Conformationally Constrained Dipeptide Surrogates with Aromatic Side-Chains: Synthesis of 4-Aryl Indolizidin-9-one Amino Acids by Conjugate Addition to a Common α,ω-Diaminoazelate Enone Intermediate
Bibliographic record
Abstract
Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.
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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 | 0.000 | 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) | 0.000 | 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 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".