Bulky N-Phosphino-Functionalized N-Heterocyclic Carbene Ligands: Synthesis, Ruthenium Coordination Chemistry, and Ruthenium Alkylidene Complexes for Olefin Metathesis.

Ruthenium chemistry and applications in catalytic olefin metathesis based on N-phosphino-functionalized N-heterocyclic carbene ligands (NHCPs) are presented. Alkyl NHCP Ru coordination chemistry is described, and access to several potential synthetic precursors for ruthenium alkylidene complexes is outlined, incorporating both trimethylsilyl and phenyl alkylidenes. The Ru alkylidene complexes are evaluated as potential olefin metathesis catalysts and were shown to behave in a latent fashion. They displayed catalytic activity at elevated temperatures for both ring closing metathesis and ring opening metathesis polymerization.

Endothelial nitric oxide synthase is regulated by ERK phosphorylation at Ser602.

eNOS (endothelial nitric oxide synthase) contains a MAPK (mitogen-activated protein kinase)-binding site associated with a major eNOS control element. Purified ERK (extracellular-signal-regulated kinase) phosphorylates eNOS with a stoichiometry of 2-3 phosphates per eNOS monomer. Phosphorylation decreases NO synthesis and cytochrome c reductase activity. Three sites of phosphorylation were detected by MS. All sites matched the SP and TP MAPK (mitogen-activated protein kinase) phosphorylation motif. Ser602 lies at the N-terminal edge of the 42-residue eNOS AI (autoinhibitory) element. The pentabasic MAPK-binding site lies at the opposite end of the AI, and other critical regulatory features are between them. Thr46 and Ser58 are located in a flexible region associated with the N terminus of the oxygenase domain. In contrast with PKC (protein kinase C), phosphorylation by ERK did not significantly interfere with CaM (calmodulin) binding as analysed by optical biosensing. Instead, ERK phosphorylation favours a state in which FMN and FAD are in close association and prevents conformational changes that expose reduced FMN to acceptors. The close associations between control sites in a few regions of the molecule suggest that control of signal generation is modulated by multiple inputs interacting directly on the surface of eNOS via overlapping binding domains and tightly grouped targets.

Dynamic association of the PI3P-interacting Mon1-Ccz1 GEF with vacuoles is controlled through its phosphorylation by the type 1 casein kinase Yck3.

Maturation of organelles in the endolysosomal pathway requires exchange of the early endosomal GTPase Rab5/Vps21 for the late endosomal Rab7/Ypt7. The Rab exchange depends on the guanine nucleotide exchange factor activity of the Mon1-Ccz1 heterodimer for Ypt7. Here we investigate vacuole binding and recycling of Mon1-Ccz1. We find that Mon1-Ccz1 is absent on vacuoles lacking the phosphatidic acid phosphatase Pah1, which also lack Ypt7, the phosphatidylinositol 3-kinase Vps34, and the lipid phosphatidylinositol 3-phosphate (PI3P). Interaction of Mon1-Ccz1 with wild-type vacuoles requires PI3P, as shown in competition experiments. We also find that Mon1 is released from vacuoles during the fusion reaction and its release requires its phosphorylation by the type 1 casein kinase Yck3. In contrast, Mon1 is retained on vacuoles lacking Yck3 or when Mon1 phosphorylation sites are mutated. Phosphorylation and release of Mon1 is restored with addition of recombinant Yck3. Together the results show that Mon1 is recruited to endosomes and vacuoles by PI3P and, likely after activating Ypt7, is phosphorylated and released from vacuoles for recycling.

Spread of virulent group A Streptococcus type emm59 from Montana to Wyoming, USA.

Full-genome sequencing showed that a recently emerged and hypervirulent clone of group A Streptococcus type emm59 active in Canada and parts of the United States has now caused severe invasive infections in rural northeastern Wyoming. Phylogenetic analysis of genome data indicated that the strain was likely introduced from Montana.

Rearrangements of phosphinoimines to phosphine-imines in ruthenium chelate complexes.

Thermal reaction of 1:1 mixtures of the RuCl(2)(PPh(3))(3) and phosphinoimine R(2)PN=CPh(2) (R = Ph, iPr, Me) at 140 °C results in isolation of the dimeric species [RuCl(µ-Cl)(PPh(3))(C(6)H(4)(PPh(2))C(Ph)NH)](2) (R = Ph 1, iPr 2, Me 3) containing phosphine-imine chelating ligands. Subsequent reaction of 1 and 3 with one equivalent of pyridine at room temperature give RuCl(2)(PPh(3))(py)(C(6)H(4)(PR(2))C(Ph)NH) (R = Ph 4, Me 5). Excess pyridine reacts with 2 to give a mixture of the cis and trans-isomers of RuCl(2)(py)(2)(C(6)H(4)(PiPr(2))C(Ph)NH) 6 and 7 respectively. Treatment of 5 with excess PPh(3) affords RuCl(2)(PPh(3))(2)(C(6)H(4)(PMe(2))C(Ph)NH) 8. Aspects of the mechanism of the thermal rearrangements of the phosphinoimine to the phosphine-imine ligands are considered and the isolation of RuCl(2)(Ph(2)PN=CPh(2))(SIMes)(CHPh) 9 and RuCl(2)(PPh(3))(2)(HN=C(Ph)C(6)H(4)) 10 provide support for a proposed mechanism involving a intermediate containing a Ru-bound metallated aryl-imine fragment.

Metal-free catalytic hydrogenation of polar substrates by frustrated Lewis pairs.

