Diels-Alder Click Chemistry for Tissue Engineering Hydrogel

Biomacromolecules, 2011, 12 (3), pp 824–830

Diels-Alder cycloaddition satisfies click chemistry criteria and features elegant multiple-bond formation in a single step in very high yeild. Here a furan diene was installed onto the natural polymer hyaluronic acid and it was cross-linked by a bifunctional dienophile, dimaleimide poly(ethylene glycol) to form the cytocompatible hydrogels for potential soft tissue engineering. The click reaction runs smoothly in aqueous buffer without initiator, catalyst, or other coupling reagents. 
 

Click chemistry Now and Then

Click chemistry "now and then" by numbers

No intention to be exclusive or "scientific", this is to perform a simple "statistical" count on click chemistry application in different areas . A "historical" view is provided by comparing two periods, 1999-2007 for "then" and 2011 ( Jan 1 - June 12) for "now". The data for the first period was from Sharpless laboratory's compilation of click chemistry (937 articles). The data for the second period was from a Chemical Abstract search (525 articles). 

Published articles titles were searched by selected key words and the counts are recorded as a simplified reflection of research intensity or trend. The format is "key word / number from 1st period / number from 2nd period.   

click /415/308
click chemistry /262/178
poly- /389/371
polymer /173/253
dendrimer /37/15
material /17/52
dye /2/6
fluorescence & fluorescent / 12/14
cyclodextrin /4/12
drug /26/21
inhibitor /34/25
enzyme /16/6
screen /9/3
combinatorial /10/1
Sharpless /105/1
Huisgen /22/3
synthesis /315/150
cycloaddition /121/24
nano /51/71
epoxide /9/0
triazole /129/47
Diels-Alder /12/2
water /34/9
ligation /21/5
conjugate /49/46
bioconjugate /16/21
oligo /26/16
DNA /24/18
protein /48/29
peptide /51/32
glyco /64/53
sugar /7/7

The first period was roughly the rising and maturation of click chemistry over a few years (937) while the second is the application of click chemistry in many fields in merely half a year (525). Although to obvious dissatisfaction of statisticians it is safe to conclude that click chemistry is much more widely used now than then.  
                                                       

Danishefsky Cyclobutenone in Diels-Alder Reaction

JACS 2010, 11004

Diels-Alder has been a beautiful and powerful cycloadition reaction for many masters such as Woodward. It is an atom-efficient, 4+2, environment-insensitive ring-formation reaction and fits click chemistry concept in many aspects . 

Danishefsky's work expanded its scope by using cyclobutenone as a highly reactive dienophile. The strained cyclobutanone in the Diels-Alder product undergoes regioselective ring-expansion to give cyclopentanone, lactam, lactone. As an example indicated in the graph, the approach provides a variety of structures not accesible via direct Diels-Alder reaction.      
                    

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.