Peptides 1,3-dipolar cycloaddition reactions

R. J. Pieters, D. T. S. Rijkers, and R. M. J. Liskamp, Application of the 1,3-dipolar cycloaddition reaction in chemical biology Approaches toward multivalent carbohydrates and peptides and peptide-based polymers, QSAR Comb. Sci., 26 (2007) 1181-1190. 

FIGURE 8.20 Peptides activated at an IV-methylamino-acid residue are postulated to epimer-ize because of the formation of the oxazolonium ion. Evidence for the latter resides in spectroscopic studies,96 and the isolation of a substituted pyrrole that was formed when methyl propiolate was added to a solution of Z-Ala-MeLeu-OH in tetrahydrofuran 10 minutes after dicyclohexylcarbodiimide had been added.95 The acetylenic compound effected a 1,3-dipolar cycloaddition reaction (B), with release of carbon dioxide, with the zwitter-ion that was generated (A) by loss of a proton by the oxazolonium ion. 

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... 

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. 

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. 

A large number of peptidomimetics are currently entering clinical trials, typically protease inhibitors and anti-cancer agents, which emphasizes the importance of developing reactions which efficiently modify peptides or peptide-like structures to increase their drug-like properties. Azides are important dipoles in 1,3-dipolar cycloaddition reactions and react with dipolarophiles such as alkynes and nitriles, to afford [l,2,3]-triazoles and tetrazoles, respectively. 

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. 

General. Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in peptide synthesis, " and as a versatile reagent in a wide array of organic transformations. DPPA has been successfully utilized in the synthesis of a-amino acids and o-aryl carboxylic acids direct preparation of thiol esters from carboxylic acids and thiols the stereospecific preparation of alkyl azides and the phosphorylation of alcohols and amines The application of DPPA in a modified Curtius reaction permits a simple one-step conversion of carboxylic acids to urethanes under mild reaction conditions. DPPA acts as a nitrene source, and can undergo 1,3-dipolar cycloaddition reactions. The Curtius degradation of carboxylic acids in the presence of f-butanol gives the Boc-protected amine directly (eq 1). 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Cycloaddition reactions between azides and alkynes—exemplified by the Huisgen 1,3-dipolar cycloaddition—have tremendous potential for the development of biomolecules and have been employed for conjugation of sugars to peptides [184]. Drawbacks of the Huisgen cycloadditions, however, are poor regioselectivity and incompatibility with physiological conditions. These limitations, which hinder MOE applications in living cells, were first overcome by cop-... 

The first application of copper(I)-catalyzed 1,3-dipolar cycloaddition in preparation of [18F]fluoropeptides was reported by Marik and Sutcliffe in 2006 (Figure 14.9) [92]. Three [18F]fluoroalkynes (n = 1, 2, and 3) were prepared in yields ranging from 36% to 80% by nucleophilic substitution of a p-toluenesulfonyl moiety with [18F]fluoride ion. Reaction of these [18F]fluoroalkynes with various peptides (previously derivatized with 3-azidopropionic acid) via the Cu(I)-mediated 1,3-dipolar cycloaddition provided the desired 18F-labeled peptides in 10 minutes at room temperature with yields of 54-99% and great radiochemical purity (81-99%) [82]. 

Polystyrene-sulfonyl hydrazide resins 153 reacted with various amines to give regiospecifically 1,4-disubstituted-l,2,3-triazoles 154 via traceless cleavage reactions <04TL6129>. A library of peptidotriazoles were prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkynes and protected amino azides <04JCO312>. 

Further attempts to increase the kinetics and biocompatibility of 1,3-dipolar cycloadditions led organic chemists to explore altemative dipoles that react with multiple-bond reaction partners. Nitrile oxides are highly reactive dipoles that can react with various alkenes and alkynes to provide isoxazolines and isoxazoles, respectively. In the absence of a suitable reacting partner, nitrile oxides tend to dimerize to form fiiroxane derivatives, or can alternatively act as electrophiles. However, when generated in situ from suitable precursors such as hydroximoyl chlorides or by mild oxidation directly from oximes, nitrile oxides were successfully applied to the labeling of nucleic acids [43], peptides [44] and carbohydrates [45] (Fig. 7). 

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