Synthesis of β-amino-α-trifluoromethyl-α-amino acids exhibiting intramolecular interaction of CF3 with NHβ

Article abstract of DOI:10.1016/j.tetlet.2014.10.107

We prepared β-amino-α-trifluoromethyl-α-amino acids through ring-opening reaction of N-tosyl-2-trifluoromethyl-2-ethoxycarbonylaziridine with aromatic and benzylic amines, and investigated the intramolecular interaction between the trifluoromethyl (CF₃) group at the α-position and the NH group at the β-position (NH_β). NMR, UV/vis, and circular dichroism measurements indicated that the conformation of these compounds is fixed by intramolecular interaction of CF₃ with NH_β to form a six-membered ring.

Full text of DOI:10.1016/j.tetlet.2014.10.107

Tetrahedron Letters 55 (2014) 6915–6918
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of b-amino-
a-trifluoromethyl-a-amino acids exhibiting
intramolecular interaction of CF3 with NHb
b
a
a
Minoru Waki a, , Toshimasa Katagiri , Kenji Matsuno , Hiroyuki Miyachi
⇑
a Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan
b Faculty of Engineering, Okayama University, 3-1-1, Tsushima-Naka, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We prepared b-amino-a-trifluoromethyl-a-amino acids through ring-opening reaction of N-tosyl-2-tri-
fluoromethyl-2-ethoxycarbonylaziridine with aromatic and benzylic amines, and investigated the intra-
Received 11 August 2014
Revised 16 October 2014
Accepted 20 October 2014
Available online 24 October 2014
molecular interaction between the trifluoromethyl (CF3) group at the -position and the NH group at the
a
b-position (NHb). NMR, UV/vis, and circular dichroism measurements indicated that the conformation of
these compounds is fixed by intramolecular interaction of CF3 with NHb to form a six-membered ring.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aziridine
Trifluoromethyl group
Amino acid
Intramolecular interaction
Installation of fluorine atom(s) into organic molecules leads to
drastic changes in chemical properties, owing to its strongly elec-
tron-withdrawing nature.1,2 For example, fluorine-substituted
pharmaceuticals often show increased biological stability due to
the high binding energy of the CAF bond (484 kcal molÀ1), result-
ing in greater metabolic stability and bioavailability, and various
pharmaceutical candidates containing fluorine, difluoromethyl, or
trifluoromethyl (CF3) moieties have been reported.3 Indeed, at
present approximately 20% of all pharmaceuticals contain fluorine
in their molecular structure.4–6
of an aziridine with nucleophiles such as amine, alcohol, and thiol
gives ring-opened products with various functional groups at the
b-position in good to moderate yields.13 In particular, nucleophilic
attack of aniline on the trifluoromethylated (CF3)-aziridine 1
affords b-phenylamino-a-trifluoromethyl-a-amino acid structure
(Scheme 1), in which the NH group at the b-position (NHb) can
function as a proton donor for intramolecular hydrogen bonding
with the CF3 group to form a six-membered ring. Such intramolec-
ular interaction would stabilize the molecular conformation. In this
Letter, we describe the synthesis of b-amino-a-trifluoromethyl-a-
Fluorine atom(s) have also found application in the fields of
artificial enzymes and peptides.7–9 For example, trifluoromethyla-
