Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides

Recent research in medicinal chemistry suggests a correlation between an increase in the fraction of sp3 carbons in drug candidates with their improved success rate in clinical trials. As such, the development of robust and selective methods for the construction of C(sp3)-C(sp3) bonds remains a critical problem in modern organic chemistry. Owing to the broad availability and synthetic accessibility of alkyl halides, their direct cross coupling—commonly known as cross-electrophile coupling (XEC)—provides a promising route toward this objective. However, achieving high selectivity in C(sp3)-C(sp3) XEC remains a largely unmet challenge. Herein, we employ electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution (SN2) to forge a new C–C bond. This transition-metal free protocol enables the efficient XEC of a variety of functionalized and unactivated alkyl electrophiles and exhibits substantially improved chemoselectivity versus existing methodologies.

Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides

Recent research in medicinal chemistry suggests a correlation between an increase in the fraction of sp3 carbons in drug candidates with their improved success rate in clinical trials. As such, the development of robust and selective methods for the construction of C(sp3)-C(sp3) bonds remains a critical problem in modern organic chemistry. Owing to the broad availability and synthetic accessibility of alkyl halides, their direct cross coupling—commonly known as cross-electrophile coupling (XEC)—provides a promising route toward this objective. However, achieving high selectivity in C(sp3)-C(sp3) XEC remains a largely unmet challenge. Herein, we employ electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution (SN2) to forge a new C–C bond. This transition-metal free protocol enables the efficient XEC of a variety of functionalized and unactivated alkyl electrophiles and exhibits substantially improved chemoselectivity versus existing methodologies.

Structural Basis for an Unprecedented Enzymatic Alkylation in Cylindrocyclophane Biosynthesis

The cyanobacterial enzyme CylK assembles the cylindrocyclophane natural products by performing two unusual alkylation reactions, forming new carbon-carbon bonds between aromatic rings and secondary alkyl halide substrates. This transformation is unprecedented in biology and the structure and mechanism of CylK are unknown. Here, we report x-ray crystal structures of CylK, revealing a distinctive fusion of a Ca2+ binding domain and a β-propeller fold. We use a mutagenic screening approach to locate CylK’s active site at its domain interface, identifying two residues, Arg105 and Tyr473, that are required for catalysis. Anomalous diffraction datasets collected with bound bromide ions, a product analog, suggest these residues interact with the alkyl halide electrophile. Additional mutagenesis and molecular dynamics simulations implicates Asp440 and Glu374 in activating the nucleophilic aromatic ring. Bioinformatic analysis of CylK homologs from other cyanobacteria establishes that they conserve these key catalytic amino acids but they are likely associated with divergent reactivity and altered secondary metabolism. By gaining a molecular understanding of this unusual biosynthetic transformation, this work fills a gap in our understanding of how alkyl halides are activated and used by enzymes as biosynthetic intermediates, informing enzyme engineering, catalyst design, and natural product discovery.

Investigation of halloysite nanotubes and Schiff base combination with deposited copper iodide nanoparticles as a novel heterogeneous catalytic system

The design, preparation and characterization of a novel composite based on functionalization of halloysite nanoclay with Schiff base followed by immobilization of copper iodide as nanoparticles is revealed. This novel nano composite was fully characterized by utilization of FTIR, SEM/EDX, TGA, XRD and BET techniques. This Cu(I) NPs immobilized onto halloysite was successfully examined as a heterogeneous, thus easily recoverable and reusable catalyst in one of classist organic name reaction so-called “Click Reaction”. That comprised a three component reaction of phenylacetylene, α-haloketone or alkyl halide and sodium azide in aqueous media to furnish 1,2,3‐triazoles in short reaction time and high yields. Remarkably, the examination of the reusability of the catalyst confirmed that the catalyst could be reused at least six reaction runs without appreciable loss of its catalytic activity.

Synthesis of heterocyclic ring (1,2,4-triazole) as polystyrene photo stabilizer

New heterocyclic compounds contain triazole ring (play very important role in photostabilization as UV absorber) synthesized by reaction between the di Schiff base (compound 3) with aromatic alkyl halide (Benzyl bromide) and shows there activity as photostabilizer for polystyrene through exposure to the UV-Light (300 hours). Finally Infrared spectroscopy, 1H-NMR, 13C-NMR and instrumental methods were used to characterize products and their structures.

