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A new method for the cyanation of thiols and disulfides using cyanobenziodoxol(on)e hypervalent iodine reagents is described. Both aliphatic and aromatic thiocyanates can be accessed in good yields in a few minutes at room temperature starting from a broad range of thiols with high chemioselectivity. The complete conversion of disulfides to thiocyanates was also possible. Preliminary computational studies indicated a low energy concerted transition state for the cyanation of the thiolate anion or radical. The developed thiocyanate synthesis has broad potential for various applications in synthetic chemistry, chemical biology and materials science.

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking. In this article, we describe the mechanism and full scope of the alkynylation of thiols using ethynyl benziodoxolone (EBX) hypervalent iodine reagents. Computations led to the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of thioalkynes.

The first total synthesis of the alkaloid natural product jerantinine E is based on a selective cyclization of an aminocyclopropane. Preliminary investigations show that it inhibits the polymerization of tubulin, displaying significant cytotoxicity and antimigratory activity against both breast and lung cancer cell lines.

A thiol-alkynylation procedure utilizing the hypervalent iodine alkyne transfer reagent TIPS-ethynyl-benziodoxolone has been developed. This scalable reaction proceeds in five minutes at room temperature in an open flask using commercially available reagents. The scope of the reaction is broad, with a variety of phenolic, benzylic, heterocyclic, and aliphatic thiols undergoing alkynylation in excellent yield. The method is highly chemoselective as a vast array of functional groups are tolerated. The utility of the thiol-alkynylation in postsynthetic elaboration has been demonstrated through the facile installment of a fluorophore tag on a cysteine-containing peptide.

The reaction between (3-aminopropyl)dimethylmethoxysilane (APDMS) with silica and silsesquioxane 3,5,7,9,11,13,15-heptacyclopentylpentacyclo[9.5.1.1(3,9).1(5,15).1(7,13)]octasiloxan-1-ol was studied in hexane and tetrahydrofuran (THF) using experimental (reaction kinetics, FTIR) and quantum chemistry methods. In hexane at temperatures above 245 K, the reaction rate decreases with increasing temperature due to a reduction of prereaction complex formation at higher temperature. Below 245 K the reaction itself is rate limiting, resulting in a reaction rate decrease with decreasing temperature. The reaction occurs much faster in hexane than in THF in part because of stronger competitive effects of the O-containing polar solvent with the formation of APDMS/silsesquioxane prereaction complexes due to hydrogen bonding. Analysis of the experimental data and computational results suggest that the catalytic reaction is second-order with respect to APDMS, the second APDMS molecule plays the role of catalyst. Estimation of the activation energy using dynamic calculations give results much more in agreement with experiment than nondynamic calculations, since the limiting H(+) transfer stage occurs so quickly (approximately 15 fs) that displacements of other atoms are insignificant to the activation energy.

Improving the synthesis of complex organic molecules is essential for progress in many fields such as medicine, agrochemicals or materials. Since 2007, our laboratory has been focusing on the development of non-classical bond disconnections based on the use of small, energy-loaded organic molecules: hypervalent iodine reagents and strained rings. In this overview article, we report our progress since 2011 in these areas. The use of cyclic hypervalent iodine reagents has been extended to the C2-selective alkynylation of indoles, the domino cyclization alkynylation of allenes, the alkynylation of thiols and the azidation of carbonyl compounds. Amino-substituted aminocyclopropanes and aminocyclobutanes were used in [3+2] and [4+2] annulations to access nitrogen-rich building blocks, including nucleoside analogues. The first example of dynamic kinetic [3+2] annulation of aminocyclopropanes with both enol ethers and aldehydes was also reported.

A new method for the cyanation of thiols (I), (VI), and disulfides (IX) using cyanobenziodoxol(on)e hypervalent iodine reagents, such as (II) and (VII) is described.

The reaction tolerates alkyl and aryl ethynyl substituted benziodoxolone reagents equipped with various functional groups.

In this study, we present a highly efficient method for proteomic profiling of cysteine residues in complex proteomes and in living cells. Our method is based on alkynylation of cysteines in complex proteomes using a "clickable" alkynyl benziodoxolone bearing an azide group. This reaction proceeds fast, under mild physiological conditions, and with a very high degree of chemoselectivity. The formed azide-capped alkynyl-cysteine adducts are readily detectable by LC-MS/MS, and can be further functionalized with TAMRA or biotin alkyne via CuAAC. We demonstrate the utility of alkynyl benziodoxolones for chemical proteomics applications by identifying the proteomic targets of curcumin, a diarylheptanoid natural product that was and still is part of multiple human clinical trials as anticancer agent. Our results demonstrate that curcumin covalently modifies several key players of cellular signaling and metabolism, most notably the enzyme casein kinase I gamma. We anticipate that this new method for cysteine profiling will find broad application in chemical proteomics and drug discovery.

