Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthranilate, reduction of the resulting α-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-benzodiazepines showed significant selective binding affinity at cholecystokinin CCK₁ receptors (IC₅₀=156.5±33.2 nM).     

A novel synthetic use of 2-bromo- 1-methylpyridinium iodide for macrolactamization

Using 2-bromo-1-methylpyridimium iodide as carboxyl activating agent, 10 ansa-macrolactams were prepared conveniently from the corresponding seco-precursor w-aminoacids in the yields of 78-2%.     

Crosslinking of polyimides via spirodilactone unit in polymer backbone

A new approach for the crosslinking of polyimides via the lactamization of spirodilactone unit in polyimide backbone was studied by two means: model reaction and the comparison of the properties of the polyimide precursors to those of the crosslinking polymers. Polyimides 4 and 5 were soluble in N,N′dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N′-methylpyrrolidone (NMP), and other common organic solvents, whereas their corresponding crosslinking polymers were insoluble in these solvents. The glass transition temperatures for polyimide 5 and its crosslinking polymer were 262°C and 291°C, whereas those for polyimide 4 and its crosslinking polymer were 265°C and 360°C. The weight-loss rate of the crosslinking polymers was apparently slower than that of the precursors when the temperature was > 400°C. The 10% weight-loss temperature for the polyimides 4 and 5 was < 500°C, whereas that for the crosslinking polymers was close to or above 600°C. The results indicate that this type of crosslinking polymer has good thermal properties. The temperature for the formation of lactam was above 180°C. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3680–3686, 1999     

Oxidative Reactions of Azines. 6. Lactamization of 4-Aryl- and 4-Phenethenyl-substituted 1,2,3,6-Tetrahydropyridines and Dihydroxylation of 4-Aryl-1,2,5,6-tetrahydropyrid-2-ones Using Potassium Permanganate

Oxidation of 4-phenyl-, 4-(4-pyridyl)-, and 4-phenethenyl-1,2,3,6-tetrahydropyridines with potassium permanganate can stop at the stage of the introduction of an oxo group into the allyl C₍₂₎ position of the piperideine fragment. In contrast to their precursors, 4-aryltetrahydropyridin-2-ones obtained in this way can be converted to 3,4-dihydroxy-2-oxopiperidines under Wagner reaction conditions.     

Enantioselective Total Syntheses of (−)-20-epi-Vincamine and (−)-20-epi-Eburnamonine by Ir-Catalyzed Asymmetric Imine Hydrogenation/Lactamization Cascade

The Eburnamine-Vincamine alkaloids have been studied intensively over the past six decades for their outstandingly potent vasorelaxation activity. Stereocontrolled assembly of the C20/C21 adjacent chiral centers has been a formidable challenge in the synthesis of this family. Herein, we report a concise stereoselective total synthesis of two trans-ring-fused non-natural analogues, (−)-20-epi-Vincamine and (−)-20-epi-Eburnamonine, that features the following key steps: a) a continuous-flow oxidation/lactam alcoholysis cascade producing the symmetrical dihydro-β-carboline diester precursors, and b) a highly stereoselective Ir/f-Binaphane-catalyzed hydrogenation/lactamization cascade leading to the privileged trans-(20R, 21S) lactam ester scaffold with high-level enantio- and diastereocontrol.     

Lactamization of sp2 C−H Bonds with CO2: Transition‐Metal‐Free and Redox‐Neutral

The first direct use of carbon dioxide in the lactamization of alkenyl and heteroaryl C?H bonds to synthesize important 2‐quinolinones and polyheterocycles in moderate to excellent yields is reported. Carbon dioxide, a nontoxic, inexpensive, and readily available greenhouse gas, acts as an ideal carbonyl source. Importantly, this transition‐metal‐free and redox‐neutral process is eco‐friendly and desirable for the pharmaceutical industry. Moreover, these reactions feature a broad substrate scope, good functional group tolerance, facile scalability, and easy product derivatization.     

Efficient PhB(OH)2-catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones under solvent free conditions

An efficient and practical one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones has been developed under solvent free-conditions using non-toxic and cheap phenylboronic acid as excellent catalyst. This strategy involves the sequential two-step Mannich/lactamization cascade reaction of inexpensive 2-formylbenzoic acid with primary amines and a wide variety of ketones, and an aldol/lactonization cascade reaction of 2-formylbenzoic acid with a broad range of ketones.     

Effect of obligatory replacement and conformational restriction on psychotropic activity of thyroliberin analogs

Easy lactamization of Gln(Asn)−Pro−NH₂ with the formation of cyclic dipeptides with the diketopiperazine structure (mimetics of the conformational fragments of linear tripeptides with the X−Protrans-bond) was observed in the synthesis of tripeptide Glp−Gln−Pro−NH₂ modified by the replacement of histidine with obligatory similar glutamine in thyroliberin (Glp−His−Pro−NH₂, TRH) and in the synthesis of its structural analog [Asn²]TRH. Ion peaks corresponding to the Glp and Pro amino acid residues were revealed in the mass spectra of the peptides synthesized. The biological properties of the compounds obtained were determined indicating that the obligatory replacement resulted in an increased physiological specificity of [Gln²]TRH. The enhanced activity of conformationally restricted cyclic peptides compared to linear ones suggests that the biologically active conformation responsible for the antidepressant activity of linear TRH analogs is the conformation with X−Protrans-bond. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2015–2020, October, 1998.     

Ultrasound-assisted green one-pot synthesis of linked bis-heterocycle peptidomimetics via IMCR/post-transformation/tandem strategy

The sequential aligning of two eco-friendly and powerful tools for the synthesis of peptidomimetics resulted in the rapid generation of molecular complexity in target molecules. We herein report a versatile IMCR/post-transformation/tandem synthetic strategy that emphasizes the special role of orthogonal bifunctional reagents in isocyanide based multicomponent reactions (IMCR) to generate a synthetic platform for subsequent heterocyclization reactions. This is the first one-pot synthesis of a 2,5-diketopiperazine linked to a 1,4-disubstituted 1,2,3-triazole. The Ugi-4CR/lactamization/click sequence is facile, mild, atom-economical, and green. The present work contributes to the green and one-pot synthesis of bis-heterocycle peptidomimetics and design of new bioactive molecules.