Dipolar Cycloaddition Reactions in Peptide Chemistry

Dipolar cycloaddition reactions (DCRs) are unique reactions when considering their versatility, their atom economy and the highly functionalized heterocyclic products they provide. The significant contributions by Rolf Huisgen has led to the description of a 

3- dipolar cycloaddition reaction, where a dipole (formally a zwitterionic molecule) adds to a dipolarophile (an alkene or alkyne) to form a five-membered heterocyclic ring. Two (T-bonds are formed in this concerted reaction where bond breaking and bond formation occurs simultaneously and in a stereospecific manner, which also can be described by frontier molecular orbital theory as the highest occupied molecular orbital of one component reacting with the lowest unoccupied molecular orbital of the other component. 

The field of dipolar cycloaddition reactions with azides in peptide chemistry has developed rapidly since Tompe and Meldal first described the copper(l)-catalyzed cycloaddition between azides and peptide-linked terminal alkynes to exclusively form the 

4- substituted [l,2,3]-peptidotriazoles. This reaction was later termed CuAAC (copper-catalyzed azide-alkyne cycloaddition) or simply the click reaction, and has been used extensively in all areas of chemistry, biology and material sciences due to its mild reaction conditions, high functional group tolerance, generally high yields and exclusive formation of 1,4-substituted [l,2,3]-triazoles. The mechanistic aspects of the CuAAC leading to the 1,4-substitution are complicated and have been discussed elsewhere.  

Organic Azides Syntheses and Applications Edited by Stefan Erase and Klaus Banert 2010 John Wiley Sons, Ltd. ISBN 978-0-470-51998-1 

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Even though the CuAAC is a rather new reaction, more than 800 publications on Cu AAC chck chemistry has been pubhshed (May 2008), and it has been extensively reviewed. The focus of this chapter will be on azides in 1,3-dipolar cycloaddition reactions, mainly catalyzed by transition metals, in peptide chemistry. Protein ligation and protein modification by dipolar cycloaddition reactions has been reviewed and will not be included. Angell and Burgess published an excellent review on peptidomimetics generated by CuAAC in early 2007 with a thorough overview of the field and since then more than twenty new pubhcations describing dipolar cycloaddition reactions in peptide chemistry have appeared. 

Copper-catalyzed azide-alkyne cycloadditions have become increasingly popular due to their almost quantitative formation of 1,4-substituted triazoles, regioselectively, and the remarkable functional group tolerance, which is important when dealing with peptides or peptidomimetics. The majority of publications on dipolar cycloaddition reactions in peptide chemistry has focused on the CuAAC and reported peptide bond isosteres, side-chain functionalization, glycoconjugation, macrocyclization and isotopic labeling of peptides. We will most likely see an inaeasing number of applications where peptides are modified by dipolar cycloadditions in the future. 

This review is intended to cover all reactions and technology in peptide chemistry concerning dipolar cycloaddition reactions of azides, and the collection of literature was concluded on May 15 2008. The authors would like to apologize in advance if any references are missing. 

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