Cyclization and annulation reactions initiated by ring-opening of small rings, especially cyclopropanes and cyclobutanes are now well-established in synthetic chemistry. Nevertheless, the potential of aminocyclopropanes and cyclobutanes, an important subclass for the synthesis of nitrogen-rich building blocks, has remained unexploited for a long time, despite important pioneering results. In the last decade, the situation has changed dramatically and new catalytic methods have emerged both for cyclization and annulation reactions. The purpose of this feature article is to present recent progress in this area, including our own work using donor-acceptor cyclopropanes and cyclobutanes.

The first total synthesis of the target compound in 17 steps and 16% overall yield is reported.

A thiol-alkynylation procedure applies a hypervalent iodine alkyne agent and can be applied to a wide range of aromatic, aliphatic, heteroaromatic thiols as well as to cysteines and peptides.

We report the highly efficient syntheses of a series of focused libraries in the small molecule macroarray format using Suzuki–Miyaura and copper-catalyzed azide–alkyne cycloaddition (or “click”) reactions. The libraries were based on stilbene and triazole scaffolds, which are known to have a broad range of biological activities, including quorum-sensing (QS) modulation in bacteria. The library products were generated in parallel on the macroarray in extremely short reaction times (∼10–20 min) and isolated in excellent purities. Biological testing of one macroarray library post-cleavage (ex situ) revealed several potent agonists of the QS receptor, LuxR, in Vibrio fischeri. These synthetic agonists, in contrast to others that we have reported, were only active in the presence of the native QS signal in V. fischeri, which is suggestive of a different mode of activity. Notably, the results presented herein showcase the ready compatibility of the macroarray platform with chemical reactions that are commonly utilized in small molecule probe and drug discovery today. As such, this work serves to expand the utility of the small molecule macroarray as a rapid and operationally straightforward approach toward the synthesis and screening of bioactive agents.

We report an approach to preventing bacterial biofilm formation that is based on the surface-mediated release of 5,6-dimethyl-2-aminobenzimidazole (DMABI), a potent and non-bactericidal small-molecule inhibitor of bacterial biofilm growth. Our results demonstrate that DMABI can be encapsulated in thin films of a model biocompatible polymer [poly(lactide-co-glycolide), PLG] and be released in quantities that inhibit the formation of Pseudomonas aeruginosa biofilms by up to 75–90% on surfaces that otherwise support robust biofilm growth. This approach enables the release of this new anti-biofilm agent for over one month, and it can be used to inhibit biofilm growth on both film-coated surfaces and other adjacent surfaces (e.g., on other uncoated surfaces and at air/water interfaces). Our results demonstrate a non-bactericidal approach to the prevention of biofilm growth and provide proof of concept using a clinically relevant human pathogen. In contrast to coatings designed to kill bacteria on contact, this release-based approach should also permit the design of strategically placed depots that disseminate DMABI more broadly and exert inhibitory effects over larger areas, which could prove useful in applications where the design or function of a surface prohibits the application of a uniform coating. This approach could also be used to design new polymer-coated surfaces useful for fundamental studies of bacterial biofilm growth. In a broader context, the non-bactericidal nature of DMABI could also provide opportunities to address concerns related to evolved resistance that currently face approaches based on the release of traditional microbicidal agents (e.g., antibiotics). Finally, the results of initial in vitro mammalian cell culture studies indicate that DMABI is not toxic to cells at concentrations required for strong anti-biofilm activity, suggesting that this new agent is well suited for further investigation in biomedical and personal care contexts. The surface-mediated approach reported here provides new tools useful for fundamental studies of biofilm formation and could, with further development, prove useful in a range of other industrial and commercial contexts in which bacterial biofilm growth is endemic.

A small library of 2-aminobenzimidazole derivatives (III)/(IV) is synthesized to probe their capability of inhibiting growth and dispersing Pseudomonas aeruginosa biofilms.

