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Numajiri Y.,California Institute of Technology | Jimenez-Oses G.,University of California at Los Angeles | Wang B.,BioTools, Inc. | Houk K.N.,University of California at Los Angeles | Stoltz B.M.,California Institute of Technology
Organic Letters | Year: 2015

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds. © 2015 American Chemical Society. Source


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 125.00K | Year: 2010

This Small Business Innovation Research (SBIR) Phase I project is focused on the creation of a new revolutionary imaging instrumentation that combines vibrational circular dichroism (VCD) spectroscopy with infrared (IR) spectral microscopy. VCD microscopy represents a new class of spectroscopic imaging diagnostic capable of measuring VCD images with millimeter to sub-millimeter spatial resolution. The recent discovery that long-range structural chirality in protein fibrils is characterized by unusually large and distinctive VCD spectra provides the backdrop for this project. None of the currently available techniques can characterize the fibrillation pathway or the final fibril state with the same ease and detail as VCD. VCD microscopy can be thought of as circular polarization contrast microscopy that is sensitive to long-range chiral order in localized regions of biological samples. The broader impacts of this research are studies of the supramolecular chirality of fibrils. This product is not a small improvement of an existing technology but a distinctly new method of studying long-range biochirality that is more sensitive, provides more detail, and is easy and fast to use. A secondary, higher-impact long-term impact will be clinical research laboratories where this innovation can be used for the detection and characterization of amyloids in vivo, i.e. for tissue biopsies, rapid detection of amyloids and drug screening.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 431.69K | Year: 2011

This Small Business Innovation Research (SBIR) Phase II project is focused on the creation of a new revolutionary imaging instrumentation that combines vibrational circular dichroism (VCD) spectroscopy with infrared (IR) spectral microscopy. VCD microscopy represents a new class of spectroscopic imaging diagnostic capable of measuring VCD images with millimeter to sub-millimeter spatial resolution. The recent discovery that long-range structural chirality in protein fibrils is characterized by unusually large and distinctive VCD spectra provides the backdrop for this project. None of the currently available techniques can characterize the fibrillation pathway or the final fibril state with the same ease and detail as VCD. VCD microscopy can be thought of as circular polarization contrast microscopy that is sensitive to long-range chiral order in localized regions of biological samples. The broader impacts of this research are studies of the supramolecular chirality of fibrils. This product is not a small improvement of an existing technology but a distinctly new method of studying long-range biochirality that is more sensitive, provides more detail, and is easy and fast to use. A secondary, higher-impact long-term impact will be clinical research laboratories where this innovation can be used for the detection and characterization of amyloids in vivo, i.e. for tissue biopsies, rapid detection of amyloids and drug screening.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: SMALL BUSINESS PHASE II | Award Amount: 476.69K | Year: 2011

This Small Business Innovation Research (SBIR) Phase II project is focused on the creation of a new revolutionary imaging instrumentation that combines vibrational circular dichroism (VCD) spectroscopy with infrared (IR) spectral microscopy. VCD microscopy represents a new class of spectroscopic imaging diagnostic capable of measuring VCD images with millimeter to sub-millimeter spatial resolution. The recent discovery that long-range structural chirality in protein fibrils is characterized by unusually large and distinctive VCD spectra provides the backdrop for this project. None of the currently available techniques can characterize the fibrillation pathway or the final fibril state with the same ease and detail as VCD. VCD microscopy can be thought of as circular polarization contrast microscopy that is sensitive to long-range chiral order in localized regions of biological samples.

The broader impacts of this research are studies of the supramolecular chirality of fibrils. This product is not a small improvement of an existing technology but a distinctly new method of studying long-range biochirality that is more sensitive, provides more detail, and is easy and fast to use. A secondary, higher-impact long-term impact will be clinical research laboratories where this innovation can be used for the detection and characterization of amyloids in vivo, i.e. for tissue biopsies, rapid detection of amyloids and drug screening.


Kurouski D.,Albany State University | Dukor R.K.,BioTools, Inc. | Lu X.,BioTools, Inc. | Nafie L.A.,Syracuse University | And 2 more authors.
Biophysical Journal | Year: 2012

Fibrils are β-sheet-rich aggregates that are generally composed of several protofibrils and may adopt variable morphologies, such as twisted ribbons or flat-like sheets. This polymorphism is observed for many different amyloid associated proteins and polypeptides. In a previous study we proposed the existence of another level of amyloid polymorphism, namely, that associated with fibril supramolecular chirality. Two chiral polymorphs of insulin, which can be controllably grown by means of small pH variations, exhibit opposite signs of vibrational circular dichroism (VCD) spectra. Herein, using atomic force microscopy (AFM) and scanning electron microscopy (SEM), we demonstrate that indeed VCD supramolecular chirality is correlated not only by the apparent fibril handedness but also by the sense of supramolecular chirality from a deeper level of chiral organization at the protofilament level of fibril structure. Our microscopic examination indicates that normal VCD fibrils have a left-handed twist, whereas reversed VCD fibrils are flat-like aggregates with no obvious helical twist as imaged by atomic force microscopy or scanning electron microscopy. A scheme is proposed consistent with observed data that features a dynamic equilibrium controlled by pH at the protofilament level between left- and right-twist fibril structures with distinctly different aggregation pathways for left- and right-twisted protofilaments. © 2012 by the Biophysical Society. Source

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