tion of leucine and valine improves the thermal stability of
coiled-coil structure in artificial peptides containing these amino
acids.10 The high lipophilicity of CF3 within hydrophobic regions
of peptides increases the stability of assembled peptide structures.
Thus, trifluoromethylated (CF3-) amino acid residues can be a pow-
erful tool for protein engineering. However, there are still relatively
few biological applications of CF3-amino acids, even though syn-
thetic methodologies have advanced.11 Further understanding of
the functionality of CF3 groups in peptides is still required.
amino acids through ring-opening reaction of CF3-aziridine 1 with
amines. Intramolecular interaction between the CF3 and NHb
groups in these molecules was characterized by means of NMR,
UV/vis, and circular dichroism (CD) spectroscopic measurements.
As reported previously, the ring-opening reaction selectively
proceeds via nucleophilic attack on the aziridine ring.12 The ring-
opened products 2a–2j formed by nucleophilic addition of
aromatic amines and benzylic amines were obtained in good to
moderate yields, and detosylation by treatment with concentrated
H2SO4 afforded b-amino-a-trifluoromethyl-a-amino acids 3a–3j as
Recently, we reported the preparation of
a-trifluoromethyl-a-
amino acids through ring-opening reaction of N-tosyl-2-trifluoro-
methyl-2-ethoxycarbonyl aziridine (1) with nucleophiles and
detosylation of the aziridine N-atom (Scheme 1).12 The reaction
⇑
Scheme 1. Strategy for the synthesis of b-amino-a-trifluoromethylated-a-amino
acids.
Corresponding author. Tel./fax: +81 86 251 7932.
E-mail address: mwaki@pharm.okayama-u.ac.jp (M. Waki).
http://dx.doi.org/10.1016/j.tetlet.2014.10.107
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6916
M. Waki et al. / Tetrahedron Letters 55 (2014) 6915–6918
Table 1
Optical properties of b-amino-
a
-trifluoromethyl-
a
-amino acids 3a–3j and their analogues 4 and 5
Compound
19Fa (ppm)
eb (L molÀ1cmÀ1
)
kmax (nm)
[h]c (deg cm2 dmolÀ1
)
NH2
EtOOC
1.0 Â 104
2.1 Â 103
248
291
3a
3b
85.0
2.0 Â 103
F3C
HN
NH2
EtOOC
F3C
85.1
85.1
2.5 Â 103
292
1.5 Â 103
1.7 Â 103
HN
NH2
EtOOC
F3C
3c
9.1 Â 104
2.1 Â 103
248
292
HN
NH2
Br
3d
EtOOC
F3C
9.7 Â 104
3.0 Â 103
245
298
85.0
85.1
2.5 Â 103
HN
NH2
OMe
EtOOC
F3C
1.2 Â 105
4.1 Â 103
254
301
3e
N.D.d
HN
NH2
Br
EtOOC
F3C
3f
1.1 Â 105
2.0 Â 103
250
295
85.8
85.2
À3.8 Â 103
N
Me
NH2
EtOOC
F3C
2.1 Â 102
259
263
—
HN
3g
NH2
EtOOC
F3C
HN
85.2
2.8 Â 102
—
3h
F3i
NH2
EtOOC
F3C
HN
85.1
85.6
1.4 Â 103
265
260
—
—
CF3
NH2
EtOOC
3j
F3C
N
6.1 Â 102
NH2
H
9.4 Â 104
1.8 Â 103
244
293
4
5
84.0
—
2.5 Â 103
F3C HN
NH2
H
9.1 Â 104
1.7 Â 103
248
296
0.58 Â 103
H3C
HN
a
b
c
Chemical shift based on C6F6 as an internal standard.
Reagents and conditions: concentration; 1.2 Â 10À4 M, solvent; CHCl3, temperature; 25 °C, light path length; 10 mm.
Reagents and conditions: concentration; 1.0 Â 10À3 M, solvent; CHCl3, temperature; 25 °C, light path length; 10 mm.
Not determined.
d
shown in Table 1. The chirality at the optically active center of the
product prepared from optically pure aziridine 1 was retained
throughout these reaction processes, as reported previously.14
Compounds 4 and 5 were synthesized for comparison of their
structural properties with those of b-amino- -trifluoromethyl-
amino acids. Analogue 4 lacking the ethyl ester group was
a
a-