Synthesis, characterization and photostability study of triazole derivatives

heterocyclic derivative contain triazole ring was synthesized and characterized the product and their structures by infrared spectroscopy, 1H-NMR, 13C-NMR and instrumental techniques. Compound (4) was synthesized by reacting of Schiff base (3) with an three moles of alkyl halide (p-phenyl phenacyl bromide). Final product played an important role in photostabilizer of polymer (PS), and showed the activity as a photostabilizer when exposed to UV light (300 hours).

Synthesis and Biological Evaluation of Trehalose Glycolipids

<p>Numerous α,α-trehalose diesters have been isolated from bacteria such as Mycobacteria and Corynebacteria, and more recently from Caenorhabditis elegans dauer larvae. Although these glycolipids are thought to confer protection to the bacteria and larvae against harsh environmental conditions, it is the biological activities of these compounds, including anti-tumour and adjuvant activities, which have been of major interest to scientists over recent years. In this thesis, three different aspects relating to the synthesis and testing of defined trehalose glycolipids will be presented. First, the synthesis of a variety of fatty acid trehalose diesters (TDEs) with varying lipid lengths was performed and the ability of these glycolipids to activate macrophages was studied. Two different synthetic strategies were employed to attain the TDEs of interest and it was observed that lipid lengths of more than 18 carbons were required for macrophage activation. Furthermore, the C22 fatty acid trehalose monoester (TME) and the C26 TME were also synthesised and interestingly they both showed macrophage activation abilities, with subsequent studies indicating that like TDEs, the TMEs were also ligands for mincle, a C-type lectin found on macrophages. This is the first time that TMEs have been tested for their ability to activate macrophages via Mincle. The cytotoxicity of these compounds and subsequent anti-tumour activity of a few selected compounds were also studied and although the TDEs and TMEs did not exhibit any significant cytotoxicity, in in vivo models the C10 TDE and C22 TDE both showed anti-tumour activity. This depicts that the mechanism for anti-tumour activity of these compounds is not due to cytotoxicity but due to as yet unidentified pathway. Methodology that can be applied to the synthesis of more complex trehalose glycolipids, such as trehalose dicorynomycolates (TDCMs, isolated from Corynebacteria) and trehalose dimycolates (TDMs, isolated from Mycobacteria) was also explored. One of the key steps frequently used in the synthesis of these glycolipids is the Fráter-Seebach alkylation. To improve the efficacy of this methodology allylic iodides, rather than alkyl iodides were used for theα-alkylation of β-hydroxy esters. Our results showed that for all substrates studied, the yield of the α-alkylation was greatly improved when the allylic, rather that the alkyl halide was used. The use of this methodology in the synthesis of trehalose monocorynomycolate (TMCM) was also investigated. The third aspect of this thesis focuses on the use of Affinity Based Proteome Profiling (AƒBPP) for elucidating the receptors that TDMs bind to upon interacting with host cell. AƒBPP focuses on using small molecules which mimic the natural substrate for a particular protein and through the use of ‘trap’ and ‘tag’ groups on the molecule the identity of the protein/receptors can be determined. The synthesis of a TDM probe containing a benzophenone ‘trap’ group and an alkyne ‘tag’ group will be discussed.</p>

