4‐Fluorophenyl 3‐nitro‐2‐pyridinesulfenate as a practical
protecting agent for amino acids
Department of Medicinal Chemistry, Tokyo
University of Pharmacy and Life Sciences,
1432‐1 Horinouchi, Hachioji, Tokyo 192‐
Prof. Yoshio Hayashi, Department of
Medicinal Chemistry, Tokyo University of
Pharmacy and Life Sciences, 1432‐1
Horinouchi, Hachioji, Tokyo 192‐0392, Japan.
Japan Society for the Promotion of Science
(JSPS), KAKENHI; Basic Science and Platform
Technology Program for Innovative Biological
Medicine; Grant‐in‐Aid for Young Scientists
(B), Grant/Award Number: 16K18914
We report a new protecting agent (1, Npys‐OPh(pF)) for 3‐nitro‐2‐pyridine (Npy) sulfenylation of
amino, hydroxy, and thiol functional groups. Several Npys phenoxides were synthesized from
Npys chloride (Npys‐Cl) and phenols in the presence of base in 1‐step reaction, and their ability
for Npy‐sulfenylation was evaluated. As a result, 1 was selected as a new Npy‐sulfenylation agent
with advantages including improved physicochemical stability, more controllable reactivity, and
easier handling than the conventional protecting agent Npys‐Cl.
3‐nitro‐2‐pyridinesulfenyl (Npys) group, amino acid, Npys phenoxides, protecting agent, stability,
In 1970s, the 3‐nitro‐2‐pyridinesulfenyl (Npys) group was discovered
by Matsueda et al.
The first Npys to be synthesized was Npys chloride
(Npys‐Cl), a moderately stable heterocyclic sulfenyl halide.
tions of Npys‐Cl to synthetic chemistry were reported in 1980, when
it was demonstrated that the Npys group could selectively protect
amino, hydroxy, and thiol groups.
In 1981, Matsueda and Kaiser
investigated the synthesis of alkyl 3‐nitro‐2‐pyridinesulfenates
(Npys‐OR) which were formed by coupling various hydroxy
compounds to Npys‐Cl.
The unique conditions used for removal of
the Npys protective group provide an orthogonal strategy: this
protecting group can be deprotected in the presence of thiols or phos-
phines, but the protecting group is resistant to acidic conditions such
as trifluoroacetic acid and HF.
Moreover, it can also be removed
under basic conditions using piperidine or NaOH.
These led to the
wide use of the Npys protecting group in peptide and protein
One of the most valuable uses of the Npys group was illus-
trated by Matsueda et al in 1981. In a cysteine whose side chain is
protected by an S‐Npys group, the protecting group can react
with another unprotected thiol group generating a disulfide bond.
Inspired by this finding, we recently developed an original
disulfide‐forming reagent using an Npys core which is supported on
Olsen et al reported that an O‐Npys group at Ser/Thr side
chains promotes an elimination reaction under mild conditions to
obtain a dehydroalanine or dehydrobutyrine.
These reports suggest
that the use of Npys group has the great potential in peptide and
To the best of our knowledge, Npys‐Cl is the only reagent that has
been used to date for Npys protection. This sulfenyl chloride, however,
has some obvious defects including instability with light or moisture
and its tendency to dimerize, even at low temperatures,
a major draw-
back in Npys protection strategy. Developed with a view to overcoming
this, Npys‐OR compounds are known to be stable and very attractive
Npys derivatives, and we have found that methyl 3‐nitro‐2‐
pyridinesulfenate, an Npys‐OMe derivative could be obtained as a
stable crystalline compound.
In the present study, we describe a new
Npys protecting reagent based on the sulfenate derivatives. Any new
reagent should meet the following criteria: (1) it should be producible
from available compounds under mild conditions, (2) it should be
reactive with amino, hydroxy, and thiol groups for the Npys protection,
and (3) it should be stable under storage conditions. We began by inves-
tigating the syntheses of various Npys‐OR derivatives. Then, using the
Npys‐OR synthesized by these methods, the protection of various
functional groups commonly encountered in peptide chemistry was
Received: 12 December 2017 Revised: 18 January 2018 Accepted: 20 January 2018
J Pep Sci. 2018;24:e3070.
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