Thiol-yne click chemistry

Sounds familiar? "A perusal of the literature from 1940s to 1960s" prompted this new version of click chemistry.

As indicated in the scheme, the double thiol-addition happens in two consecutive steps with the second 3-times faster than the first. The reaction can be driven either by light or radical initiators. Not only it complements established click chemistries such as alkyne-azide and thiol-ene, but also it provides a new feature which enables installation of more functional groups at once. This click chemistry was demonstrated with a few recent examples, either individually or in combination with other click chemitries. It is best suited for construction of dendrimers, networked structures, polymers, and other functional materials. I would expect it to find applications in biotechnology, nanotechnology, surface chemistry,  etc. 

Andrew B. Lowe et al, J. Mater. Chem., 2010, DOI: 10.1039/b917102a
      

Bioorthogonal click chemistry - Carolyn Bertozzi the champion

Chem. Soc. Rev., 2010 DOI: 10.1039/b901970g

Carolyn Bertozzi et al clearly defined the bioorthognal click chemistry. They used this figure to illustrate a general bioorthogonal reaction. Best described: "we must first look at an organic chemistry textbook and remove any reaction that is sensitive to water. Second, with an abundant supply of thiols and amines in the cell, we must also remove reagents that are prone to nucleophilic attack. Third, because of the reducing environment in the cytosol, we have to remove reactions that are sensitive to redox chemistry. If a reaction requires heat (above 37 °C), pressure, or high concentrations to work then it is also unacceptable. Lastly, some functionalities can be digested by cellular enzymes that have an ase in their name (e.g., esterase, phosphatase, sulfatase, etc.). Add reagent toxicity to this list and you will find a select few reactions that remain viable for performance in living systems."

Indeed one needs to be very picky in picking a good bioothogonal reaction from the already- small click chemistry tool box. The review covers the most viable reactions up-to-date, lists their pros and cons, and potentials. The chemistry aspects are detailed, with great insights and perspectives from a mechanistic point of view.

And did I mention the secret - go back to the old dusty organic chemistry toolbox and find treasures, such as click chemistry?
                      

Definition of click chemistry: a reminder

Yes, click chemistry is hot - so hot that it becomes a difficult task to track the huge body of "click chemistry" publications. But let us see how many publication have somewhat misused the term "click chemistry". Some of those uses are unnecessary, to say the least. BTW, How many times have I used "click chemistry" in this short paragraph?

Let us look at the definition of "click chemistry" by Sharpless et al in their paper (Angew Chem. Int. Ed. 2001, 40, 2004):  

"We have termed the foundation of this approach "click chemistry," and have defined a set of stringent criteria that a process must meet to be useful in this context. The reaction must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific (but not necessarily enantioselective). The required process characteristics include simple reaction conditions (ideally, the process should be insensitive to oxygen and water), readily available starting materials and reagents, the use of no solvent or a solvent that is benign (such as water) or easily removed, and simple product isolation. Purification - if required - must be by nonchromatographic methods, such as crystallization or distillation, and the product must be stable under physiological conditions."

So this is the reminder for proper use of the term "click chemistry".
                    
           

Click Chemitry patent applications

    
I did a USPTO patent application search (2/12/2010) and here is the result with "click chemistry" in the title:
1 20090306310 Method of using click chemistry to functionalize dendrimers
2 20090247651 Bioadhesive Composition Formed Using Click Chemistry
3 20090214755 CLICK CHEMISTRY SURFACE FUNCTIONALIZATION FOR RESONANT MICRO-CAVITY SENSORS
4 20090123372 DEVELOPMENT OF MOLECULAR IMAGING PROBES FOR CARBONIC ANHYDRASE-IX USING CLICK CHEMISTRY
5 20090069561 CLICK CHEMISTRY ROUTE TO TRIAZOLE DENDRIMERS
6 20090054619 Functionalization of polyglycolides by "click" chemistry
7 20080311412 Polymeric Materials Via Click Chemistry
8 20080213175 Click chemistry-derived cyclic peptidomimetics as integrin markers
9 20080170992 Click chemistry-derived cyclopeptide derivatives as imaging agents for integrins
10 20060269942 In situ click chemistry method for screening high affinity molecular imaging probes
11 20060263293 Click chemistry method for synthesizing molecular imaging probes

It would be interesting to keep an eye on the following - which ones will be finally issued and what the implications will be in regard to the original Sharpless patent.

The list can clearly tell us the scope click chemistry has extended into: dendrimer, functional materials, surface, imaging, polymer, biomolecules, biomedicine, etc.

