Staudinger reaction using 2,6-dichlorophenyl azide derivatives for robust aza-ylide formation applicable to bioconjugation in living cells

Staudinger reaction using 2,6-dichlorophenyl azide derivatives for robust aza-ylide formation applicable to bioconjugation in living cells

Abstract

Efficient formation of water- and air-stable aza-ylides has been achieved using the Staudinger reaction between electron-deficient aromatic azides such as 2,6-dichlorophenyl azide and triarylphosphines. The reaction proceeds rapidly and has been successfully applied to chemical modification of proteins in living cells.

Graphical abstract: Staudinger reaction using 2,6-dichlorophenyl azide derivatives for robust aza-ylide formation applicable to bioconjugation in living cells
Click reactions,1 including copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC)2 and strain-promoted azide–alkyne cycloaddition (SPAAC),3 have been recognized as epoch-making methods for reliable conjugations of molecules over a broad range of research fields within chemistry and biology. In particular, click reactions resulting in efficient formation of stable covalent bonds have been widely utilized for chemical modification of biomolecules in chemical biology and drug discovery research.4 However, several problems using conventional methods, such as non-specific in-cell click labeling by SPAAC, have been reported; thus, a new method is required to address these issues.5

Staudinger–Bertozzi ligation using triarylphosphines bearing an ortho ester moiety in conjugation with aliphatic azides has emerged as an early bioorthogonal reaction (Fig. 1A).6 The method forms a robust amide bond and has been demonstrated to be useful for the chemical modification of various biomolecules. Nevertheless, Bertozzi and coworkers developed a SPAAC reaction to achieve a faster and more efficient bioconjugation. Thereafter, a number of methods using cyclooctynes with improved characteristics have been reported.7 In the course of our recent studies regarding phosphorus chemistry8 and molecular conjugation chemistry,9 we revisited the Staudinger reaction between aromatic azides and various phosphines.8b These studies gave us an idea of preparing an aza-ylide that would be stable toward hydrolysis and oxidation. We considered that this type of aza-ylide would be useful for chemical modification of biomolecules. Herein, we report a new method for molecular conjugation using the Staudinger reaction to form robust aza-ylides. This chemistry has been found to be applicable to efficient bioconjugation in living cells (Fig. 1B).10,11

Journal Article

JOURNAL:
Chemical Communications

TITLE:
Staudinger reaction using 2,6-dichlorophenyl azide derivatives for robust aza-ylide formation applicable to bioconjugation in living cells

DOI:
https://doi.org/10.1039/c8cc00179k

Correspondence to

Takamitsu HOSOYA, Ph.D.,Professor
Suguru YOSHIDA, Ph.D., Associate Professor
Department of Chemical Bioscience,
Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University(TMDU)
E-mail:thosoya.cb(at)tmd.ac.jp (HOSOYA)
   s-yoshida.cb(at)tmd.ac.jp (YOSHIDA)