Synthesis of isotopomers of N-(tert-butoxycarbonyl)-4-cyano-l-phenylalanine methyl ester: Choice of cyanation solvent

Article abstract of DOI:10.1016/j.tetlet.2011.10.050

N-(tert-butoxycarbonyl)-4-cyano-l-phenylalanine methyl ester and three isotopomers (C¹⁵N, ¹³CN, and ¹³C¹⁵N) were successfully synthesized in two steps to expand the utility of the nitrile symmetric stretch vibra

Full text of DOI:10.1016/j.tetlet.2011.10.050

Tetrahedron Letters 52 (2011) 6865–6868
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of isotopomers of N-(tert-butoxycarbonyl)-4-cyano-L-phenylalanine
methyl ester: choice of cyanation solvent
⇑
Christopher G. Bazewicz, Jacob S. Lipkin, Kristen A. Lozinak, Matthew D. Watson, Scott H. Brewer
Franklin & Marshall College, Department of Chemistry, Lancaster, PA 17604-3003, USA
a r t i c l e i n f o
a b s t r a c t
N-(tert-butoxycarbonyl)-4-cyano-L
-phenylalanine methyl ester and three isotopomers (C15N, 13CN, and
Article history:
13C15N) were successfully synthesized in two steps to expand the utility of the nitrile symmetric stretch
vibration of this modified amino acid as a vibrational reporter of local environments. The choice of cya-
nation solvent directly impacted the level of isotopic enrichment of the isotopomers. The commonly used
solvent acetonitrile resulted in an isotopic enrichment of only ꢀ80% with a cyanation reaction time of
4.5 h, however, the cyanation solvent N,N-dimethylformamide afforded the isotopomers with >98% iso-
topic enrichment.
Received 21 July 2011
Revised 5 October 2011
Accepted 10 October 2011
Available online 17 October 2011
Keywords:
4-Cyano-L-phenylalanine
Infrared spectroscopy
Isotope editing
Ó 2011 Elsevier Ltd. All rights reserved.
Vibrational reporters
The nitrile group has shown great promise as a sensitive, site-
specific vibrational reporter of local environments in a number of
biological systems.1–16 This vibrational probe is attractive due to
the position of the nitrile symmetric stretching frequency, which
is in a relatively clear region of the IR spectrum, and the sensitivity
of the nitrile IR absorbance band (peak position and/or fwhm) to
the local environment.2,8,11,17 Additionally, the small size (two-
atom) and intermediate polarity of this group allow addition of this
probe at various positions of proteins to be well tolerated.18–20
isotopomers could be used for accurate identification5,23 of nitrile
IR absorbance bands based upon known isotopic shifts of the nitrile
symmetric stretch vibration. Additionally, multiple isotopomers
could be used in concert to probe multiple local protein environ-
ments simultaneously. Also, the isotopomers could potentially be
used as vibrational distance probes due to vibrational coupling be-
tween nitrile groups as observed with C14N and C15N variants of 5-
cyano-20-deoxyuridine in DNA oligomers.7
Here we discuss the synthesis of three isotopomers of a fully
The nitrile-modified amino acid, 4-cyano-
L
-phenylalanine
protected version of PheCN, N-(tert-butoxycarbonyl)-4-cyano-L-
(PheCN), has been especially utilized as a vibrational probe of pep-
tide and protein structure and dynamics.2,3,9,11,12,21 This unnatural
amino acid (UAA) has been incorporated into peptides by solid-
phase peptide synthesis2,9,11,12,21 and into larger proteins utilizing
an engineered, orthogonal aminoacyl-tRNA synthetase.3,9,20 This
nitrile-modified amino acid has provided an insight into the local
environments in proteins through vibrational spectroscopy,
including both infrared and Raman spectroscopy.2,21 PheCN has
also been coupled with fluorescence spectroscopy to yield distance
information between PheCN and the natural amino acid, trypto-
phan, since PheCN and tryptophan form a FRET pair with a Förster
distance of 16.0 0.5 Å.22
phenylalanine methyl ester (Boc-PheCN-OMe, 3). These protected
isotopomers can be subsequently de-protected in a straightfor-
ward manner20 to generate isotopically labeled PheCN. The choice
of solvent in the nickel-catalyzed cyanation step was found to be
especially important to obtain isotopically pure (>98% isotopic
enrichment) isotopomers of 3. The impact of the isotopic labels
on the position and line shape of the nitrile IR absorbance band
for each isotopomer is discussed. The experimentally measured
isotopic shifts of the nitrile symmetric stretch vibration are com-
pared with density functional theory (DFT) calculated isotopic
shifts.
