抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/1521-3773%2820010601%2940%3A11%3C2004%3A%3AAID-ANIE2004%3E3.0.CO%3B2-5

Click Chemistry: Diverse Chemical Function from a Few Good Reactions.

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

2.1. Kinetic Resolution of Alcohols and Amines 2987 2.2. Ketene Acylation 2995 2.3. Cycloadditions 2996 2.3.1. â-Lactone Formation 2996 2.3.2. â-Lactam Formation 2997 2.3.3. Ketene Dimerization 2999 2.4. Halogenation 3000 2.5. Baylis−Hillman Reactions 3000 2.6. Desymmetrization of Cyclic Anhydrides 3002 2.7. C-Acylation 3004 2.8. Cyanation 3004 3. Solid Phase Chemistry 3007 3.1. Solution Catalysis 3007 3.2. Catalysis on Sequentially-Linked Columns 3008 4. Conclusion 3009 5. References 3009

/pdf/nucleophilic-chiral-amines-as-catalysts-in-asymmetric-oc4ic21tzv.pdf

Nucleophilic Chiral Amines as Catalysts in Asymmetric Synthesis

We report practical methodology for the catalytic, asymmetric synthesis of β-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the β-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.

The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of β-Lactams

In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature’s catalysts, enzymes In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increase

/pdf/bifunctional-asymmetric-catalysis-cooperative-lewis-acid-4fmsds5obo.pdf

Bifunctional Asymmetric Catalysis: Cooperative Lewis Acid/Base Systems

Bis(oxazoline)copper(II) complexes are highly enantioselective catalysts in Diels−Alder reactions involving bidentate dienophiles. Cationic [Cu((S,S)-t-Bu-box)]X2 complexes with different counterions have been used as catalysts, revealing a profound influence of the counterion on the rate and stereoselectivity of the catalyst. A square-planar catalyst−substrate complex is proposed to account for the high diastereo- and enantioselectivities observed. Three bis(oxazoline)−Cu(II) X-ray structures have been obtained that support this model. Double-stereodifferentiating experiments, performed employing chiral dienophiles, afforded results that are fully consistent with the proposed square-planar transition-state assemblage. In addition to imide-based substrates, α,β-unsaturated thiazolidine-2-thiones have been introduced as a new class of dienophiles with enhanced reactivity. Kinetics experiments were performed to quantify the role that product inhibition plays in the course of the reaction. Rate and equilibri...

Chiral bis(oxazoline)copper(ii) complexes as lewis acid catalysts for the enantioselective diels-alder reaction

Cz-symmetric bis(oxazo1ine)copper complexes have proven to be excellent catalysts for enantioselective olefin cyclopropanation2 and aziridination.3 In addition, Corey has demonstrated that the Mg(I1) and Fe(II1) complexes4of thesesameligandsshow promise as chiral Lewis acid catalysts for the Diels-Alder reactions of unsubstituted acrylimides. The purpose of this communication is to report our observations on the utility of chiral Cu(1I) bis(oxazoline) complexes as Lewis acids in the catalysis of these reactions. Attractive attributes of this catalyst system include an expanded scope of utilizable dienophiles and a clearly interpretable geometry for the catalyst-dienophile complex which rationalizes the sense of asymmetric induction for the cycloaddition process.

Thomas Lectka

Papers

Nucleophilic Chiral Amines as Catalysts in Asymmetric Synthesis

The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of β-Lactams

Bifunctional Asymmetric Catalysis: Cooperative Lewis Acid/Base Systems

Chiral bis(oxazoline)copper(ii) complexes as lewis acid catalysts for the enantioselective diels-alder reaction

Bis(oxazoline)copper(II) complexes as chiral catalysts for the enantioselective Diels-Alder reaction