Fibrillar collagens in connective tissues are organized into complex and diverse hierarchical networks. In dermis, bone and tendon, one common phenomenon at the micrometer scale is the organization of fibrils into bundles. Previously we have reported that collagen fibrils in these tissues exhibit a 10 nm width distribution of D-spacing values. This study expands the observation to a higher hierarchical level by examining fibril D-spacing distribution in relation to the bundle organization. We used Atomic Force Microscopy (AFM) imaging and two dimensional Fast Fourier Transform (2D FFT) analysis to investigate dermis, tendon and bone tissues. We found that in each tissue type, collagen fibril D-spacings within a single bundle were nearly identical, and frequently differing by less than 1 nm. The full 10 nm range in D-spacing values arises from different values found in different bundles. The similarity in D-spacing was observed to persist for up to 40 µm in bundle length and width. A nested mixed model analysis of variance examining 107 bundles and 1710 fibrils from dermis, tendon and bone indicated that fibril D-spacing differences arise primarily at the bundle level (~76%), independent of species or tissue types.
A new chiral dirhodium tetracarboxylate catalyst, Rh( S-2-Cl-5-BrTPCP), has been developed for C-H functionalization reactions by means of donor/acceptor carbene intermediates. The dirhodium catalyst contains four ( S)-1-(2-chloro-5-bromophenyl)-2,2-diphenylcyclopropane-1-carboxylate ligands, in which all four 2-chloro-5-bromophenyl groups are on the same face of the catalyst, leading to a structure, which is close to C symmetric. The catalyst induces highly site selective functionalization of remote, unactivated methylene C-H bonds even in the presence of electronically activated benzylic C-H bonds, which are typically favored using earlier established dirhodium catalysts, and the reactions proceed with high levels of diastereo- and enantioselectivity. This C-H functionalization method is applicable to a variety of aryl and heteroaryl derivatives. Furthermore, the potential of this methodology was illustrated by sequential C-H functionalization reactions to access the macrocyclic core of the cylindrocyclophane class of natural products.
Collagen molecules, self-assembled into macroscopic hierarchical tissue networks, are the main organic building block of many biological tissues. A particularly common and important form of this self-assembly consists of type I collagen fibrils, which exhibit a nanoscopic signature, D-periodic gap/overlap spacing, with a distribution of values centered at approximately 67 nm. In order to better understand the relationship between type I collagen self-assembly and D-spacing distribution, we investigated surface-mediated collagen self-assembly as a function of substrate and incubation concentration. Collagen fibril assembly on phlogopite and muscovite mica as well as fibrillar gel coextrusion in glass capillary tubes all exhibited D-spacing distributions similar to those commonly observed in biological tissues. The observation of D-spacing distribution by self-assembly of type I collagen alone is significant as it eliminates the necessity to invoke other preassembly or postassembly hypotheses, such as variation in the content of collagen types, enzymatic cross-linking, or other post-translational modifications, as mechanistic origins of D-spacing distribution. The D-spacing distribution on phlogopite mica is independent of type I collagen concentration, but on muscovite mica D-spacing distributions showed increased negative skewness at 20 μg/mL and higher concentrations. Tilted D-spacing angles were found to correlate with decreased D-spacing measurements, an effect that can be removed with a tilt angle correction, resulting in no concentration dependence of D-spacing distribution on muscovite mica. We then demonstrated that tilted D-spacing is uncommon in biological tissues and it does not explain previous observations of low D-spacing values in ovariectomized dermis and bone.
A general method for the enantioselective synthesis of carbo- and heterocyclic carbonyl compounds bearing fluorinated α-tetrasubstituted stereocenters using palladium-catalyzed decarboxylative allylic alkylation is described. The stereoselective Csp3 –Csp3 cross-coupling reaction delivers five- and six-membered ketone and lactam products bearing (poly)fluorinated tetrasubstituted chiral centers in high yields and enantioselectivities. These fluorinated, stereochemically rich building blocks hold potential value in medicinal chemistry and are prepared using an orthogonal and enantioselective approach into such chiral moieties compared to traditional approaches, often without the use of electrophilic fluorinating reagents.
We recently reported a method for selective macro(mono)cyclization of dienes utilizing catalysts confined inside the pores of mesoporous silica, which we believe occurs due to suppression of oligomerization due to pore size. We hypothesized, however, that the system of cationic molybdenum imido alkylidene N-heterocyclic carbene (NHC) catalysts immobilized selectively inside the mesopores of silica materials could address much more subtle selectivity differences, such as E/Z selectivity in ring-opening/cross-metathesis (ROCM). Upon investigation, we observed that surface-bound cationic molybdenum imido alkylidene NHC catalysts indeed display an increased Z-selectivity, especially during the early stages of the reaction. This effect was present when the catalyst was confined inside a pore, as well as when the catalyst was bound to nonporous silica, which led us to conclude it is an effect caused by the catalyst being bound directly to the surface of a silica material where the proximity of the catalyst to the surface governs the transition state. Kinetic investigations revealed that significant post-metathesis olefin isomerization occurs, the amount of which seems to be governed by the rate of diffusion of the product away from the active catalyst, with smaller pore sizes resulting in higher Z-selectivity at higher conversion, attributable to faster diffusion of the product out of the pore than diffusion back into the pore.
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