Phosphoramidate‐peptide synthesis by solution‐ and solid‐phase Staudinger‐phosphite reactions

Abstract

The chemoselective incorporation of phosphoramidate moieties into peptides by a Staudinger-phosphite reaction of azides can be performed in many solvents, including water. In this report, we present two strategies for an efficient synthesis of phosphoramidate-containing peptides, in which the Staudinger-phosphite reaction is performed either on the solid support or in solution with aryl azido-containing peptides. The corresponding Staudinger reactions proceed in high conversion rates and deliver phosphoramidate peptides, in which the modification site is located in the middle of the peptide sequence.

Staudinger Ligation as a Method for Bioconjugation

“…Moreover, the same research group applied the Staudinger-phosphite method to the solid-phase synthesis of phosphoramidate-containing peptides. [113] This method was extended towards the synthesis of phosphoramidate-linked glycopeptides. [114] The strategy involved a two-step approach in which serine-containing peptides were first converted into phosphite peptides by phosphitylation with phosphoramidites.…”

Chemoselective Staudinger-phosphite reaction of symmetrical glycosyl-phosphites with azido-peptides and polygycerols

“…Peptide 10 was obtained by standard SPPS, coupling para-azido-Phe as the last amino acid. 13 This experiment already revealed a very good conversion of the azido-peptide 10 to the peptidic phosphoramidate 11 of 86% in DMSO at room temperature, as determined by HPLC-MS with a deuterium-labeled peptide as internal standard (see ESI ‡). 14 In order to further demonstrate the chemoselectivity of the Staudinger-phosphite reaction 6,13 another fluorescencelabeled peptide 12 with an NBD-group attached to the ε-amino group of Lys prepared, in which the NBD-Lys was introduced as Fmoc-protected building block.…”

Stabilization of Peptides for Intracellular Applications by Phosphoramidate‐Linked Polyethylene Glycol Chains

“…Subsequent Staudinger‐phosphite PEGylation with readily available PEG‐phosphites (see the Supporting Information) is possible by employing as substrates either a protected arylazido‐BH3 peptide on the solid support or an unprotected peptide in solution. First, we focused on the Staudinger‐phosphite reaction on the solid support (Scheme left), because an excess of the PEG‐phosphites as well as the PEG‐alcohol that is formed during the reaction can be washed away directly 23. Unfortunately, despite various efforts of attempts at optimization, the occurrence of several truncated peptidic side products during SPPS led to an mixture of modified peptides after the Staudinger‐phosphite PEGylation on the solid support, which was inseparable by HPLC owing to the broad retention time of the PEGylated molecules (Scheme ).…”