α-Difluoroalkylation of Benzyl Amines with Trifluoromethylarenes.

An α-difluoroalkylation of benzyl amines with trifluoromethylarenes is disclosed herein. This protocol is characterized by its operational simplicity, excellent chemoselectivity and broad scope-even with advanced synthetic intermediates-, thus offering a new entry point to medicinally-relevant α-difluoroalkylated amines from simple, yet readily accessible, precursors.

Catalytic Hydrodifluoroalkylation of Unactivated Olefins.

Herein, we report a modular catalytic technique that streamlines the preparation of gem-difluoroalkanes from unactivated sp3 precursors. The method is characterized by its simplicity, generality, and site selectivity, including the functionalization of advanced intermediates and olefin feedstocks. Our approach is enabled by a cooperative interplay of halogen- and hydrogen-atom transfer, thus offering a new entry point to difluorinated alkyl bioisosteres of interest in drug discovery.

[Feasibility of Single-Breath-Hold Compressed Sensing Real-Time Cine Imaging for Assessment of Ventricular Function and Left Ventricular Strain in Cardiac Magnetic Resonance].

Objective: To explore the feasibility of single-breath-hold compressed sensing real-time cine imaging (CS-cine) in the assessment of ventricular function and left ventricular (LV) strain. Methods: A total of 70 subjects were enrolled prospectively, and all subjects underwent cardiac magnetic resonance imaging (cardiac MRI) using both the standard steady-state free procession cine (sta-cine) acquisition and a prototype CS-cine sequence. For both CS-cine and sta-cine imaging, continuous short-axis cine images were acquired from the base to the apex to cover the entire left ventricle, and long-axis cine images including two-, three-, and four-chamber views were also acquired. The scanning range, number of slices, slice thickness and intervals were kept identical for the two cine images of the same participant. Subjective evaluation of the image quality was performed on all cine images. For both sequences, the conventional function parameters of the left and the right ventricles and LV strain values were assessed with post-processing software analysis. The cine image quality, conventional ventricular function parameters, and LV strain values were compared between the two cine groups and the differences were examined. Inter- and intraobserver agreements for CS-cine images were measured using intraclass correlation coefficient ( ICC). Bland-Altman analysis was performed to assess reproducibility between the two cine methods. Results: The median scanning time of CS-cine was 21 s versus 272 s for sta-cine ( P<0.001). The median image quality scores of two groups were significantly different, 4 points for sta-cine and 2 points for CS-cine ( P<0.001). Bi-ventricular end-diastolic volumes (EDV), stroke volume (SV) and ejection fraction (EF) were significantly smaller in CS-cine ( P<0.001). Nevertheless, no significant differences between the two groups in bi-ventricular ESV or LV mass were observed ( P>0.05). LV strain parameters, including the peak radial strain, peak circumferential strain and peak longitudinal strain derived from LV mid-ventricular slice, were significantly different in the two sequences ( P<0.001). Moreover, CS-cine-derived functional parameters and strain measurements have a good correlation with those of sta-cine (for RV function parameters, and left ventricular PLS, PCS values, more than 95% points fell within the limits of agreement [ LoA]; meanwhile, more than 91% points fell within the LoA for other parameters) and inter- and intraobserver agreements were strong ( ICC=0.88 to 0.99) for CS-cine. Conclusion: CS-cine can well realize the rapid acquisition of cine images for quantitative analysis of cardiac function, and the conventional ventricular function parameters and LV globalized strain values obtained from CS-cine imaging have good reproducibility.

Copper(I)-Catalyzed Asymmetric Synthesis of Unnatural α-Amino Acid Derivatives and Related Peptides Containing γ-(aza)Aryls.

Chiral α-amino acids are indispensable compounds in organic chemistry, biochemistry, and medicinal chemistry. Herein, by means of copper(I)-catalyzed asymmetric conjugate addition of derivatives of glycine, serine, cysteine, and ß-amino-alanine to electron-deficient vinyl(aza)arenes, an array of novel unnatural chiral α-amino acid derivatives bearing a γ-(aza)aryl is prepared in moderate to high yields with high enantioselectivity. Various azaarenes, such as pyrimidine, 1,3,5-triazine, pyridine, pyridine-N-oxide, quinoline, quinoxaline, purine, benzo[d]imidazole, benzothiazole, and 1,2,4-oxadiazole, are well tolerated. Moreover, the electrophiles are nicely extended to (Z)/(E) mixtures of electron-deficient butadienylpyridine and benzene, which are transformed to the corresponding chiral α-amino acid derivatives in high (E)/(Z) ratio and high enantioselectivity. More importantly, the present methodology is successfully applied in the catalytic asymmetric functionalization of Schiff bases derived from peptides, which finally afforded a new chiral tripeptide bearing two electron-deficient azaaryls and one electron-deficient aryl in high total yield with high diastereo- and excellent enantioselectivities.

