Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach

Macrocyclic compounds occupy an important chemical space between small molecules and biologics and are prevalent in many natural products and pharmaceuticals. The growing interest in macrocycles has been fueled, in part, by the design of novel synthetic methods to these compounds. One appealing strategy is ring-closing metathesis (RCM) that seeks to construct macrocycles from acyclic diene precursors using defined transition-metal alkylidene catalysts. Despite its broad utility, RCM generally gives rise to a mixture of E- and Z-olefin isomers that can hinder efforts for the large-scale production and isolation of such complex molecules. To address this issue, we aimed to develop methods that can selectively enrich macrocycles in E- or Z-olefin isomers using an RCM/ethenolysis strategy. The utility of this methodology was demonstrated in the stereoselective formation of macrocyclic peptides, a class of compounds that have gained prominence as therapeutics in drug discovery. Herein, we report an assessment of various factors that promote catalyst-directed RCM and ethenolysis on a variety of peptide substrates by varying the olefin type, peptide sequence, and placement of the olefin in macrocycle formation. These methods allow for control over olefin geometry in peptides, facilitating their isolation and characterization. The studies outlined in this report seek to expand the scope of stereoselective olefin metathesis in general RCM

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors

Microminiaturized, biopotential conditioning system (MBCS)

Multichannel, medical monitoring system allows almost complete freedom of movement for subject during monitoring periods. System comprises monitoring unit (biobelt), transmission line, and data acquisition unit. Belt, made of polybenzimidizole fabric, is wrapped around individual's waist and held in place by overlapping sections of Velcro closure material

Composition, Morphology, and Stratigraphy of Noachian Crust around the Isidis basin

Definitive exposures of pristine, ancient crust on Mars are rare, and the finding that much of the ancient Noachian terrain on Mars exhibits evidence of phyllosilicate alteration adds further complexity. We have analyzed high-resolution data from the Mars Reconnaissance Orbiter in the well-exposed Noachian crust surrounding the Isidis basin. We focus on data from the Compact Reconnaissance Imaging Spectrometer for Mars as well as imaging data sets from High Resolution Imagine Science Experiment and Context Imager. These data show the lowermost unit of Noachian crust in this region is a complex, brecciated unit of diverse compositions. Breccia blocks consisting of unaltered mafic rocks together with rocks showing signatures of Fe/Mg-phyllosilicates are commonly observed. In regions of good exposure, layered or banded phyllosilicate-bearing breccia rocks are observed suggestive of pre-Isidis sedimentary deposits. In places, the phyllosilicate-bearing material appears as a matrix surrounding mafic blocks, and the mafic rocks show evidence of complex folded relationships possibly formed in the turbulent flow during emplacement of basin-scale ejecta. These materials likely include both pre-Isidis basement rocks as well as the brecciated products of the Isidis basin–forming event at 3.9 Ga. A banded olivine unit capped by a mafic unit covers a large topographic and geographic range from northwest of Nili Fossae to the southern edge of the Isidis basin. This olivine-mafic cap combination superimposes the phyllosilicate-bearing basement rocks and distinctly conforms to the underlying basement topography. This may be due to draping of the topography by a fluid or tectonic deformation of a previously flatter lying morphology. We interpret the draping, superposed olivine-mafic cap combination to be impact melt from the Isidis basin–forming event. While some distinct post-Isidis alteration is evident (carbonate, kaolinite, and serpentine), the persistence of olivine from the time of Isidis basin suggests that large-scale aqueous alteration processes had ceased by the time this unit was emplaced

First Gale Western Butte Capping-Unit Compositions, and Relationships to Earlier Units Along Curiosity's Traverse

The Curiosity rover has been traversing through the clay-bearing unit (Glen Torridon; GT), approaching Greenheugh pediment, a large, fan-shaped surface surrounding the mouth of Gediz Vallis on the lower slope of Mt. Sharp. The pediment unconformably overlies the underlying bedrock, and is hence younger than units of the Mt. Sharp group. Orbital imaging of the pediment has shown it to have a slightly lower albedo and higher thermal inertia than neighboring units, to be relatively retentive of craters (e.g., erosion resistant), and to exhibit curved bedforms suggestive of lithified eolian bedforms. No diagnostic spectral signature has been observed from orbit. Recent rover positions allowed remote imaging of the contact between Greenheugh pediment and the eroded Murray formation strata below it, showing that the pediment capping material is cross-bedded and relatively thin (1-3 m), and suggesting that the pediment may have been much larger at one time. As Curiosity approached the edge of the pediment, the team investigated two buttes named Central and Western. The latter butte contains dark capping material that initially looked similar to the pediment cap, but close inspection revealed important physical differences. Here we report on compositions from ChemCam of two float rocks that appear to have rolled down from the capping unit, and on potential relation-ships to other targets along the traverse of the rover

Diffusion of Mn interstitials in (Ga,Mn)As epitaxial layers

Magnetic properties of thin (Ga,Mn)As layers improve during annealing by out-diffusion of interstitial Mn ions to a free surface. Out-diffused Mn atoms participate in the growth of a Mn-rich surface layer and a saturation of this layer causes an inhibition of the out-diffusion. We combine high-resolution x-ray diffraction with x-ray absorption spectroscopy and a numerical solution of the diffusion problem for the study of the out-diffusion of Mn interstitials during a sequence of annealing steps. Our data demonstrate that the out-diffusion of the interstitials is substantially affected by the internal electric field caused by an inhomogeneous distribution of charges in the (Ga,Mn)As layer.Comment: 11 pages, 5 figure

Apatites in Gale Crater

ChemCam is an active remote sensing instrument suite that has operated successfully on MSL since landing Aug. 6th, 2012. It uses laser pulses to remove dust and to analyze rocks up to 7 m away. Laser-induced breakdown spectroscopy (LIBS) obtains emission spectra of materials ablated from the samples in electronically excited states. The intensities of the emission lines scale with the abundances of the related element. ChemCam is sensitive to most major rock-forming elements as well as to a set of minor and trace elements such as F, Cl, Li, P, Sr, Ba, and Rb. The measured chemical composition can then be used to infer the mineralogical composition of the ablated material. Here, we report a summary of inferred apatite detections along the MSL traverse at Gale Crater. We present the geologic settings of these findings and derive some interpretations about the formation conditions of apatite in time and space