Electrophilic Pt(II) Complexes: Precision Instruments for the Initiation of Transformations Mediated by the Cation–Olefin Reaction

A discontinuity exists between the importance of the cation–olefin reaction as the principal C–C bond forming reaction in terpene biosynthesis and the synthetic tools for mimicking this reaction under catalyst control; that is, having the product identity, stereochemistry, and functionality under the control of a catalyst. The main reason for this deficiency is that the cation–olefin reaction starts with a reactive intermediate (a carbocation) that reacts exothermically with an alkene to reform the reactive intermediate; not to mention that reactive intermediates can also react in nonproductive fashions. In this Account, we detail our efforts to realize catalyst control over this most fundamental of reactions and thereby access steroid like compounds. Our story is organized around our progress in each component of the cascade reaction: the metal controlled electrophilic initiation, the propagation and termination of the cyclization (the cyclase phase), and the turnover deplatinating events. Electrophilic Pt(II) complexes efficiently initiate the cation–olefin reaction by first coordinating to the alkene with selection rules that favor less substituted alkenes over more substituted alkenes. In complex substrates with multiple alkenes, this preference ensures that the least substituted alkene is always the better ligand for the Pt(II) initiator, and consequently the site at which all electrophilic chemistry is initiated. This control element is invariant. With a suitably electron deficient ligand set, the catalyst then activates the coordinated alkene to intramolecular addition by a second alkene, which initiates the cation–olefin reaction cascade and generates an organometallic Pt(II)-alkyl. Deplatination by a range of mechanisms (β-H elimination, single electron oxidation, two-electron oxidation, etc.) provides an additional level of control that ultimately enables A-ring functionalizations that are orthogonal to the cyclase cascade. We particularly focus on reactions that combine an initiated cyclization reaction with a turnover defining β-hydride elimination, fluorination, and oxygenation. These latter demetalation schemes lead to new compounds functionalized at the C3 carbon of the A-ring (steroid numbering convention) and thus provide access to interesting potentially bioactive targets. Progress toward efficient and diverse polycyclization reactions has been achieved by investing in both synthetic challenges and fundamental organometallic reactivity. In addition to an interest in the entrance and exit of the metal catalyst from this reaction scheme, we have been intrigued by the role of neighboring group participation in the cyclase phase. Computational studies have served to provide nuance and clarity on several key aspects, including the role (and consequences) of neighboring group participation in cation generation and stabilization. For example, these calculations have demonstrated that traversing carbonium ion transition states significantly impacts the kinetics of competitive 6-endo and 5-exo A-ring forming reactions. The resulting nonclassical transition states then become subject to a portion of the strain energy inherent to bicyclic structures, with the net result being that the 6-endo pathway becomes kinetically favored for alkene nucleophiles, in contrast to heteroatom nucleophiles which progress through classical transition states and preferentially follow 5-exo pathways. These vignettes articulate our approach to achieving the desired catalyst control

Rolesville, North Carolina, Wake County : an action-oriented community diagnosis : findings and next steps of action

In the fall of 2003 six students from the UNC School of Public Health were requested by Wake County Human Services to work with the Rolesville community through the spring of 2004 to conduct an Action Oriented Community Diagnosis (AOCD). The team interviewed twenty-five community members and twelve service providers in the area, and then organized a committee of interested residents to plan the Rolesville Community Forum. The Forum was a venue for people to discuss the team's findings and generate ideas about action that can be taken to address the findings. Rolesville has remained small and rural since it was settled during the Revolutionary War, despite being only fourteen miles from Raleigh, the state capitol.1 However, in the last ten years, Rolesville has been undergoing rapid growth and suburbanization, and may see its population increase more than tenfold in the next twenty years.9 This unprecedented growth presents challenges to the generational families of the community, but also creates opportunities for individuals and the community as a whole. In order to effectively confront these challenges and create change, a community must have many assets, and Rolesville certainly does. Among them are: community spirit and dedication to volunteerism, its small size, the town’s emphasis on providing opportunities for youth, particularly through the Parks and Recreation programs, and its vibrant local institutions, such as the churches, EMS, and the Fire Department. Five areas in which community members expressed concern were: Community Identity and Involvement, Diversity and Change, Health and Other Services, Planning Growth, and Traffic. Several overlapping themes emerged among these five concerns, resulting in two overarching themes: rapid growth and the new diversity that growth has brought. The main action step determined at the Forum is for community members, town officials, and church leaders to increase pressure on officials at the state-level to increase funding for the U.S. 401 bypass and services for Rolesville. It was also strongly recommended that the town to diversify its communication channels to publicize town events, meetings, and planning sessions to reach long-time residents, newcomers, and Spanish-speaking residents. Another important action step is to create a public relations or welcoming committee to assist in incorporating newcomers into the community and improve communication between the town government and town residents. Finally, the AOCD team concluded that Rolesville has many resources and strengths that could be mobilized to meet the challenges being brought by exponential growth and changing demographics. With leadership from its town government and its churches, the Rolesville community can embody its motto: “Small town, bright future.”Master of Public Healt