Recent efforts in our lab with biomolecular vibrational reporters
have necessitated the ability to selectively isotopically label the ni-
Cyanation solvent: acetonitrile (MeCN)
trile group of 4-cyano-L
-phenylalanine (PheCN). Specifically C15N,
Scheme 1 illustrates the general procedure utilized in the syn-
thesis of Boc-PheCN-OMe (3). Initially, N-(tert-butoxycarbonyl)-4-
((trifluoromethyl)sulfonyl)-L-phenylalanine methyl ester (2) was
13CN, and 13C15N labeled versions of PheCN are of interest to
enhance and expand the utility of this vibrational reporter. These
produced by the reaction of N-(tert-butoxycarbonyl)-L-tyrosine
methyl ester (1) with trifluoromethanesulfonic anhydride.24,25
The second step involved the nickel-catalyzed cyanation25–27 of 2
⇑
Corresponding author. Tel.: +717 358 4766; fax: +717 291 4343.
E-mail address: scott.brewer@fandm.edu (S.H. Brewer).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.050

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C. G. Bazewicz et al. / Tetrahedron Letters 52 (2011) 6865–6868
Scheme 1. Reagents and conditions: (a) C5H5N, (CF3SO2)2O, CH2Cl2, 0 °C, 91%; (b) Ni(PPh3)2Br2, PPh3, Zn, (KCN, KC15N, K13CN, or K13C15N), (MeCN or DMF), 60 °C.
with bis(triphenylphosphine)nickel (II) bromide (Ni(PPh3)2Br2,
10 mol %), triphenylphosphine (PPh3, 20 mol %), zinc (Zn) powder
(60 mol %), and 1.1 equiv of potassium cyanide (KCN) in acetoni-
trile (MeCN) at 60 °C for 4.5 h to afford 3 with a yield of 58% (see
Supplementary data for complete synthetic details and NMR char-
acterization). Figure 1A shows the resulting FTIR absorbance spec-
product from this reaction is a mixture of 3 (23%) and 3a (77%) de-
spite KC15N being 98+% 15N enriched. Therefore, the observed per-
centage of 3 in the product mixture is not a result of incomplete
enrichment (98+%) of the 15N labeled potassium cyanide employed
as starting material.
A possible explanation for this mixture of 3 and 3a is that MeCN
is serving as both the solvent and the unlabeled nitrile (CN) source,
while KC15N is serving as the 15N labeled nitrile (C15N) source. A
previous study has demonstrated the nickel-catalyzed cyanation
of the aryl chloride, o-chlorotoluene, in acetonitrile in the absence
of another cyanide source, such as potassium cyanide, where the
nitrile group of MeCN was transferred to the aryl chloride.29 How-
ever, this reaction required 4 equiv of Zn, a reaction time of 24 h,
and a reaction temperature of 90 °C.29 Here, less than a stoichiom-
etric amount of Zn was used with a shorter reaction time (4.5 h)
and a lower reaction temperature (60 °C). Under these conditions,
attempts to generate 3 from 2 in the absence of KCN have been
unsuccessful, which suggest that these milder conditions do not
readily promote nitrile group transfer from MeCN to 2. An alterna-
tive to a nitrile group transfer from MeCN to 2 could be that the ni-
trile group of acetonitrile is exchanging with the 15N labeled
cyanide anion from the 15N labeled potassium cyanide generating
an unlabeled cyanide anion. The extent of this exchange would
thus modulate the percentage of 3 and 3a obtained. There is debate
in the literature as to whether the cyanide anion can exchange
with the nitrile group of acetonitrile.30–35 This debate is due in part
to the relatively low solubility of potassium cyanide in acetonitrile,
which severely limits the ability to determine if this exchange does
occur. Here, FTIR spectroscopy was not able to observe the pres-
ence of 15N labeled MeCN due to cyanide exchange between
C15Nꢁ and MeCN after the 4.5 h cyanation reaction used to gener-
ate 3a.