Site-Selective Defluorinative sp3 C-H Alkylation of Secondary Amides.

A site-selective defluorinative sp3 C-H alkylation of secondary amides that rapidly and reliably incorporates gem-difluoroalkene motifs into previously unfunctionalized sp3 sites is disclosed. This protocol is distinguished by its mild conditions, wide scope, and exquisite site-selectivity, thus unlocking a new platform to introduce carbonyl isosteres at saturated hydrocarbon sites.

Copper(I)-Catalyzed Asymmetric Vinylogous Aldol-Type Reaction of Allylazaarenes.

A vinylogous aldol-type reaction of allylazaarenes and aldehydes is disclosed that affords a series of chiral γ-hydroxyl-α,ß-unsaturated azaarenes in moderate to excellent yields with high to excellent regio- and enantioselectivities. With (R,RP )-TANIAPHOS and (R,R)-QUINOXP* as the ligand, the carbon-carbon double bond in the products is generated in (E)-form. With (R)-DTBM-SEGPHOS as the ligand, (Z)-form carbon-carbon double bond is formed in the major product. In this vinylogous reaction, aromatic, α,ß-unsaturated, and aliphatic aldehydes are competent substrates. Moreover, a variety of azaarenes, such as pyrimidine, pyridine, pyrazine, quinoline, quinoxaline, quinazoline, and benzo[d]imidazole are well-tolerated. At last, the chiral vinylogous product is demonstrated as a suitable Michael acceptor towards CuI-catalyzed nucleophilic addition with organomagnesium reagents.

Rapid Synthesis of Chiral 1,2-Bisphosphine Derivatives through Copper(I)-Catalyzed Asymmetric Conjugate Hydrophosphination.

1,2-Bisphosphines have been identified as one class of important and powerful chiral ligands in asymmetric catalysis with transition metals. Herein, a copper(I)-catalyzed asymmetric hydrophosphination of α,ß-unsaturated phosphine sulfides was developed with the assistance of "soft-soft" interaction between copper(I)-catalyst and the phosphine sulfide moiety, which afforded 1,2-bisphosphine derivatives with diversified electronic nature and steric hindrance in high to excellent yields with high to excellent enantioselectivity. Moreover, the challenging catalytic asymmetric hydrophosphination/protonation reaction was achieved with excellent enantioselectivity. Strikingly, the dynamic kinetic resolution of racemic diarylphosphines was also successfully carried out with high to excellent diastereo- and enantioselectivities. Interestingly, the nucleophilic copper(I)-diphenylphosphide species was characterized by 31 P NMR spectrum and mass spectrum. At last, three products were transformed to chiral 1,2-bisphosphines, which were employed as ligands in Rh-catalyzed asymmetric hydrogenation of α-amino-α,ß-unsaturated ester. The α-amino acid derivative was produced in high enantioselectivity, which demonstrated the utility of the present methodology.

Asymmetric Vinylogous Aldol-type Reactions of Aldehydes with Allyl Phosphonate and Sulfone.

Two catalytic asymmetric vinylogous aldol-type reactions of aldehydes with allyl phosphonate and allyl sulfone have been uncovered in good to high yields for the first time. The bulky ligand-(R)-DTBM-SEGPHOS-was found to be the key to perfectly control both regio- and enantioselectivities. Transformations of the vinylogous products (including Horner-Wadsworth-Emmons and Julia olefinations) were successfully realized by virtue of the phosphonate and sulfone moieties. Moreover, the present methodology was successfully applied in the asymmetric synthesis of natural products.

Catalytic Asymmetric Construction of Halogenated Stereogenic Carbon Centers by Direct Vinylogous Mannich-Type Reaction.

A catalytic asymmetric vinylogous Mannich-type reaction of γ-halo-α,ß-unsaturated N-acylpyrazoles and N-Boc-aldimines was disclosed, which afforded an array of halogenated (F-, Cl-, and Br-) allylic stereogenic carbon centers in high yields with good to high regio-, diastereo-, and enantioselectivities. The brominated product served as a suitable electrophile for common SN2 nucleophilic substitution and copper-mediated SN2' allylic alkylation with metal reagents. The utility of present methodology was demonstrated by the asymmetric synthesis of a common intermediate toward the synthesis of two chiral 2,3-disubstituted piperidine pharmaceuticals.