Chemoenzymatic Total Synthesis of Morphine alkaloids: Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Strategy and ent-Hydromorphone via an Oxidative Dearomatization/intramolecular [4+2] Cycloaddition

This thesis describes the chemoenzymatic synthesis of three morphine alkaloids. The total synthesis of dihydrocodeine and hydrocodone was accomplished starting from bromobenzene in 16 and 17 steps, respectively. The key steps included a microbial oxidation of bromobenzene by E. coli JM109 (pDTG601A), a Kazmaier-Claisen rearrangement of glycinate ester to generate C-9 and C-14 stereo centers, a Johnson-Claisen rearrangement to set the C-13 quaternary center, and a C-10/C-11 ring closure via a Friedel-Crafts reaction. In addition, the total synthesis of ent-hydromorphone starting from β-bromoethylbenzene in 12 steps is also described. The key reactions included the enzymatic dihydroxylation of β-bromoethylbenzene to the corresponding cis-cyclohexadienediol, a Mitsunobu reaction, and an oxidative dearomatization followed by an intramolecular [4+2] cycloaddition

Structural and functional insight into human O-GlcNAcase

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value

Structural and functional insight into human O-GlcNAcase.

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value

Power, Performance and Area Consequences of Multi-context Support in Coarse-grained Reconfigurable Arrays

Coarse-Grained Reconfigurable Arrays (CGRAs) are programmable logic devices comprising a two-dimensional array of large, often ALU-like, logic blocks, and datapath-style (multi-bit) programmable interconnect. A feature frequently associated with CGRAs is dynamic reconfigurability, wherein the CGRA supports multiple contexts. The multiple contexts form a set of configuration bitstreams that are loaded into the CGRA simultaneously and cycled through according to a schedule. Multi-context allows the CGRA hardware to be time-multiplexed: the logic blocks and interconnect can perform different functions according to the context selected in each clock cycle. In this thesis, we consider how multi-context may be implemented at the circuit level, and evaluate four circuit implementations from the power, performance, and area (PPA) perspectives. The PPA overhead of the multi-context feature in CGRAs vs. a single-context device is also quantified. We also explore context-switching using a State Transition Controller (STC), which can switch contexts without a fully predefined pattern.M.A.S

Synthesis and characterisation of mono- and binuclear palladium and platinum complexes with organochalcogenides

Singhal, Anshu ; Jain, Vimal K. ; Varghese, Babu ; Tiekink, Edward R.T

A novel pseudo four component reaction involving homoenolate for the synthesis of γ-aminobutyric acid (GABA) derivatives

Homoenolate generated from α,β-unsaturated aldehydes by NHC catalysis underwent facile addition to conjugated sulfonimines, generated in situ, and subsequent methanolysis to afford protected GABA derivatives stereoselectively and in high yields, thus constituting a novel pseudo four component reaction

2-(N,N-dimethylamino)ethylselenolates of cadmium(II): syntheses, structure of [Cd<SUB>3</SUB>(OAc)<SUB>2</SUB>(SeCH<SUB>2</SUB>CH<SUB>2</SUB>NMe<SUB>2</SUB>)<SUB>4</SUB>] and their use as single source precursors for the preparation of CdSe nanoparticles

The reaction of Cd(OAc)2 · 2H2O with NaSeCH2CH2NMe2 gave a homoleptic cadmium selenolate, [Cd(SeCH2CH2NMe2)2]. The latter complex, on treatment with Cd(OAc)2 · 2H2O, afforded [Cd3(OAc)2(SeCH2CH2NMe2)4], which was structurally characterized by single-crystal X-ray diffraction analysis. Pyrolysis of [Cd(SeCH2CH2NMe2)2] either in a mixture of hot hexadecylamine (HDA) and tri-n-octylphosphine oxide (TOPO) or in a furnace (180 and 200 °C) gave CdSe nanoparticles with average sizes varying between 3 and 21 nm. Both cubic and hexagonal phases of CdSe nanoparticles have been isolated under different experimental conditions. The CdSe nanoparticles were characterized by UV-Vis, photoluminescence, X-ray diffraction and electron microscopy. Time resolved luminescence measurements showed three different decay times for both band edge and trap state emissions

NHC-catalysed annulation of enals to tethered dienones: efficient synthesis of bicyclic dienes

Homoenolates generated from α,β-unsaturated aldehydes using NHC catalysis underwent facile addition to dibenzylidene cyclohexanone to afford bicyclic cyclopentenes as single diastereomers

Novel nucleophilic heterocyclic carbene mediated stereoselective conjugate addition of enals to nitrostyrenes via homoenolate

A stereoselective Michael addition of homoenolate, generated from enals by nucleophilic heterocyclic carbene (NHC) catalysis, to β-nitrostyrenes is reported for the first time. The products of this reaction obtained in good yields are of potential value in the synthesis of a variety of acyclic and heterocyclic compounds

Utility of clot waveform analysis in Russell's viper bite victims with hematotoxicity

Introduction: In Russell's viper bites, due to the lack of a better alternative, whole blood clotting test (WBCT) remains the standard test even though its reliability and sensitivity has been shown to be low. Activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA) is an optic absorbance assay that can be used as a global clotting test. In this study, the objective was to assess the changes in CWA and to compare CWA to WBCT and aPTT in patients with Russell's viper envenomation. Methods: The datum was collected prospectively over 2 months as a pilot observational study in a tertiary care center. All proven cases of Russell's viper-envenomated individuals with preliminary CWA data and WBCT were included in the study. The clot wave (CW) of the five individuals, which met all the stringent inclusion criteria, was analyzed and interpreted. Results: CW absorbance sigmoid waveform was deranged in all 5 cases, of which 4 showed a change in CWA even before an abnormal aPTT. Three of the 5 had a normal WBCT but showed early changes in CWA. Atypical biphasic waveform reported in disseminated intravascular coagulation in other prior studies is seen in venom-induced consumptive coagulopathy also. In all patients where a second derivative was plotted, the second (lower) phase of the second derivative showed a slow rise to baseline. Conclusion: CWA showed changes which provided information earlier than the conventional coagulation studies in the snakebite victims studied. While aPTT or WBCT reflects clotting time, CWA conveys the dynamic process of clot formation and stabilization. CWA may reveal disorders of clotting in snakebite victims before the conventional tests become abnormal. Future research should assess the speed and accuracy of the test in diagnosing hemotoxic envenomation and its potential role in guiding antivenom therapy