trum of
3 dissolved in tetrahydrofuran (THF) in the nitrile
symmetric stretching region. This spectrum shows the nitrile IR
absorbance band at 2229.2 cmꢁ1 as a single band, as expected
based upon previous studies with Fmoc-PheCN in THF and PheCN
in water.2 The choice of the commonly used solvent acetonitrile
was based upon the previous literature procedures involving the
nickel-catalyzed cyanation of aryl triflates.25–27
Due to the success of Scheme 1 in generating 3, the 15N isotopo-
mer 3a was subsequently synthesized based upon this procedure
using 15N labeled potassium cyanide (KC15N) instead of KCN. The
resulting FTIR absorbance spectra of the purified cyanation prod-
uct(s) dissolved in THF is shown in Figure 1B. This spectrum shows
two absorbance bands in the nitrile symmetric stretching region at
2229.2 and 2202.1 cmꢁ1. DFT calculations at the B3PW91/6-
31++G(d,p) level predict that the 15N isotope label should result
in a 29 cmꢁ1 red shift in the nitrile symmetric stretch vibration rel-
ative to 3. Based upon this calculation and the position of the ni-
trile IR absorbance band of 3 (Fig. 1A), the absorbance bands at
2229.2 and 2202.1 cmꢁ1 are assigned to the nitrile symmetric
stretch vibration of 3 and 3a, respectively. Thus the experimental
15N isotopic shift is 27 cmꢁ1. The DFT calculated isotopic shift is
in qualitative but not quantitative agreement with the experimen-
tal isotopic shift since the calculation was performed in the gas
phase and excluded anharmonic effects.28 The integrated area of
the two nitrile IR absorbance bands in Figure 1B shows that the
The percentage of 3 in this mixture of 3 and 3a was also found
to be dependent upon the length of the cyanation reaction increas-
ing to 43% after 24.5 h at 60 °C based upon the FTIR absorbance
spectrum of the isolated cyanation product(s) (see Supplementary
data Fig. S1). However, the overall yield of the reaction was not im-
proved with this longer reaction time. One possible explanation for
these results is that the cyanation step is reversible. The percent-
age of nonisotopically labeled cyanide anion in the reaction mix-
ture should increase with time if 15N labeled cyanide anion can
exchange with MeCN. A reversible cyanation would allow for the
incorporation of unlabeled cyanide formed from this exchange
thereby increasing the percentage of 3 in the final reaction mix-
ture. Additionally, the concentration of 15N labeled cyanide in the
reaction mixture could be decreasing with time due to the forma-
tion of volatile 15N labeled hydrogen cyanide resulting from the
presence of trace amounts of water.36 Thus, if the nitrile group of
acetonitrile can be transferred (through a nickel-mediated pro-
cess)29 to the aryl triflate 2, less competition from C15Nꢁ in the
reaction mixture could result in a larger percentage of 3 over time.
A second related possibility is that the nitrile group of 3a could
exchange (likely through a nickel-mediated process)37–39 with
Figure 1. FTIR absorbance spectra of isotopomers of N-(tert-butoxycarbonyl)-4-
cyano-L-phenylalanine methyl ester (3) in the nitrile symmetric stretching region
recorded at 298 K in THF. The isotopomers were synthesized based upon Scheme 1
with MeCN and either KCN (A), KC15N (B), K13CN (C), or K13C15N (D) in the cyanation
step. The spectra have been area normalized and offset for comparison.