Partial change in EphA4 knockout mouse phenotype: Loss of diminished GFAP upregulation following spinal cord injury

In a previous study we found that the EphA4 receptor inhibits regeneration following spinal cord injury by blocking regrowth of axons and regulation of astrocyte reactivity. In our original studies using EphA4 null mice [Goldshmit et al., J. Neurosci., 2004] we found attenuated astrocyte reactivity following spinal cord injury. Several other studies have now supported the role of EphA4 in regulating neural regeneration but a recent study [Herrmann et al., Exp. Neurol., 2010] did not find an effect of EphA4 on astrocyte reactivity. Re-examination of astrocytic gliosis following injury in our current cohort of EphA4 null mice revealed that they no longer showed attenuation of astrocyte reactivity, however other EphA4 null mouse phenotypes, such as decreased size of the dorsal funiculus were unaltered. We hypothesised that long-term breeding on the C57Bl/6 background may influence the EphA4-mediated astrocyte phenotype and compared astrocytic gliosis at 4 days following spinal cord injury in wildtype and EphA4 null mice on the C57Bl/6 background and backcrossed C57Bl/6×129Sv(F2) mice, as well as wildtype 129Sv mice. 129Sv mice had increased GFAP expression and increased numbers of reactive GFAP astrocytes compared to C57Bl/6 mice. There was no significant effect of EphA4 deletion on GFAP expression in C57Bl/6 mice or the F2 crosses other than a moderately decreased number of EphA4 null astrocytes in C57Bl/6 mice using one of two antibodies. Therefore, there has been an apparent change in EphA4-mediated astroglial phenotype associated with long term breeding of the EphA4 colony but it does not appear to be influenced by background mouse strain

Net Hydrogenation of Pt-NHPh Bond Is Catalyzed by Elemental Pt

This article discusses the net hydrogenation of Pt-NHPh bond catalyzed by elemental Pt

Isolation and Chemical Composition of Dinoflagellate Nuclei *

Nuclei were isolated from Peridinium cinctum. Peridinium trochoideum, Gyrodinium cohnii ( Cryptothecodinium cohnii ) and Gymnodinium nelsoni. The nuclei of G. cohnii, P. trochoideum and G. nelsoni were found to contain ∼ 6.9, 34 and 143 picograms of DNA respectively. The ratios to DNA of RNA, acid-soluble and acid-insoluble protein for G. cohnii were 0.32, 0.13 and 0.99, respectively. The corresponding values for P. trochoideum were 0.22, 0.08 and 1.22, while those for G. nelsoni were 0.21, 0.10 and 1.09. The chemical composition of dinoflagellate nuclei is compared and contrasted with that of typical eukaryotic nuclei. The culture of these difficult organisms also is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72006/1/j.1550-7408.1973.tb03595.x.pd

Response of the solar atmosphere to magnetic field evolution in a coronal hole region

Methods. We study an equatorial CH observed simultaneously by HINODE and STEREO on July 27, 2007. The HINODE/SP maps are adopted to derive the physical parameters of the photosphere and to research the magnetic field evolution and distribution. The G band and Ca II H images with high tempo-spatial resolution from HINODE/BFI and the multi-wavelength data from STEREO/EUVI are utilized to study the corresponding atmospheric response of different overlying layers. Results. We explore an emerging dipole locating at the CH boundary. Mini-scale arch filaments (AFs) accompanying the emerging dipole were observed with the Ca II H line. During the separation of the dipolar footpoints, three AFs appeared and expanded in turn. The first AF divided into two segments in its late stage, while the second and third AFs erupted in their late stages. The lifetimes of these three AFs are 4, 6, 10 minutes, and the two intervals between the three divisions or eruptions are 18 and 12 minutes, respectively. We display an example of mixed-polarity flux emergence of IN fields within the CH and present the corresponding chromospheric response. With the increase of the integrated magnetic flux, the brightness of the Ca II H images exhibits an increasing trend. We also study magnetic flux cancellations of NT fields locating at the CH boundary and present the obvious chromospheric and coronal response. We notice that the brighter regions seen in the 171 A images are relevant to the interacting magnetic elements. By examining the magnetic NT and IN elements and the response of different atmospheric layers, we obtain good positive linear correlations between the NT magnetic flux densities and the brightness of both G band (correlation coefficient 0.85) and Ca II H (correlation coefficient 0.58).Comment: 9 pages, 9 figures. A&A, in pres

Dystropathology increases energy expenditure and protein turnover in the mdx mouse model of Duchenne muscular dystrophy

The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles