Chemoselective Modification of Vinyl DNA by Triazolinediones

A new method for the post‐synthetic modification of nucleic acids was developed that involves mixing a phenyl triazolinedione (PTAD) derivative with DNA containing a vinyl nucleobase. The resulting reactions proceeded through step‐wise mechanisms, giving either a formal [4+2] cycloaddition product, or, depending on the context of nucleobase, PTAD addition along with solvent trapping to give a secondary alcohol in water. Catalyst‐free addition between PTAD and the terminal alkene of 5‐vinyl‐2′‐deoxyuridine (VdU) was exceptionally fast, with a second‐order rate constant of 2×10³ m ⁻¹ s⁻¹. PTAD derivatives selectively reacted with VdU‐containing oligonucleotides in a conformation‐selective manner, with higher yields observed for G‐quadruplex versus duplex DNA. These results demonstrate a new strategy for copper‐free bioconjugation of DNA that can potentially be used to probe nucleic acid conformations in cells.     

Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles from Ethenesulfonyl Fluoride and Organic Azides

The boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts.     

Trifluoroacetic Anhydride Promoted Copper(I)‐Catalyzed Interrupted Click Reaction: From 1,2,3‐Triazoles to 3‐Trifluoromethyl‐Substituted 1,2,4‐Triazinones

A copper(I)‐catalyzed interrupted click reaction in the presence of trifluoroacetic anhydride has been developed, wherein an N‐trifluoroacetyl group is used to accelerate the ring‐opening of the putative 5‐copper(I) triazolide intermediate. Under the optimized reaction conditions, a broad range of azides and alkynes were found to participate in this transformation, thus affording 3‐trifluoromethyl‐substituted 1,2,4‐triazinones in moderate to excellent yields. The reaction has proven to be compatible with a variety of electron‐withdrawing and electron–donating groups, halogens, and nitrogen‐ and sulfur‐containing heterocycles, as well as pharmaceutically relevant molecules.     

Boron‐Containing Probes for Non‐optical High‐Resolution Imaging of Biological Samples

Boron has been employed in materials science as a marker for imaging specific structures by electron energy loss spectroscopy (EELS) or secondary ion mass spectrometry (SIMS). It has a strong potential in biological analyses as well; however, the specific coupling of a sufficient number of boron atoms to a biological structure has proven challenging. Herein, we synthesize tags containing closo‐1,2‐dicarbadodecaborane, coupled to soluble peptides, which were integrated in specific proteins by click chemistry in mammalian cells and were also coupled to nanobodies for use in immunocytochemistry experiments. The tags were fully functional in biological samples, as demonstrated by nanoSIMS imaging of cell cultures. The boron signal revealed the protein of interest, while other SIMS channels were used for imaging different positive ions, such as the cellular metal ions. This allows, for the first time, the simultaneous imaging of such ions with a protein of interest and will enable new biological applications in the SIMS field.     

Photo‐Tethers for the (Multi‐)Cyclic,Conformational Caging of Long Oligonucleotides

Intramolecular circularization of DNA oligonucleotides was accomplished by incorporation of alkyne‐modified photolabile nucleosides into DNA sequences, followed by a Cu^I‐catalyzed alkyne–azide cycloaddition with bis‐azido linker molecules. We determined a range of ring sizes, in which the caged circular oligonucleotides exhibit superior duplex destabilizing properties. Specific binding of a full‐length 90 nt C10 aptamer recognizing human Burkitt's lymphoma cells was then temporarily inhibited by locking the aptamer in a bicircularized structure. Irradiation restored the native aptamer conformation resulting in efficient cell binding and uptake. The photo‐tether strategy presented here provides a robust and versatile tool for the light‐activation of longer functional oligonucleotides, noteworthy without prior knowledge on the structure and the importance of specific nucleotides within a DNA aptamer.     

Unclicking the Click: Metal‐Assisted Mechanochemical Cycloreversion of Triazoles Is Possible

The mechanochemical cycloreversion of 1,2,3‐triazole compounds, which serve as unusually stable building blocks in materials and biomolecular chemistry as a result of mild “click chemistry”, remains puzzling. We show that the hitherto discussed straight‐forward retro‐click mechanism of the 1,4‐disubstituted isomer, even if Cu^I catalyzed, can be ruled out in view of more favorable activation free energies of destructive pathways. In stark contrast, the 1,5‐regioiomer can undergo cycloreversion under rather mild mechanochemical conditions owing to its favorable response to the external force in conjunction with standard Ru^II catalysis.     

Palladium‐Catalyzed Fluorosulfonylvinylation of Organic Iodides

A palladium‐catalyzed fluorosulfonylvinylation reaction of organic iodides is described. Catalytic Pd(OAc)₂ with a stoichiometric amount of silver(I) trifluoroacetate enables the coupling process between either an (hetero)aryl or alkenyl iodide with ethenesulfonyl fluoride (ESF). The method is demonstrated in the successful syntheses of eighty‐eight otherwise difficult to access compounds, in up to 99 % yields, including the unprecedented 2‐heteroarylethenesulfonyl fluorides and 1,3‐dienylsulfonyl fluorides.