Staudinger ligation of peptides at non-glycyl residues.
The Staudinger ligation provides a means to form an amide bond between a phosphinothioester and azide. This reaction holds promise for the ligation of peptides en route to the total chemical synthesis of proteins. (Diphenylphosphino)methanethiol is the most efficacious of known reagents for mediating the Staudinger ligation of peptides, providing high (> 90%) isolated yields for equimolar couplings in which a glycine residue is at the nascent junction. Surprisingly, the yields are lower (< 50%) for non-glycyl couplings due to an aza-Wittig reaction that diverts the reaction toward a phosphonamide byproduct. Here, the partitioning of the reaction toward Staudinger ligation (and away from the aza-Wittig reaction) is shown to increase with increasing electron density on phosphorus. This electron density can be tuned either by installing functional groups on the phenyl substituents of (diphenylphosphino)methanethiol or by changing the polarity of the solvent. Installing p-methoxy groups and using a solvent of low polarity (such as toluene or dioxane) provide especially high (> 80%) isolated yields for the ligation of two non-glycyl residues. These conditions retain the high chemoselectivity of the reaction and do not lead to a substantial change in reaction rate. The traceless Staudinger ligation is now poised to enable the iterative ligation of peptides with little regard for their sequence, as well as the synthesis of amide bonds for other purposes.
Soellner
Matthew B
MB
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Tam
Annie
A
Raines
Ronald T
RT
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D004146:Dioxanes / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D005663:Furans / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
D000577:Amides; D001386:Azides; D004146:Dioxanes; D004952:Esters; D005663:Furans; D008024:Ligands; D010455:Peptides; D014867:Water; C018674:tetrahydrofuran; C025223:1,4-dioxane