Sharpless patent claims and click chemistry

This patent by Sharpless et al was issued on May 20, 2008, titled "Copper-catalysed ligation of azides and acetylenes ". It claims:

1. A Cu(I) catalyzed process for preparing a 1,4-disubstituted 1,2,3-triazole comprising: contacting an organic azide and a terminal alkyne with a catalytic quantity of Cu(I) ion for a time sufficient to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole.
2. The process in accordance with claim 1 wherein the cycloaddition is carried out at ambient temperature.
3. The process in accordance with claim 1 wherein equimolar amounts of the organic azide and the terminal alkyne are contacted with a catalytic quantity of the Cu(I) ion.
4. The process in accordance with claim 1 wherein said catalytic quantity of the Cu(I) ion is generated in situ by reduction of Cu(II) to Cu(I) with a reducing agent.
5. The process in accordance with claim 4 wherein the reducing agent is sodium ascorbate.
6. The process in accordance with claim 4 wherein Cu(II) sulfate pentahydrate is reduced by sodium ascorbate.

It appears the claim is the Cu(+) catalysed reaction ITSELF. Already having some impact on biotechnology and materials science, evidenced by licensing and product launches, it is expected to have a larger influence on more industries such as medicinal chemistry, nanotechnology, biomedical science, etc.

Click Chemistry: some working experience

  
Click chemistry is not equal to Cu(+) catalyzed triazole formation although literature centers on it. At least two types of Cu-free exist, which comforts many workers in toxicity concerns. Another click reaction, ene-thiol reaction, may find the best practical use in industry.

Running a click reaction is not as easy as a piece of cake. Actually one may need quite some tweaking in starting trials, particularly in catalyst and solvent selection. There are very good reviews detailing all these aspects. Once you get it working for you, click chemistry can be very rewarding and productive.

In early days, one had to make all the reagents themselves before coming to the final "click". No doubt it did not help those who were not familiar with organic synthesis but could potentially be interested and would not mind in "clicking". Last several years has seen increasing reagent offering from a wide range of vendors, both domestic and international. One would see more and more reagents available in "clickable" forms: biotin, fluorophore, quenchers, amino acids, carbohydrate, PEG, nucleosides for biotechnology, and many precursors, dendrons, intermediates for material science. There are even more for thiols and terminal alkenes.

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Click Chemistry: Reagent Vendors Matter

To some extent, the availability of reagents will decide how far the click chemistry can reach into the non-chemist community. Initially many efforts of using click chemistry would have to prepare many intermediates or starting materials, sometimes in multiple steps, before that beautiful “click” – by chemists.

In biotechnology and biomedical world, all kinds of “kits” are right there, bringing in the ultimate convenience and reliability for the end users, much like “plug-and-play” computer parts. This is the way to go – and chemists should make it happen before the biotechnology community turns away.

I have compiled some click chemistry vendors – the list will likely be updated from time to time.

Conventional organic chemical vendors: look for azides and acetylenes, thiols and alkenes, and other pairs

With click chemistry emphasis or specialization:
Aldrich
Invitrogen
Jena Biosciences
Berry Associates
Glen research
Anaspec
Creative PEGWorks
Quanta Biodesign
Primetech
GFS
Enamine
Lumiprobe
Click Chemistry Tools
Base Click
IBA BioTAGnology

Shall we do some click chemistry?

Book Review - Click Chemistry for Biotechnology and Materials Science by Joerg Lahann

Click chemistry as a concept has been received well enough in terms of ever-increasing publications. Applications mostly point to material sciences and biotechnology where beautiful examples were demonstrated (the topics of the book). On industrial level click chemistry has yet to offer anything practically important. Neither has it afforded much in pharmaceutical world which was initially targeted. Some small libraries and screening work have been published in search of enzyme inhibitors using click chemistry. It is possible that there is large body of work not disclosed by industry for IP reasons.

These should not deny the concept and some very good reactions hard to come by in organic chemists' eyes. Like anything else, there has to be a period in which theories, examples, commercial reagents are getting ready in place - and workers would doubt, hesitate, then start to try it out, overcome some difficulties, and finally like and adopt it. This will take much longer for intended biotechnology scientists than for professional chemists. The book comes in a very timely fashion and may help to significantly shorten this period.

The 411-page book has the traditional "Wiley-quality". Frontier research groups describe their own work in 16 loosely connected chapters and give a broad picture of "current" status of the application of click chemistry in two fields: biotechnology and material science. Expect 16 reviews or accounts in very recent time - perfect for one to survey and enter the field. Readers may find it useful in two ways. They may adopt the applications directly in their closely related work. Or they may be excited by the elegance of the chemistry and adopt the chemistries in their own fields. After all, it is a very, very good tool. Some readers may turn out to be interested in certain chapters, not the others, largely due to the nature of the chemistry as a tool and therefore the large scope it can be used. The index appears very thin and may be hard to use. The literature does not cover the patent world.

One would realize how fast the field is developing if I say that many significant progresses have already taken place since April 2009, the Preface date by the Editor Joerg Lahann. It is necessary to follow the most current publications in major journals to keep up with the field.