyrans are a common feature in many bioactive polyketides, including the anticancer marine polyketide laulimalide. While much of the uncharacterized biosynthetic pathway for laulimalide can be confidently postulated, the biosynthetic origins of the trans 2,6-disubstituted dihydropyran cannot. We hypothesize that a transannular oxa-conjugate addition in a macrocyclic laulimalide precursor could be the origin of the 2,6-dihydropyran. To test this hypothesis, we constructed a model containing the key functional groups for oxa-conjugate addition-mediated dihydropyran formation. Under acid-mediated conditions, the model under went regiospecific oxa-conjugate addition producing a stable trans oxetane as the only regioisomer. The desired, more stable dihydropyran was not detected. This unprecedented regiospecificity is unexpected due to the ring strain of the oxetane and the anticipated facile ring opening retro-oxa-conjugate addition. The oxetane is stable to acid and basic conditions, as are a number of literature acyclic oxetanes that could undergo similar retro-oxa-conjugate addition. While the source of the oxetane kinetic stability is yet to be characterized, it may enable general oxetane construction via oxa-conjugate addition. The more stable dihydropyran regioisomer could not be generated due to poor geometrical orbital alignment and hard-soft incompatibility between the hard oxygen nucleophile and the soft activated polyenoate electrophile. These factors disfavor the breaking of conjugation by oxa-conjugate addition. Based on these results we propose that dihydropyran formation does not occur on completed polyketide macrocycles as we had proposed but rather during polyketide biosynthesis on the growing polyketide chain.
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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) | 0.000 | 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 | 0.001 |
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".