Synthesis of Chiral Diazocine Derivatives via a Copper-Catalyzed Dearomative [5+3] Cycloaddition.

Copper-catalyzed [5+3] cycloaddition of N-aromatic zwitterions and enol diazoacetates produced enantio-enriched diazocine derivatives. A sterically encumbered BOX ligand and NaBArF additive played significant roles in driving the overall catalytic process via the unfavorable dearomatization to construct the desired eight-membered heterocyclic compounds. The induced stereoselectivity was preserved after further modifications of the skeleton, which demonstrates the potential applications of the developed asymmetric catalysis.

Contractions of 1,4-Diazepines to Pyrroles Triggered by Valence Tautomerization: A One-Pot Approach and Mechanism.

Herein, we describe the valence tautomerizations of fused 1,4-diazepines, which are reconstructed to give pyrrole derivatives and HCN gas. Several factors that influence the equilibrium between each valence tautomer of an 8π-electron diazepine skeleton are demonstrated. On the basis of these mechanistic studies, a cascade strategy for the construction of diazepines followed by ring contraction is developed to afford aryl- or alkyl-substituted pyrrolo[1,2-a]quinolines that are otherwise challenging to fabricate. In addition, further transformations of the obtained products highlight the advantages of the developed methodology.

Catalytic Ring Expansion of Activated Heteroarenes Enabled by Regioselective Dearomatization.

Catalytic ring expansion of activated heteroarenes through 1,4-dearomative addition of diazoacetates was established for the construction of various fused azepines by an elaborate control of the reaction kinetics at each step. The use of a silver catalyst was essential to drive the overall reaction for generating the desired seven-membered azepines. Because of the excellent substrate scope and selectivity, the developed methodology presents an innovative approach for the synthesis of multifused azepines, which are biologically relevant molecules.

Direct cyclopropanation of activated N-heteroarenes via site- and stereoselective dearomative reactions.

A divergent cyclopropanation reaction has been accomplished via the dearomative addition of sulfur ylides to activated N-heteroarenes. A series of biologically significant molecular skeletons was obtained by the direct cyclopropanation of quinolinium zwitterions. Furthermore, a straightforward synthetic route to optically enriched cyclopropane-fused heterocycles was developed using sulfur ylides as chiral nucleophiles in the 1,4-dearomative reaction.

Catalytic Cascade Reaction To Access Cyclopentane-Fused Heterocycles: Expansion of Pd-TMM Cycloaddition.

A palladium-catalyzed reaction of N-aromatic zwitterion and trimethylenemethane that gives fused N-heterocycles via dearomative [3 + 2] cycloaddition and intramolecular cyclization is developed, and a cyclopentane-fused cyclic product is generated. Combining computational and experimental studies, the site-selective dearomatization and the mechanism of this novel reaction are investigated in detail, and the value of pyridinium zwitterion as a reactant is demonstrated.

Multicomponent dipolar cycloadditions: efficient synthesis of polycyclic fused pyrrolizidines via azomethine ylides.

An efficient multicomponent dipolar cycloaddition for the synthesis of polycyclic fused pyrrolizidines was developed using N-aromatic zwitterions, aldehydes, and amino acids. The developed reactions proceed through azomethine ylides generated in situ from the decarboxylated reactions of aldehydes and amino acids followed by the [3 + 2] cycloaddition of N-aromatic zwitterions under mild reaction conditions.

Gold-catalyzed [5+2] cycloaddition of quinolinium zwitterions and allenamides as an efficient route to fused 1,4-diazepines.

Herein, we demonstrate a new catalytic cycloaddition of quinolinium zwitterions involving a gold-bound allylic cation intermediate. This ligand-free higher-order cycloaddition efficiently affords a variety of fused 1,4-diazepine derivatives in a stereospecific manner at room temperature.

Kinetic Resolution of ß-Hydroxy Carbonyl Compounds via Enantioselective Dehydration Using a Cation-Binding Catalyst: Facile Access to Enantiopure Chiral Aldols.

A practical and highly enantioselective nonenzymatic kinetic resolution of racemic ß-hydroxy carbonyl (aldol) compounds through enantioselective dehydration process was developed using a cation-binding Song's oligoethylene glycol (oligoEG) catalyst with potassium fluoride (KF) as base. A wide range of racemic aldols was resolved with extremely high selectivity factors ( s = up to 2393) under mild reaction conditions. This protocol is easily scalable. It provides an alternative approach for the syntheses of diverse biologically and pharmaceutically relevant chiral aldols in enantiomerically pure form. For example, racemic gingerols could participate in this kinetic resolution with superb efficiency ( s > 240), affording both enantiomerically pure gingerols and corresponding shogaols simultaneously in a single step. The dramatic effectiveness of such kinetic resolution process can be ascribed to systematic cooperative hydrogen-bonding catalysis in a densely confined supramolecular chiral cage in situ generated from the chiral catalyst, substrate, and KF.

