ORGANIC
LETTERS
2009
Vol. 11, No. 2
477-480
Exploration of the “Traceless”
Reductive Ligation of S-Nitrosothiols
Jiming Zhang, Hua Wang, and Ming Xian*
Department of Chemistry, Washington State UniVersity, Pullman, Washington 99164
Received November 18, 2008
ABSTRACT
The first “traceless” reductive ligation of S-nitrosothiols using phosphine ester/thioester conjugates is reported. Experiments also show that
stable thioimidate compounds could be formed in the reaction between S-nitrosothiols and some phosphine-thioester substrates.
S-Nitrosothiol (RSNO) formation on cysteine residues rep-
resents an important post-translational modification that
transduces nitric oxide (NO)-dependent signals.1 However,
the detection of RSNOs in biological systems is still a
challenge due to the lability of the SNO moiety.2 The
analytical deficiencies become evident when it is observed
that reported values of the analysis of the same tissue or
biological fluid by different research groups cover some
orders of magnitude.3 In our opinion, SNO is a unique
functional group that should have distinct reactivity from
other biological functional groups. If we can develop new
bioorthogonal reactions specifically targeting SNO and
converting unstable S-nitrosothiols to stable products, such
a reaction would hold considerable promise in applications
for RSNO detection.
mechanism is similar to the Staudinger ligation of azides.5
RSNO 1 reacts with 2 equiv of ligation substrate 2 to
generate the corresponding phosphine oxide and aza-ylide
3.4,6 Then, an intramolecular reaction between the ester and
aza-ylide may occur to provide phosphorane 5. Finally,
hydrolysis of 5 in the presence of water should furnish the
final product 6. This reductive ligation is quite selective for
SNO moieties and could potentially be applied for RSNO
detection.4
Although the ligation reaction using the phosphine-ester
substrate shown in Scheme 1 has been demonstrated, a
modification in which an amide bond is formed between the
two coupling partners to give a product without the phosphine
oxide moiety might be even more attractive. It might provide
a new way to prepare useful sulfenamide derivatives. Similar
to the well-studied traceless Staudinger ligation pioneered
by Raines and Bertozzi,7 we proposed that compounds like
7 should undergo a traceless reductive ligation with RSNOs
(Scheme 2). As such, the nucleophilic nitrogen atom gener-
Recently, our laboratory developed a reductive ligation
of RSNOs which converts RSNOs to stable sulfenamide
products in one step (Scheme 1).4 We believe the reaction
(1) For selected reviews, see: (a) Lancaster, J. R., Jr. Nitric Oxide 2008,
19, 68. (b) Foster, M. W.; McMahon, T. J.; Stamler, J. S. Trends Mol.
Med. 2003, 9, 160. (c) Zhang, Y.; Hogg, N. Free Radical Biol. Med. 2005,
38, 831.
(4) Wang, H.; Xian, M. Angew Chem. Int. Ed. 2008, 47, 6598.
(5) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Lin,
F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R. G.; Bertozzi, C. R. J. Am.
Chem. Soc. 2005, 127, 2686. (c) Koehn, M.; Breinbauer, R. Angew. Chem.,
Int. Ed. 2004, 43, 3106.
(2) For recent reviews on RSNO detection, see: (a) Gow, A.; Doctor,
A.; Mannick, J.; Gaston, B. J. Chromatogr. B 2007, 851, 140. (b)
Kettenhofen, N. J.; Broniowska, K. A.; Keszler, A.; Zhang, Y.; Hogg, N.
J. Chromatogr. B. 2007, 851, 152. (c) MacArthur, P. H.; Shiva, S.; Galdwin,
M. T. J. Chromatogr. B 2007, 851, 93. (d) Jaffrey, S. R. Methods Enzymol.
2005, 396, 105.
(6) Haake, M. Tetrahedron Lett. 1972, 33, 3405
.
(7) (a) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000,
2, 1939. (b) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2,
2141. (c) Soellner, M. B.; Tam, A.; Raines, R. T. J. Org. Chem. 2006, 71,
9824. (d) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Am. Chem. Soc.
2006, 128, 8820. (e) Tam, A.; Soellner, M. B.; Raines, R. T. J. Am. Chem.
Soc. 2007, 129, 11421.
(3) (a) Giustarini, D.; Milzani, A.; Dalle-Donne, I.; Rossi, R. J. Chro-
matogr. B 2007, 851, 124. (b) Gladwin, M. T.; Wang, X.; Hogg, N. Free
Radical Biol. Med. 2006, 41, 557.
10.1021/ol802663q CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society