C. G. Bazewicz et al. / Tetrahedron Letters 52 (2011) 6865–6868
6867
the nitrile group of cyanide or acetonitrile in the reaction mixture
without reforming 2. This possibility was tested by substituting 2
for 3b (>98% 13C enrichment, synthesis described below) in the
cyanation reaction step, while keeping the reaction time, tempera-
ture, and amounts of all other reagents (Ni(PPh3)2Br2, PPh3, Zn,
KC15N, and MeCN) unchanged. After 4.5 h, FTIR spectroscopy re-
vealed the presence of 3b (92%), 3a (6%), and 3 (2%) in the reaction
mixture (see Supplementary data Fig. S2). Thus nitrile exchange
between 3b and C15Nꢁ from KC15N can occur to generate 3a in
the presence of the cyanation reagents, while the amount of 3 pres-
ent can be explained based upon the original isotopic enrichment
of 3b and the isotopic enrichment of KC15N.
To further explore the potential of this synthetic route to gener-
ate isotopomers of 3, K13CN or K13C15N was utilized in the nickel-
catalyzed cyanation of 2 to generate 3b and 3c, respectively. The
resulting FTIR absorbance spectra are shown in Figures 1C and D,
respectively. Figure 1C shows two nitrile IR absorbance bands at
2229.2 and 2176.1 cmꢁ1. Based upon the position of the nitrile IR
absorbance spectrum of 3 and the DFT predicted isotopic shift,
the bands at 2229.2 and 2176.1 cmꢁ1 are attributed to the nitrile
symmetric stretch vibrations of 3 and 3b, respectively. Similarly,
the two bands at 2229.2 and 2148.6 cmꢁ1 in Figure 1D are assigned
to the nitrile symmetric stretch vibrations of 3 and 3c, respectively.
The relative integrated areas of the nitrile IR absorbance bands in
Figures 1C and D show the presence of 17% and 21% of 3, respec-
tively, in addition to the desired isotopomers (3b and 3c, respec-
tively). As expected based upon the change in the reduced mass
of the nitrile oscillator and DFT calculations, the magnitude of
the isotopic shift is the largest for 3c (relative to 3) followed by
3b and 3a. The magnitude of the isotopic shift results in the nitrile
IR absorbance bands of 3, 3a, 3b, and 3c being well resolved from
each other. Therefore, the synthetic procedure outlined in Scheme 1
using MeCN as the solvent in the second step successfully gener-
ated the desired isotopomers of 3. The incorporation of isotopically
enriched cyanide was only ꢀ80%.
Figure 2. FTIR absorbance spectra of isotopomers of N-(tert-butoxycarbonyl)-4-
cyano-L-phenylalanine methyl ester (Boc-PheCN-OMe, 3) in the nitrile symmetric
stretching region recorded at 298 K in THF. The isotopomers were synthesized
based upon Scheme 1 with DMF and either KCN (Boc-PheCN-OMe, 3), KC15N (Boc-
PheC15N-OMe, 3a), K13CN (Boc-Phe13CN-OMe, 3b), or K13C15N (Boc-Phe13C15N-
OMe, 3c) in the cyanation step. The spectra have been area normalized and offset
for comparison.
could be due to different conformations of the molecule, different
solute–solvent interactions, or accidental Fermi resonance be-
tween the fundamental nitrile symmetric stretch vibration and a
near-resonant overtone or combination band. The first two possi-
bilities are unlikely since the other isotopomers of 3 show essen-
tially
a symmetric nitrile IR absorbance band that can be
reasonably modeled with a single line shape. The third possibility
is most likely. For instance, DFT calculations of 3a reveal 33 combi-
nation bands within 10 cmꢁ1 of the fundamental nitrile symmetric
stretch vibration. The energy difference between the fundamental
nitrile symmetric stretch vibration and the near-resonant combi-
nation bands will be modulated upon isotopic labeling of the nitrile
group of 3, which could modulate the accidental Fermi resonance
likely present in the nitrile symmetric stretching region of 3a. Pre-
vious work with 3-azidopyridine and phenyl cyanate has demon-
strated the ability to modulate accidental Fermi resonance
through isotopic editing.40 The assignment of accidental Fermi res-
onance in 3a would explain the nearly symmetric line shapes mea-
sured for the nitrile IR absorbance bands in 3, 3b, and 3c. However,
2D IR experiments41–43 would be required for a definitive assign-
ment of accidental Fermi resonance in 3a.