Bacteria can grow into surface-associated communities termed biofilms that are pervasive virtually everywhere on earth.[1] This mode of growth poses a significant obstacle to the successful treatment of infectious disease, with an estimated 80% of human infections in the biofilm state.[2] Biofilms are particularly problematic to clear due to their encasement in a protective and impermeable extracellular matrix,[3] which render biofilm-associated bacteria resistant to both host immune responses and standard antibiotic agents. Indeed, treatment with ~10-1000-fold higher doses of antibiotic is often required for biofilm clearance relative to planktonic bacteria.[2] Biofilm growth by the Gram-negative bacterium Pseudomonas aeruginosa has attracted particular attention, as biofilms of this pathogen are the origin of the fatal chronic lung infections in most cystic fibrosis patients.[4] P. aeruginosa biofilm infections also plague burn victims, AIDS patients, and are endemic on the medical implants and devices universal in healthcare today.[5] As such, the development of new methods to attenuate bacterial biofilm growth is of significant importance and represents a major research area.[6] Small molecules capable of inhibiting the growth of or removing (i.e., dispersing) preformed biofilms would be extremely useful to combat bacterial infection and in a range of other applications in industry, agriculture, and the environment.[7] Molecules of this class, however, remain rare.[5-8] Here, we report our discovery of a chemical approach for the inhibition and dispersion of P. aeruginosa biofilms based on 2-aminobenzimidazoles.

Objective— To compare the mechanical properties of 2 configurations of a veterinary fixation system (VFS) for large animal long bones with dynamic compression plating (DCP). Sample Population— Eighteen pairs of Canevasit tubes (Canevasit; Amsler und Frei, Schinznach Dorf, Switzerland) (length, 170 mm; diameter, 47.5 mm; cortex thickness, 10 mm), aligned with a 10-mm gap, and stabilized with 2 DCP or 2 VFS implants. Methods— Three groups (n = 6) were compared. Group 1 Canevasit tubes were stabilized with two 10-hole, broad 4.5-mm stainless steel DCP applied with both plates centered over the gap, in orthogonal planes parallel to the long axis of the tubes and staggered to allow bicortical fixation with ten 4.5-mm, 52-mm-long cortex screws each. Group 2 tubes were stabilized similarly with 2 VFS implants, each composed of a stainless steel rod (length, 167 mm; diameter, 8 mm), and 10 clamps were applied in alternating fashion left and right on the rod and fixed bicortically with ten 4.5-mm, 52-mm-long, cortex screws. Group 3 tubes were stabilized similarly, but using only 6 clamps/rod. All groups were tested initially in torsion within elastic limits and subsequently in 4-point bending, with 1 implant on the tension side, until gap closure occurred. Results— None of the constructs failed, but all had plastic deformation after 4-point bending. No statistically significant differences were found among the 3 groups in torsional stiffness. Double DCP fixation was significantly stiffer and stronger in 4-point bending, compared with both configurations of double VFS fixation. Conclusions— The plate design was favored in this study. The VFS system may have to be adapted before further tests are conducted. Test modalities have to be chosen closer to clinical conditions (real bone, cyclic loading, closed gap). Clinical Relevance— The veterinary fixation system has not yet proven its advantages for large animal long bone fracture repair. From the pure mechanical point of view, double DCP is the favored method for the treatment mentioned.

Cyclization and annulation reactions initiated by ring-opening of small rings, especially cyclopropanes and cyclobutanes are now well-established in synthetic chemistry. Nevertheless, the potential of aminocyclopropanes and cyclobutanes, an important subclass for the synthesis of nitrogen-rich building blocks, has remained unexploited for a long time, despite important pioneering results. In the last decade, the situation has changed dramatically and new catalytic methods have emerged both for cyclization and annulation reactions. The purpose of this feature article is to present recent progress in this area, including our own work using donor-acceptor cyclopropanes and cyclobutanes.

Improving the synthesis of complex organic molecules is essential for progress in many fields such as medicine, agrochemicals or materials. Since 2007, our laboratory has been focusing on the development of non-classical bond disconnections based on the use of small, energy-loaded organic molecules: hypervalent iodine reagents and strained rings. In this overview article, we report our progress since 2011 in these areas. The use of cyclic hypervalent iodine reagents has been extended to the C2-selective alkynylation of indoles, the domino cyclization alkynylation of allenes, the alkynylation of thiols and the azidation of carbonyl compounds. Amino-substituted aminocyclopropanes and aminocyclobutanes were used in [3+2] and [4+2] annulations to access nitrogen-rich building blocks, including nucleoside analogues. The first example of dynamic kinetic [3+2] annulation of aminocyclopropanes with both enol ethers and aldehydes was also reported.