A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes.

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.

/pdf/self-assembled-monolayers-of-thiolates-on-metals-as-a-form-1neb0hj3k4.pdf

Self-assembled monolayers of thiolates on metals as a form of nanotechnology.

Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

/pdf/in-situ-click-chemistry-generation-of-cyclooxygenase-2-zyy8rhnlnx.pdf

In situ click chemistry generation of cyclooxygenase-2 inhibitors

3.2.3. Hydroformylation 2467 3.2.4. Dimerization 2468 3.2.5. Oxidative Cleavage and Ozonolysis 2469 3.2.6. Metathesis 2470 4. Terpenes 2472 4.1. Pinene 2472 4.1.1. Isomerization: R-Pinene 2472 4.1.2. Epoxidation of R-Pinene 2475 4.1.3. Isomerization of R-Pinene Oxide 2477 4.1.4. Hydration of R-Pinene: R-Terpineol 2478 4.1.5. Dehydroisomerization 2479 4.2. Limonene 2480 4.2.1. Isomerization 2480 4.2.2. Epoxidation: Limonene Oxide 2480 4.2.3. Isomerization of Limonene Oxide 2481 4.2.4. Dehydroisomerization of Limonene and Terpenes To Produce Cymene 2481

Chemical Routes for the Transformation of Biomass into Chemicals

Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of organic chemists as the most commonly used S(VI) electrophiles, and the parent sulfuryl chloride, O2 S(VI) Cl2 , has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S(VI) Cl bond is exceedingly sensitive to reductive collapse yielding S(IV) species and Cl(-) . Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2 -F and SO2 F2 ) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany.6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here we seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2 CH-SO2 -F, the most perfect Michael acceptor ever found.98 To this history we add several new observations, including that the otherwise very stable gas SO2 F2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.

Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

Catalytic Asymmetric Aminohydroxylation (AA) of Olefins

Preparation de dioxyde-2,2 de dioxathiolannes-1,3,2(I) a partir de glycols et reactions des sulfates cycliques(I) avec divers nucleophiles (H − , N 3 − , F − , PhCO 2 − , NO 3 − , SCN − , PhCH 2 − )

Vicinal diol cyclic sulfates. Like epoxides only more reactive

The search for new metal-catalyzed asymmetric reactions has provided some fascinating insights into the effects imposed on the metal catalysts by chiral ligands. A practical consequence is the discovery of ligand-accelerated catalysis (LAC). Thus, an existing catalyzed process is improved by the addition of a specific ligand, which leads to a faster, “ligand-accelerated” reaction. Both homogeneous and heterogeneous catalysts are known to exhibit this behavior. The concept is especially valuable in reactions catalyzed by early transition metals, where dynamic ligand exchange processes require an efficient in situ self-selection of a highly reactive catalyst from a variety of thermodynamically dictated assemblies. Results of detailed mechanistic studies will be presented, and the significance of LAC phenomena in transformations catalyzed by early and late transition metals will be discussed.

Ligand-Accelerated Catalysis

The processes for the selective oxidation of olefins have long been among the most useful tools for day-to-day organic synthesis. Herein, the focus is on the asymmetric-epoxidation (AE) and asymmetric-dihydroxylation (AD) reactions developed by Sharpless and co-workers. The reactions have a wide scope, are simple to run, and involve readily available starting materials. Ligand-accelerated catalysis is crucial to these reactions and might be the agent for uncovering more catalytic processes. In addition to the selectivity benefits of catalysis, the phenomenon of turnover (amplification) raises its potential impact. The author and his co-workers developed small, highly enantioselective catalysts that were unfettered by the "lock-and-key" selectivity of Natures enzymes, and tolerant of substrates throughout the entire range of olefin substitution patterns.

K. Barry Sharpless

Papers

Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

Catalytic Asymmetric Aminohydroxylation (AA) of Olefins

Vicinal diol cyclic sulfates. Like epoxides only more reactive

Ligand-Accelerated Catalysis

Searching for New Reactivity (Nobel Lecture)