Bioinspired Synthesis of Chiral 3,4-Dihydropyranones via S-to-O Acyl-Transfer Reactions.

A bioinspired synthesis of chiral 3,4-dihydropyranones via S-to-O acyl-transfer reactions is described. Asymmetric Michael addition-lactonization reactions of ß,γ-unsaturated α-keto esters with thioesters are catalyzed by proline-derived urea, providing 3,4-dihydropyranones and spiro-3,4-dihydrocoumarin-fused 3',4'-dihydropyranones in high yield (up to 94%) with excellent stereoselectivities (up to >20:1 dr, 99% ee) under catalyst loadings as low as 1 mol %.

Synthesis of Fused Polycyclic 1,4-Benzodiazepines via Metal-Free Cascade [5 + 2]/[2 + 2] Cycloadditions.

A metal-catalyst-free, mild, and efficient synthetic protocol for polycyclic 1,4-benzodiazepines via cascade [5 + 2]/[2 + 2] cycloadditions between pyridinium zwitterions and arynes is reported. Mechanistic experiments revealed that pyridinium zwitterions act as 1,5-dipoles in [5 + 2] cycloadditions with arynes for the construction of 1,4-benzodiazepines, which further undergo [2 + 2] cycloaddition resulting in the one-pot formation of one C-N bond and three C-C bonds.

3,5-Diarylimidazo[1,2-a]pyridines as Color-Tunable Fluorophores.

A new protocol for the synthesis of color-tunable fluorescent 3,5-diarylimidazo[1,2-a]pyridines has been achieved via palladium-catalyzed C-H amination of pyridinium zwitterions. Based on experimental results and computational analysis, we extracted a high correlation of photophysical properties with the theoretical concept and predicted emission wavelengths of 3,5-diarylimidazo[1,2-a]pyridines. The emission wavelengths of imidazo[1,2-a]pyridines increase as a function of the electron-withdrawing nature of the substituent on the C5-aryl group of imidazo[1,2-a]pyridine as a result of inductive effects on the LUMO levels. Varying the substituent on the C3-aryl group imidazo[1,2-a]pyridine changes the HOMO levels. Combining these two sites, the HOMO and LUMO levels can be tuned fairly decoupled from each other. This conceptual trend is demonstrated across a series where the C3 and C5 positions were functionalized independently and then utilizes a combination strategy where both sites are used to prepare fluorophores with a large window of emission wavelengths. In view of the biological properties of imidazo[1,2-a]pyridines, the developed method provides an efficient approach for understanding and preparing strongly fluorescent bioprobes.

Rhodium(II)-Catalyzed Cycloaddition Reactions of Non-classical 1,5-Dipoles for the Formation of Eight-Membered Heterocycles.

A new type of intermolecular rhodium(II)-catalyzed [5+3] cycloaddition has been developed. This higher-order cycloaddition between pyridinium zwitterion 1,5-dipole equivalents and enol diazoacetates enables the formation of eight-membered heterocyclic skeletons, which are otherwise difficult to construct. The optimized cycloaddition occurs efficiently under mild conditions with a wide range of pyridinium zwitterions and with high functional-group tolerance.

Efficient synthesis of C-N-coupled heterobiaryls by sequential N-H functionalization reactions.

C-N-coupled heterobiaryls were synthesized by sequential N-H functionalization reactions: stereoselective rhodium-catalyzed N-H insertion, followed by regioselective palladium-catalyzed C-H amination. Because of the good substrate scope and excellent selectivity, the developed method presents a novel approach for the synthesis of heterobiaryls, which are potent antibiotics.

Multicomponent [5 + 2] cycloaddition reaction for the synthesis of 1,4-diazepines: isolation and reactivity of azomethine ylides.

Air-stable azomethine ylides with an unusual pattern of charge distribution were efficiently prepared via the rhodium-catalyzed reaction between pyridines and 1-sulfonyl-1,2,3-triazoles. This reaction allowed for the first example of the catalytic multicomponent [5 + 2] cycloaddition reactions, thus resulting in the formation of biologically active 1,4-diazepine compounds.

A Rh-catalyzed regio- and stereoselective route to enamides: benzamides as assembling reagents.

