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B. H. Jones et al. / Tetrahedron Letters 56 (2015) 5731–5734
reported recently for several chemical reactions involving boronic
acids.8,10 For example, Fu et al., reported that secondary amines
catalyze air oxidation of aryl boronic acids and boronate esters to
the corresponding phenols, while primary and tertiary amines do
not, due to the relative basicity of amines: 2° > 1° > 3°.8b Their
work could implicate the secondary amine resulting from imine
reduction as having a critical role in deboronation; however,
ortho-substituted products, unlike para-substituted ones, can
form a B–N dative bond accompanied by decreased basicity of
the amine,5a which is contrary to the poorer stability of the
ortho-substituted product we have observed. Other work has
shown oxidation of aryl boronic acids to be dramatically
accelerated by the presence of electron-withdrawing substituents
on the phenyl ring, yet the aminomethyl substituents at present
are electron-donating in character.10b Thus, the mechanism of
deboronation at present is decidedly more subtle. Cammidge and
coworkers,8a and Zhu and coworkers,10a have found that catalytic
amounts of certain quinones and N-oxides, respectively, can
effect deboronation of various aryl boronic acids. We suspect a
similar process is occurring here, wherein the peptide catalyzes
deboronation to which the ortho-substituted boronic acid is
particularly susceptible.
Although additional work is required to elucidate further the
mechanism and details of deboronation that we have observed,
we feel the present results serve as an important cautionary
account, particularly in light of increasing interest in peptide and
small molecule BAs. ESI-MS is regularly used to confirm the out-
come of solid phase peptide synthesis, and deboronation has been
reported as an artifact of in-source fragmentation of aryl BAs.11
However, our combined MS and NMR characterizations have
clearly shown that extensive deboronation can occur during the
reductive amination of ortho-FPBA to peptide substrates. There-
fore, the signatures of deboronation in MS must be given careful
consideration when determining the outcome of peptide BA syn-
theses. If isomerism of the boronic acid is irrelevant, the improved
stability of para-FPBA to NaCNBH3 appears to advocate its use in
reductive amination schemes. Alternatively, we recommend the
use of carboxyphenylboronic acids, which can be used to install
BAs onto peptides via standard acid–amine coupling chemistry
(exemplified by compound 6, Figs. S20–S22) with no apparent
deboronation.
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2015.09.006.
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We gratefully acknowledge James Hochrein for use of MS
equipment and Alina Martinez for performing HPLC. This research
was supported by the US Department of Energy, Office of Basic
Energy Sciences, Division of Materials Science and Engineering,
Project KC0203010. Sandia National Laboratories is a multi-pro-
gram laboratory operated by Sandia Corporation, a wholly owned
subsidiary of Lockheed Martin Corporation, for the US Department
of Energy’s National Nuclear Security Administration under con-
tract DE-AC04-94AL85000.
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Supplementary data
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Supplementary data (details of peptide syntheses and charac-
terization techniques, additional NMR, HPLC, and MS data) associ-