The results utilizing DMF as the cyanation solvent further impli-
cate acetonitrile as the source of unlabeled nitrile resulting in only
ꢀ80% isotopic enrichment of 3a, 3b, and 3c when using MeCN as
the cyanation solvent and a reaction time of 4.5 h. However, it is
unclear whether the nitrile group of acetonitrile is transferred to
the aryl triflate 2 through a nickel-catalyzed process or whether
the nitrile group of MeCN first exchanges with the labeled cyanide
anion in the reaction mixture forming unlabeled CNꢁ, which then
participates in the nickel-catalyzed cyanation of 2.
Cyanation solvent: N,N-dimethylformamide (DMF)
In order to increase the isotopic enrichment of the isotopomers of
3, the effect of solvent in the nickel-catalyzed cyanation of 2 was
investigated. Specifically, acetonitrile was replaced with N,N-
dimethylformamide (DMF) in the cyanation step. The replacement
ofMeCNwithDMFasthecyanationsolventdidnotsignificantlyalter
the yield of 3 (see Supplementary data for complete synthetic details
and NMR characterization). The resulting FTIR absorbance spectra of
the purified cyanation product, obtained using KC15N, K13CN, or
K13C15N, in the nitrile symmetric stretching frequency region are
shown in Figure 2. As illustrated in Figure 2, the FTIR absorbance
spectra of each isotopomer dissolved in THF show a single nitrile IR
absorbance band corresponding to 3 (Boc-PheCN-OMe), 3a (Boc-
PheC15N-OMe), 3b (Boc-Phe13CN-OMe), or 3c (Boc-Phe13C15N-
OMe). Each of the isotopomers showed an isotopic enrichment
>98%, limited by the isotopic enrichment of the potassium cyanide
isotopomer used. The nitrile IR absorbance bands for 3, 3a, 3b, and
3c appeared at 2229.2, 2202.1, 2176.1, and 2148.6 cmꢁ1, respec-
tively, which are identical with the band positions of the cyanation
products generated using MeCN as the cyanation solvent.
Each of the nitrile IR absorbance bands could be fit to a single
line shape composed of a linear combination of a Gaussian and
Lorentzian function having the same central frequency (see Sup-
plementary data) except 3a. The nitrile IR absorbance band of 3a
was slightly asymmetric and required two line shapes to suffi-
ciently model the experimental absorbance band. The position of
the smaller component is 2202.7 cmꢁ1 while the larger component
has a central frequency of 2200.9 cmꢁ1. These two components
Conclusions
Three isotopomers (C15N, 13CN and 13C15N) of 3 were success-
fully generated in two steps with an isotopic enrichment >98%. Sol-
vent choice for the nickel-catalyzed cyanation of 2 was found to be
critical for achieving isotopically pure (>98% isotopic enrichment)
material. The commonly used cyanation solvent, MeCN25–27 was
found to generate the desired isotopomers, but with a ꢀ20% con-
tamination of 3 with a cyanation reaction time of 4.5 h. However,
the use of DMF as the cyanation solvent yielded isotopically pure
3a, 3b, or 3c with isotopic enrichment limited by the enrichment

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Acknowledgments
We gratefully acknowledge Kristopher Kolonko for helpful dis-
cussions; Lisa Mertzman for obtaining materials and supplies; Beth
Buckwalter for acquiring NMR spectra; and Carol Strausser for
assistance in editing of the manuscript. This work was supported
by F&M Hackman funds and NSF (CHE-1053946) to SHB.
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Supplementary data
Supplementary data (synthetic methods and characterization of
3, 3a, 3b, and 3c; FTIR experimental methods; line shape analysis
of nitrile IR absorbance band of 3, 3a, 3b, and 3c; and DFT compu-
tational details) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.10.050.
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