Staudinger Ligation of Peptides at Non-Glycyl Residues

Soellner, Matthew B.; Tam, and Annie; Raines, Ronald T.

doi:10.1021/jo0620056

Cited by 56 publications

(57 citation statements)

References 54 publications

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“…In a recent development, Kleineweischede and Hackenberger have applied the traceless Staudinger reaction pioneered by Bertozzi and co-workers [121] and Raines and coworkers [122] to the preparation of non-cysteine-containing head-to-tail unprotected cyclic peptides. The synthesis of the required bifunctional azidopeptide phosphinothioester is completed by solid-phase peptide synthesis to give a fully protected peptide 136 with a borane-protected phosphine (Scheme 62).…”

Section: Traceless Staudinger Ligationmentioning

confidence: 99%

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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Achieving high levels of chemoselectivity has been the Achilles' heel of chemical synthesis. The excitement generated by the successful realization of chemoselective strategies underscores the painstaking efforts to define a set of conditions conducive to selection among the available reaction pathways. We discuss in this Review various aspects of chemoselectivity that have been addressed in a range of synthetic methods over the past decade. We have focused on the proposed mechanistic basis of the reactions under consideration in an attempt to categorize them and highlight the key concepts that have been emerging on the basis of these studies. Our overview of recent advances in chemoselective processes suggests that significant progress has been made, but a lot of challenges lie ahead.

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Section: Traceless Staudinger Ligationmentioning

confidence: 99%

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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“…A great advantage of this ligation is that it does not require the presence of a cysteine residue at the junction site, in contrast to native chemical ligation. Despite its recent introduction, many reports in the past decade have focused on the reaction mechanism and the applications of the traceless Staudinger ligation [78,[81][82][83][84][85].…”

Section: Cyclization By Staudinger Reactionmentioning

confidence: 99%

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

2009

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Although not complying with Lipinski's rule, peptides are to an increasing extent being developed into new active pharmaceutical ingredients. This is mainly due to novel application routes, formulations and chemical modifications, which confer on the peptides improved uptake and increased metabolic stability. A brief survey of currently approved peptide drugs and the present scope of the application of peptides as drugs is provided. Cyclic peptides are emerging as an interesting class of peptides with conformational rigidity and homogeneity, high receptor affinity and selectivity, increased metabolic stability and - in special cases - even oral availability. Challenges and new methodology for the synthesis of cyclic peptides are outlined and an overview of approaches toward the design of peptide conformation and peptide modification by nonproteinogenic building blocks is given.

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“…The synthesis of phosphinothiols 4 , 7 , and 13 were reported first in ref. 76, 81, and 83; for detailed experimental protocols, see ref. 93.…”

Section: Figurementioning

confidence: 99%

Chemoselectivity in Chemical Biology: Acyl Transfer Reactions with Sulfur and Selenium

McGrath

Raines

2011

Acc. Chem. Res.

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CONSPECTUS A critical source of insight into biological function is derived from the chemist’s ability to create new covalent bonds between molecules, whether they are endogenous or exogenous to a biological system. A daunting impediment to selective bond formation, however, is the myriad of reactive functionalities present in biological milieu. The high reactivity of the most abundant molecule in biology—water—makes the challenges all the more difficult. We have met these challenges by exploiting the reactivity of sulfur and selenium in acyl transfer reactions. The reactivity of both sulfur and selenium is high compared to that of their chalcogen congener, oxygen. In this Account, we highlight recent developments in this arena, emphasizing contributions from our laboratory. One focus of our research is furthering the chemistry of native chemical ligation (NCL) and expressed protein ligation (EPL), two related processes that enable the synthesis and semisynthesis of proteins. These techniques exploit the lower pKa of thiols and selenols relative to alcohols. Although a deprotonated hydroxyl group in the side chain of a serine residue is exceedingly rare in a biological context, the pKa value of the thiol in cysteine (8.5) and of the selenol in selenocysteine (5.7) often render these side chains anionic under physiological conditions. NCL and EPL take advantage of the high nucleophilicity of the thiolate as well as its utility as a leaving group, and we have expanded the scope of these methods to include selenocysteine. Although the genetic code limits the components of natural proteins to 20 or so α-amino acids, NCL and EPL enable the semisynthetic incorporation of a limitless variety of nonnatural modules into proteins. These modules are enabling chemical biologists to interrogate protein structure and function with unprecedented precision. We are also pursuing the further development of the traceless Staudinger ligation, through which a phosphinothioester and azide form an amide. We first reported this chemical ligation method, which leaves no residual atoms in the product, in 2000. Our progress in effecting the reaction in water, without an organic co-solvent, was an important step in the expansion of its utility. Moreover, we have developed the traceless Staudinger reaction as a means for immobilizing proteins on a solid support, providing a general method of fabricating microarrays that display proteins in a uniform orientation. Along with NCL and EPL, the traceless Staudinger ligation has made proteins more readily accessible targets for chemical synthesis and semisynthesis. The underlying acyl transfer reactions with sulfur and selenium provide an efficient means to synthesize, remodel, and immobilize proteins, and they have enabled us to interrogate biological systems.

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Staudinger Ligation of Peptides at Non-Glycyl Residues

Cited by 56 publications

References 54 publications

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

Chemoselectivity in Chemical Biology: Acyl Transfer Reactions with Sulfur and Selenium

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