Click chemistry in automated synthsis of 96-product library with solid-supported catalyst

First published on April 28, 2010

Girard et al, Molecules, doi:10.3390/molecules15053087

After a 2006 report (Org. Lett. 8, 1689) on a solid phase supported Copper (1+) catalyst for alkyne-azide click reaction ), this article showcases the use of the catalyst system in an automated synthesis of a 96 product-sized triazole library.

Several interesting things. First, they use the automated chemical synthesis station for high-throughput (ChemSpeed ASW-2000). Second, HNMR monitoring of the click reaction was an elegant kinetics measurement. Third, the stability and recycled use of the catalyst are impressive – 5 cycles over 5 days!

At least two questions can be asked. First, Cu(1+) leaching may still be a problem in certain applications / systems / solvents. Second, the resin swelling was not considered in the solvent effect for the click reaction.
An ideal solid-supported catalyst needs have the following: Cu(1+) should be chelated in a kinetically / thermodynamically stable complex for zero leaching yet highly reactive in catalysis; the immobilization should allow reaction components to access the catalyst easily; the resin should be insensitive to solvent choice, preferably including water.
A long way to go!
                          

Click chemistry reagents offerings from Novabiochem / EMD

Novabiochem Letters 2010, No. 1/10

The peptide giant, Novabiochem Brand from EMD, opened its click chemistry reagents offerings in peptide synthesis proucts lines. Newly availabe are a range of suitably protected amino acids bearing azide or terminal alkyne functionalities, in addition to some intermediates bearing these functional groups. They are designed for click chemistry ligations which possess the following features and benefits:
*High yielding ligation in aqueous media
*Orthogonal to standard methods of ligation
*Building blocks compatible with standard Fmoc SPPS methods

Notably, one caution was given that thiols lead to azide reduction.

Previously a list of click reagents vendors was given -
http://clickchemistry.blogspot.com/2010/02/click-chemistry-reagent-vendors-matter.html

This list is expected to grow - and that is only good news to our click chemistry users!
                                                                 

Click chemistry blog listed in Nature.com Blog

April 26th, 2010.

Click chemistry blog is listed now in Nature.com Blog.

Sincere thanks to the Nature.com Bloggers for the evaluation.  

And thanks to the readers - you are the purpose.

Hope the blog would be a good service to the community.

Believe me, click chemistry has a lot more to offer.
                      

Click chemistry between Nitrile N-Oxide and alkyne for polyrotaxanes

Macromolecules, DOI: 10.1021/ma100262g First published: April 2, 2010 Toshikazu Takata et al.

Click chemistry is more than alkyne-azide reaction - this article demonstrates a click chemistry using unstable and stable homoditopic nitrile N-oxides. Nitrile N-oxide was generated in situ through the reaction of the corresponding hydroxamoyl chloride with 4-Angstrom molecular sieves and was subjected to click reaction with alkynes. A kinetically stabilized homoditopic nitrile N-oxide was also developed for the same purpose. 

Polyrotaxane, a new class of polymer characterized by the mechanical linkage of its components, shows unique physical, chemical, mechanical, and rheological properties. Preparation of these sophisticated supramolecular systems requires powerful, highly reliable, and selective reactions. The above click chemistry is applied for the preparation of main-chain-type polyrotaxanes. The rotaxanation - polymerization by this click chemistry provides remarkable advantage of avoidance of catalyst contamination which exists in alkyne-azide click chemistry.

41683db89073a95b33ef8372d9df0f2c              

Click chemistry assembled HNO sensor in live cells

Joel Rosenthal, Stephen J Lippard
J. Am. Chem. Soc. 
DOI: 10.1021/ja909148v
First published: March 31, 2010

Unlike nitric oxide (NO) which earned prominent position in biological and medical world, other RNS (reactive nitrogen species) received less attention - least in the case of nitroxyl (HNO). However, HNO displays important biological roles with potential pharmacological applications related to K+ channels in mammalian vascular systems. A biologically compatible probe fo HNO would help the current status significantly. 

The authors came up with the Cu(2+)-complex shown in the figure. BODIPY dye - azide and tridentate amine - alkyne undergoes the click chemistry to form the triazole linkage which holds the sensing fluorophore and chelating metal complex in close proximity. One nitrogen atom from the triazole ring participates in the chelation of Cu(2+) as well. The molecules was characterizaed by ESI MS, titration, and spectroscopy.

HNO, when present in aqueous buffer or live HeLa cells, reduces Cu2+ to Cu1+ (EPR evidence and others) and fluorescence rises significantly at 526nm (4-fold) by removing Cu2+ quenching of BODIPY dye. Controls demonstrate that the other RNSs do not interfere: NO3(3-), NO2(1-), ONO2(1-), OCl(1-), H2O2, NO, SNOC. 

Interesting case where click chemistry and triazole moiety are ued in fluorogenic detection, fluorophore - quencher linker, metal-chelation, probing molecules of biological or pharmocological significance, etc.                           
                      

Post-assembly click chemistry in DNA origami structure

Kurt Vesterager Gothelf et al, Nature Nanotechnology, 2010, Vol 5, 200. First published online on February 28th.

Seeman and others have turned DNA nanostructures or DNA origami into a fascinating science with extraordinary structural features and with developing applications and potentials in many fields. This publication demonstrates that chemical reactions with single molecules can be performed and imaged at a local position on a DNA origami scaffold by atomic force microscopy via direct detection of Streptavidin anchored onto the nanostructure by biotins.


The biotins are incorporated into the DNA origami via acetylene-azide click chemistry and others. The high yields and chemoselectivities achieved in these reactions demonstrate the feasibility of post-assembly chemical modification of DNA nanostructures. This report opens the door for many applications in biotechnology and materials science since the design and formation of DNA origami is getting mature enough and now post-assembly reactions allow workers to reliably conjugate / insert the molecules of interest in a spatially controlled manner.

One of the many good uses of Huisgen–Sharpless–Meldal copper(I)-catalysed click chemistry. 
        

Click chemistry book review - 1,3-dipolar cycloaddition reactions and unplanned click chemistry implications

Padwa & Pearson
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products (Chemistry of Heterocyclic Compounds: a Series of Monographs)

Click chemistry is soaring and the most prominent ones are cycloaditions such as Diels-Alder and alkyne-azide reactions which often meet the stringent requirements for click reactions. In this background it is interesting to read this 1,3-dipolar cycloaddition book which was finished right before the birth of click chemistry concept.

In 940 pages, the many types of 1,3-dipolar cycloaddition reactions (1984-2000) were covered, with emphasis on the applications in real organic synthesis, either natural products or otherwise. Two other features are well covered as well: the transformation of cycloaddition products into other forms of products and stereochemistry of these cycloaddition reactions.

There might be an unplanned rewarding outcome - we are almost certain that some of reactions described here will be brought in for click chemistry candidates.