A new protocol for the synthesis of fully substituted enaminones has been achieved using a diverse range of benzamides and 1-sulfonyl-1,2,3-triazoles. Selective removal of the ß-amino moiety of the obtained α-amido-enaminones to form Z-enamides was also demonstrated thus improving the synthetic value of benzamides for structural diversities in a minimum number of synthetic steps.

Rhodium-catalyzed oxidative C-H activation/cyclization for the synthesis of phosphaisocoumarins and phosphorous 2-pyrones.

Rhodium-catalyzed cyclization of phosphinic acids and phosphonic monoesters with alkynes has been developed. The oxidative annulation proceeds with complete conversion of phosphinic acid derivatives and allowed the atom-economic preparation of useful phosphaisocoumarins with high yield and selectivity. The reaction is tolerant of extensive substitution on the phosphinic acid, phosphonic monoester and alkyne, including halides, ketone, and hydroxyl groups as substituents. Furthermore, we found that alkenylphosphonic monoesters proceed to give a wide range of phosphorus 2-pyrones through oxidative annulation with alkynes. Mechanistic studies revealed that C-H bond metalation was the rate-limiting step.

The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in visceral adipocytes predicts endometrial cancer progression and patient survival.

OBJECTIVE: Currently, accurately identifying endometrial cancer patients at high risk for recurrence remains poor. To ascertain if changes in the endoplasmic reticulum (ER) stress marker, glucose-regulated-protein-78 (GRP78) can serve as a prognosticator in endometrial cancer, we examined GRP78 expression in patient samples to determine its association with clinical outcome. METHODS: A retrospective cohort study was conducted in endometrial cancer patients. Archived specimens of visceral adipocytes and paired endometrial tumors were analyzed by immunohistochemistry for GRP78 and another ER stress marker, C/EBP homologous protein (CHOP). Expression of these markers was correlated with clinico-pathological information and outcomes. RESULTS: GRP78 expression in visceral adipocytes was detected in 95% of the 179 endometrial cancer patients with analyzable visceral adipocytes. Within individual samples, 24% of adipocytes (range, 0-90%, interquartile range 18%-38%) exhibited GRP78 expression. High visceral adipocyte GRP78 expression positively correlated with advanced-stage disease (p=0.007) and deep myometrial invasion (p=0.004). High visceral adipocyte GRP78 expression was significantly associated with decreased disease-free survival (DFS) in multivariate analyses (hazard ratio 2.88, 95% CI 1.37-6.04, p=0.005). CHOP expression paralleled the GRP78 expression in adipocytes (r=0.55, p<0.001) and in the tumor (p=0.018). CONCLUSIONS: Our study demonstrates that the ER stress markers, GRP78 and CHOP, are elevated in endometrial cancer patients. Furthermore, GRP78 expression levels in visceral adipocytes from these patients were significantly correlated to disease stage and patient survival. Our results demonstrate, for the first time, that the GRP78 levels in endometrial cancer patients may be a prognosticator and aid with clinical risk stratification and focused surveillance.

Pd(II)-catalyzed enantioselective C-H activation of cyclopropanes.

Systematic ligand development has led to the identification of novel mono-N-protected amino acid ligands for Pd(II)-catalyzed enantioselective C-H activation of cyclopropanes. A diverse range of organoboron reagents can be used as coupling partners, and the reaction proceeds under mild conditions. These results provide a new retrosynthetic disconnection for the construction of enantioenriched cis-substituted cyclopropanecarboxylic acids.

Pd-catalyzed intermolecular C-H amination with alkylamines.

C-H amination of N-aryl benzamides with O-benzoyl hydroxylamines has been achieved with either Pd(II) or Pd(0) catalysts. Furthermore, we demonstrate that secondary amines can be directly used with benzoyl peroxide in a one-pot procedure that proceeds via the in situ generation of the appropriate O-benzoyl hydroxylamines. This catalytic reaction provides a new disconnection for the convergent synthesis of tertiary and secondary arylalkyl amines starting from benzoic acids.

Pd(II)-catalyzed carbonylation of C(sp3)-H bonds: a new entry to 1,4-dicarbonyl compounds.

Pd(II)-catalyzed ß-C(sp(3))-H carbonylation of N-arylamides under CO (1 atm) has been achieved. Following amide-directed C(sp(3))-H cleavage and insertion of CO into the resulting [Pd(II)-C(sp(3))] bond, intramolecular C-N reductive elimination gave the corresponding succinimides, which could be readily converted to 1,4-dicarbonyl compounds. This method was found to be effective with substrates containing α-hydrogen atoms and could be applied to effect methylene C(sp(3))-H carbonylation of cyclopropanes.