Acyl Imidazole : A Promising Template for Asymmetric Lewis and Brønsted Acid Mediated 1,3-Dipolar Cycloadditions

Construction of chiral complex molecules continues to be a challenge for organic chemists all over the world and to address this challenge numerous methodologies have been developed. 1,3-Dipolar cycloaddition reactions is one such simple and elegant method, which can be employed towards the construction of chiral heterocycles. The ability to construct multiple stereocenters in one operation is one of the salient features of dipolar cycloaddition reaction. Asymmetric dipolar cycloaddition via chiral Lewis or Bronsted acid catalyzed processes is aided by the development of various templates, which provide points of attachment for these catalyst. Application of acyl imidazoles as multifunctional templates has been investigated for Lewis and Bronsted acid catalyzed 1,3-dipolar cycloaddition of azomethine imines and nitrones. Chapter 1. A review of 1,3-dipolar cycloaddition towards to construction of chiral nitrogen containing heterocycles is discussed in this chapter. This chapter intends to provide the reader a current state of asymmetric 1,3-dipolar cycloaddition. Chapter 2. Development of exo and enantioselective Cu(II) catalyzed azomethine imine cycloaddition to pyrazolidinone acrylates is discussed in this chapter. The key issues approached in this chapter includes impact of metal geometry on diastereoselectivity as well as effect of N-l and C-5 substitution on enantioselectivity of cycloadducts. Investigation into the scope and limitation of azomethine imines and dipolarophiles has also been discussed. Chapter 3. This chapter introduces acyl imidazoles as multifunctional template for asymmetric azomethine imine cycloaddition. Limitation of substrate scope for azomethine imine cycloaddition encountered in the previous chapter has been resolved by the use of acyl imidazoles as templates. Synthesis of complementary diastereomers of azomethine imine cycloadducts via Lewis acid and Bronsted acid catalyzed reactions has been discussed in this chapter. Chapter 4. This chapter highlights the application of acyl imidazoles as template for first Bronsted acid catalyzed exo and enantioselective nitrone cycloaddition to electron deficient olefins. Study of appropriate chiral Bronsted acid and investigation of breadth and scope of nitrones and dipolarophiles has also been discussed here. Chapter 5. This chapter address one of the most challenging aspect of synthetic organic chemistry namely the construction of chiral quaternary stereocenters. This study highlights chiral Bronsted catalyzed nitrone cycloaddition to p,|3-disubstituted-a,P-unsaturated acyl imidazole leading to the formation of isoxazolidines with chiral quaternary stereocenter. This methodology is useful for the construction of chiral fluorinated heterocycles

DC motor position and speed tracking (PAST) system using neural networks

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High-Throughput Screening for Bacterial Glycosyltransferase Inhibitors

This work is licensed under a Creative Commons Attribution 4.0 International License.The enteropathogenic and enterohemorrhagic Escherichia coli NleB proteins as well as the Salmonella enterica SseK proteins are type III secretion system effectors that function as glycosyltransferase enzymes to post-translationally modify host substrates on arginine residues. This modification is unusual because it occurs on the guanidinium groups of arginines, which are poor nucleophiles, and is distinct from the activity of the mammalian O-linked N-acetylglucosaminyltransferase. We conducted high-throughput screening assays to identify small molecules that inhibit NleB/SseK activity. Two compounds, 100066N and 102644N, both significantly inhibited NleB1, SseK1, and SseK2 activities. Addition of these compounds to cultured mammalian cells was sufficient to inhibit NleB1 glycosylation of the tumor necrosis factor receptor type 1-associated DEATH domain protein. These compounds were also capable of inhibiting Salmonella enterica strain ATCC 14028 replication in mouse macrophage-like cells. Neither inhibitor was significantly toxic to mammalian cells, nor showed in vitro cross-reactivity with the mammalian O-linked N-acetylglucosaminyltransferase. These compounds or derivatives generated from medicinal chemistry refinements may have utility as a potential alternative therapeutic strategy to antibiotics or as reagents to further the study of bacterial glycosyltransferases.National Institute of Allergy and Infectious Diseases grant number AI127973COBRE P20GM113117COBRE P20GM103638CMLD Legacy (GM111385) gran

High-Throughput Screening for Bacterial Glycosyltransferase Inhibitors

The enteropathogenic and enterohemorrhagic Escherichia coli NleB proteins as well as the Salmonella enterica SseK proteins are type III secretion system effectors that function as glycosyltransferase enzymes to post-translationally modify host substrates on arginine residues. This modification is unusual because it occurs on the guanidinium groups of arginines, which are poor nucleophiles, and is distinct from the activity of the mammalian O-linked N-acetylglucosaminyltransferase. We conducted high-throughput screening assays to identify small molecules that inhibit NleB/SseK activity. Two compounds, 100066N and 102644N, both significantly inhibited NleB1, SseK1, and SseK2 activities. Addition of these compounds to cultured mammalian cells was sufficient to inhibit NleB1 glycosylation of the tumor necrosis factor receptor type 1-associated DEATH domain protein. These compounds were also capable of inhibiting Salmonella enterica strain ATCC 14028 replication in mouse macrophage-like cells. Neither inhibitor was significantly toxic to mammalian cells, nor showed in vitro cross-reactivity with the mammalian O-linked N-acetylglucosaminyltransferase. These compounds or derivatives generated from medicinal chemistry refinements may have utility as a potential alternative therapeutic strategy to antibiotics or as reagents to further the study of bacterial glycosyltransferases

Probing Chemical Space with Alkaloid-Inspired Libraries

Screening of small molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries, due to their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin, and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant