Metal‐catalyzed carbenoid cascade reactions involving a C–H insertion/annulation — applications in the synthesis of carbo- and heterocycles
Bibliographic record
Abstract
Cascade reactions have gained significant importance in the pursuit of efficient and elegant synthetic chemistry. These processes offer environmental friendliness, atom economy and enable the synthesis of highly complex molecules. This thesis covers the general topic of tandem reactions based on metallocarbene insertion into C–H bonds and subsequent trapping of carbanion intermediate via annulation chemistry in a cascade manner to access various hetero- and carbocyclic frameworks. Three related projects illustrate this strategy; the last project is based on the pericyclic cascade strategy. In Chapter 2 of this thesis, a Rh(II)-catalyzed acceptor/acceptor diazo carbene insertion/annulation strategy will be discussed. A series of N-alkylated indoles contain an alkyne electrophile were prepared for this study. These indoles were reacted with diazo reagents under Rh(II) catalysis to achieve tandem C(sp²)–H carbene insertion and subsequent Conia-ene annulation for the synthesis of pyrroloindoles. Chapter 3 of this thesis discusses a Cu(II)-catalyzed C(sp²)–H insertion/Michael annulation cascade between α-diazocarbonyls and appropriately functionalized indoles containing alkynyl-ester electrophiles to access a variety of fused indole scaffolds in a stereoselective manner. Advancements of this reaction manifold to include alkenyl-esters as electrophiles were also explored allowing access to a range of new indole frameworks. By extending the reaction protocol to donor/acceptor diazocarbonyls, an additional synthetic value was achieved. Chapter 4 of this thesis presents a preliminary study on the Rh(III)-catalyzed pyrimidine-directed C–H activation of indole, followed by coupling with Meldrum's acid-derived α-diazocarbonyls through a migratory carbene insertion pathway. The resulting intermediate, upon the elimination of acetone and carbon dioxide, undergoes a Dieckmann condensation with a pendant ester moiety, leading to the formation of a carbazole core. The progress made in this study, as well as the planned future work, regarding the application of this novel reaction in the synthesis of various carbazole-based natural products, will be discussed in detail. Finally, Chapter 5 of this thesis discusses a pericyclic cascade towards the synthesis of citridone A and tersone D natural products. The key transformation involves a domino Knoevenagel condensation between branched conjugated dienals and pyridone-type 1,3-dicarbonyl substrates followed by an oxa-6π electrocyclic ring-closure cascade to construct a cyclopenta[b]furopyridone framework. This project was completed in collaboration with the Rivera Group of Rosario Institute of Chemistry-IQUIR and for simplicity, only our total synthesis efforts will be discussed.
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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) | 0.002 | 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".