In 2006, our group reported the first metal-free systems that reversibly activate hydrogen. This finding was extended to the discovery of "frustrated Lewis pair" (FLP) catalysts for hydrogenation. It is this catalysis that is the focal point of this article. The development and applications of such FLP hydrogenation catalysts are reviewed, and some previously unpublished data are reported. The scope of the substrates is expanded. Optimal conditions and functional group tolerance are considered and applied to targets of potential commercial significance. Recent developments in asymmetric FLP hydrogenations are also reviewed. The future of FLP hydrogenation catalysts is considered.

Titanium "constrained geometry" complexes with pendant arene groups.

The synthesis of the proligands C(5)Me(4)HSiMe(2)N(H)R) (R = CMe(2)Ph 1, 2-C(6)H(4)Ph 2) was accomplished via a straightforward salt metathesis reaction of the appropriate lithium amide and ClSiMe(2)(C(5)Me(5)H). Generation of the dilithio salt and reaction with TiCl(3)·(THF)(3) followed by oxidation gave C(5)Me(4)SiMe(2)N(C(6)H(4)Ph)TiCl(2) (3) in low yield. In contrast, deprotonation of 1 and 2 and reaction with (Me(2)N)(2)TiCl(2) afforded C(5)Me(4)(SiMe(2)NR)Ti(NMe(2))(2) (R = CMe(2)Ph 4, 2-C(6)H(4)Ph 5), respectively, in good yields Treatment with MeI gave the analogs C(5)Me(4)(SiMe(2)NR)TiI(2) (R = CMe(2)Ph 6, 2-C(6)H(4)Ph 7). Reduction of 7 with potassium graphite afforded C(5)Me(4)(SiMe(2)NC(6)H(4)Ph)Ti 8. Treatment of 6 and 7 with MeMgBr afforded C(5)Me(4)(SiMe(2)NR)TiMe(2) (R = CMe(2)Ph 9, 2-C(6)H(4)Ph 10). Complexes 9 and 10 in combination with the activator [Ph(3)C][B(C(6)F(5))(4)] catalyzed the polymerization of styrene and ethylene. Copolymerization was also investigated. While the catalyst derived from 10 showed poor activity, compound 9 showed markedly higher activity than 10 and (C(5)Me(4))SiMe(2)(NtBu)]TiMe(2).

Ag(I) and Au(I) complexes of sterically crowded cyclic phosphinimine ligands.

Cyclic phosphinimines are strong bases with structural similarities to carbene ligands. The cyclic phosphinimines R(2)PNCPh(2)(CH(2)CH(CO(2)Me)) (R = Ph 4, i-Pr 5, Me 6), R(2)PNCPh(2)(CCOMe)(2) (R = Ph 7, i-Pr 8) and Ph(2)PNCPh(2)(CH(2)CH(CN)) 9 are readily prepared via cycloaddition of the compounds R(2)PNCPh(2) (R = Ph 1, i-Pr 2, Me 3) and olefins or alkynes. In the case of 4 this phosphinimine proved to be moisture sensitive, converting to Ph(2)C(NH(2))CH(CO(2)Me)CH(2)P(O)Ph(2)10 upon hydrolysis. Nonetheless, the Ag(i) and Au(i) complexes [{Ph(2)PNCPh(2)(CH(2)CH(CO(2)Me)}(2)Ag][NO(3)] 11 (Ph(2)PNCPh(2)(CH(2)CH(CO(2)Me)AuCl 12 and (Ph(2)PNCPh(2)(C(CO(2)Me)(2))AuCl 13 were prepared and characterized. Compounds 1, 2 and 7-13 have been characterized crystallographically.

Cyclopropanation of Ru-diimino-pyridine ligand complexes.

Reaction of 2,6-bis(imino)pyridines with (Cy(3)P)(2)RuCl(2)(CHPh) affords the complexes C(6)H(3)N(CMeNC(6)H(4)R)(CCH(2)CHPh) NHC(6)H(5))RuCl(2)(PCy(3)) (R = H 1, iPr 2) arising from the cyclopropanation of the ligand.

Melanoma screening with serial whole body photographic change detection using Melanoscan technology.

The use of an automated, whole-body, diffusely lit digital imaging enclosure to produce serial images, which were then compared, using an astrophysics image display method, enabled a private practice dermatologist to detect melanoma at significantly thinner Breslow depths compared to all other clinical detection paradigms examined in this study. The patients were triaged to scanning using a melanoma risk survey system. The system employed a 24 camera semicircular imaging wall, with front and back views. 10,000 whole body photographic scans were obtained. Privacy was maintained with 128-bit image encryption and off-line storage. Image to image comparison of whole body digital photography was combined with a whole body skin exam in order to sensitize a clinical dermatologist to skin changes in individuals at risk for melanoma. Mean depths (Breslow scores) were compiled from six distinct melanoma biopsy cohorts segregated and based on different clinical screening paradigms. The Breslow depth of invasive lesions of the serial screening cohort was significantly less (by at least 0.050 mm) compared to three other clinical screening groups (patient self-detection 0.55 mm, p=0.007; referred by outside non-dermatologist physician 0.73 mm, p=0.03; and serial dermatologic evaluation 0.23 mm, p=0.03) as well as two pathology laboratory cohorts (community hospital laboratory 1.45 mm, p=0.003; dermatopathology laboratory 0.18, p=0.0003). This approach provides a quick and effective method for detection of early melanomas with a significant reduction in the skin area required for lesion examination.