Synthesis and Biological Evaluation of Trehalose Glycolipids

<p>Numerous α,α-trehalose diesters have been isolated from bacteria such as Mycobacteria and Corynebacteria, and more recently from Caenorhabditis elegans dauer larvae. Although these glycolipids are thought to confer protection to the bacteria and larvae against harsh environmental conditions, it is the biological activities of these compounds, including anti-tumour and adjuvant activities, which have been of major interest to scientists over recent years. In this thesis, three different aspects relating to the synthesis and testing of defined trehalose glycolipids will be presented. First, the synthesis of a variety of fatty acid trehalose diesters (TDEs) with varying lipid lengths was performed and the ability of these glycolipids to activate macrophages was studied. Two different synthetic strategies were employed to attain the TDEs of interest and it was observed that lipid lengths of more than 18 carbons were required for macrophage activation. Furthermore, the C22 fatty acid trehalose monoester (TME) and the C26 TME were also synthesised and interestingly they both showed macrophage activation abilities, with subsequent studies indicating that like TDEs, the TMEs were also ligands for mincle, a C-type lectin found on macrophages. This is the first time that TMEs have been tested for their ability to activate macrophages via Mincle. The cytotoxicity of these compounds and subsequent anti-tumour activity of a few selected compounds were also studied and although the TDEs and TMEs did not exhibit any significant cytotoxicity, in in vivo models the C10 TDE and C22 TDE both showed anti-tumour activity. This depicts that the mechanism for anti-tumour activity of these compounds is not due to cytotoxicity but due to as yet unidentified pathway. Methodology that can be applied to the synthesis of more complex trehalose glycolipids, such as trehalose dicorynomycolates (TDCMs, isolated from Corynebacteria) and trehalose dimycolates (TDMs, isolated from Mycobacteria) was also explored. One of the key steps frequently used in the synthesis of these glycolipids is the Fráter-Seebach alkylation. To improve the efficacy of this methodology allylic iodides, rather than alkyl iodides were used for theα-alkylation of β-hydroxy esters. Our results showed that for all substrates studied, the yield of the α-alkylation was greatly improved when the allylic, rather that the alkyl halide was used. The use of this methodology in the synthesis of trehalose monocorynomycolate (TMCM) was also investigated. The third aspect of this thesis focuses on the use of Affinity Based Proteome Profiling (AƒBPP) for elucidating the receptors that TDMs bind to upon interacting with host cell. AƒBPP focuses on using small molecules which mimic the natural substrate for a particular protein and through the use of ‘trap’ and ‘tag’ groups on the molecule the identity of the protein/receptors can be determined. The synthesis of a TDM probe containing a benzophenone ‘trap’ group and an alkyne ‘tag’ group will be discussed.</p>

Structural Basis for the Friedel-Crafts Alkylation in Cylindrocyclophane Biosynthesis

The Lewis acid-catalyzed Friedel-Crafts alkylation of an aromatic ring with an alkyl halide is extensively used in organic synthesis. However, its biological counterpart was not reported until the elucidation of the cylindrocyclophane biosynthetic pathway in Cylindrospermum licheniforme ATCC 29412 by Balskus and co-workers. CylK is the key enzyme to catalyze the formation of the cylindrocyclophane scaffold through the Friedel-Crafts alkylation reactions with regioselectivity and stereospecificity. Further research demonstrates that CylK can accept other resorcinol rings and secondary alkyl halides as substrates. To date, the crystal structure of CylK has not been disclosed and the catalytic mechanism remains obscure. Herein we report the crystal structures of CylK in its apo form and its complexes with the analogues of its substrate and reaction intermediate. Combining the crystal structures, free energy simulations and the mutagenesis experiments, we proposed a concerted double-activation mechanism, which could explain the regioselectivity and stereospecificity. This work provides a foundation for engineering CylK as a biocatalyst to expand its substrate scope and applications in organic synthesis.

Agar Extraction, Physical Properties, FTIR Analysis and Biochemical Composition of Three Edible Species of Red Seaweeds Gracilaria corticata (J. Agardh), Gracilaria dentata (J. Agardh) and Gracilariopsis longissima (S. G. Gmelin)........

Three species of red algae Gracilaria corticata (J. Agardh), Gracilaria dentata (J. Agardh) and Gracilariopsis longissima (S.G. Gmelin), Steentoft, L. M; Irvine and Farnham (formerly Gracilaria verrucosa (Hudson) were collected from four different sites (Buleji, Hawks Bay, Manora and Paradise Point) of Karachi coast. The G. corticata was the dominant species and the highest yield of agar was compared to other studied species. The physical properties such as gel temperature, melting temperature, density, viscosity and gel strength showed large variations. Interestingly, the gel temperature, melting temperature, density, and gel strength had the highest value in G. corticata samples collected, while gel viscosity recorded the highest value in G. dentata samples. Intensive spectroscopic FTIR analysis was determined in all three species of G. corticata, G. dentata and G. longissima. The bands at 414.7/cm to 3917.2/cm represents stretching and bending vibrations of alcohol O-H, amine N-H, alkane C-H, alkyne C=C, nitriles C=N, carboxyl C=O, nitro aromatic N=O, alkane C-C, nitro methane C-N, aliphatic amines C-N, sulfoxides S=O, alkene C-H alkyl halide C-Cl, C-I groups. The ash content of all studied species (G. corticata, G. dentata and G. longissima) was in the range of 20-30%, while the carbohydrate content was in the range of 22-24%. The results of this study suggested the utilization of our natural resources present in Karachi coast. This could be achieved by determining the quantity and quality of agar in the edible species of Gracilaria/Gracilariopsis.