M. Waki et al. / Tetrahedron Letters 55 (2014) 6915–6918
6917
Figure 1. Chemical structure of b-phenylamino-a-trifluoromethyl-a-amino acid
3a.
prepared by ring-opening reaction of N-tosyl-2-(trifluoro-
methyl)aziridine (6) with aniline, followed by detosylation (see
Supplementary data). Replacement of F with H atoms afforded
methylated (CH3) analogue 5 from N-tosyl-2-methylaziridine (8).
A
structural model of b-phenylamino-a-trifluoromethyl-a-
amino acid 3a is shown in Figure 1. Intramolecular interaction
between the NHb and CF3 groups can be anticipated, because
weakly hydrogen-bonded six- and five-membered ring formation
is known to be favorable.15 The calculated distance between NHb
and CF in such molecules was estimated to be 1.95–2.37 Å,16 which
is appropriate for the interaction.
NMR measurements were carried out to examine the intramo-
lecular interaction between NHb and CF3. The proton signal of NHb
connected to the phenyl group on the b-amino-a-trifluoromethyl-
Figure 2. CD spectra of b-amino-
their analogues 4 and 5.
a
-trifluoromethyl-
a
-amino acids 3a–3d, 3f, and
b-amino-a-trifluoromethyl-a-amino acids 3b–3d with various
functional groups on the phenyl ring also showed a positive Cotton
effect similar to that of 3a. Compound 4 having no ester group also
showed a similar CD spectrum. On the other hand, compound 5,
which contains CH3 in place of CF3, showed only a weak signal at
the same absorption region (Fig. 2). These results suggested that
a
-amino acids was observed as a broad peak at 4.0–4.5 ppm, but
there was no clear coupling signal. In the 19F NMR spectra
(Table 1),17 signals of 3a–3e and 3g–3i were observed at 85.0–
85.2 ppm, which can be assigned to interacting fluorine species.
These chemical shifts did not appear to be influenced by functional
groups on the phenyl ring. On the other hand, N-methylated (3f) and
the phenyl group of b-amino-a-trifluoromethyl-a-amino acids
3a–3d and 4 is fixed in a specific conformation by intramolecular
interaction between the CF3 and NHb groups, whereas in 5, in
which there is little interaction between NHb and CH3, the confor-
mation of the phenyl ring is not fixed. The spectrum of N-methyl-
ated derivative 3f showed a negative CD signal, the inverse of that
of 3a. The N-methyl group sterically repels the CF3 group, which
presumably flips to the opposite side of the CF3 group, resulting
in the negative CD signal in this absorption range (Fig. 2). On the
N,N-dibenzyl (3j) b-amino-a-trifluoromethyl-a-amino acids
showed characteristic peaks at 85.8 and 85.6 ppm, respectively,
downfield from the other compounds. This may be because fluorine
does not interact with nitrogen of the tertiary amine groups of 3f
and 3j. The 19F NMR spectrum of 4, which lacks an ester group in
its molecular structure, showed a peak at 84.0 ppm due to the CF3.
UV/vis and CD spectral studies are useful for investigating spe-
other hand, b-benzylamino-
3j have unique absorption bands at 250–260 nm with the low
a-trifluoromethyl-a-amino acids 3g–
e
values of 2.1–6.1 Â 102 L molÀ1cmÀ1 due to the benzyl group (see
Supplementary data, Figs. S7–S10). The CD spectra of 3g–3j exhib-
ited a very weak Cotton effect in this absorption range (see
Supplementary data, Fig. S13), suggesting that the benzyl group
has a disordered conformation because it can rotate freely despite
the interaction of CF3 and NHb. These interpretations of the spectral
studies are all consistent with our proposal of intramolecular inter-
action between CF3 and NHb. In future, further support for this pro-
posal will be obtained by additional analysis such as X-ray crystal
study and the effort to broaden the scope of substituents on NHb.
cific interactions in solution.18 The UV/vis spectra of b-amino-
fluoromethyl- -amino acids 3a–3f and their analogues 4 and 5
exhibited two absorption bands at around 250 and 290 nm, which
were assigned to the * and n– * transition modes, respectively
a-tri-
a
p–p
p
(see Supplementary data, Figs. S1–S6, S11, and S12). The molar
absorption coefficient at 291 nm for 3a was estimated to be
2.1 Â 103 L molÀ1 cmÀ1 from a Lambert–Beer plot (see Supplemen-
tary data, Fig. S1). The fact that the plot obeyed Beer’s law indicates
that the intermolecular association of 3a was negligible in this
concentration range. Compounds 3b–3f, 4, and 5 showed similar
e
values of 1.7 Â 103–4.1 Â 103 L molÀ1 cmÀ1 in this concentration
In conclusion, we have synthesized a number of b-amino-
a-tri-
fluoromethyl- -amino acids through ring-opening reaction of
a
range, irrespective of the presence/absence of ester at the
a
-position
CF3-aziridine. 19F NMR, UV/vis, and CD studies were consistent
with stabilization of the structure by intramolecular interaction
between CF3 and NHb. Application of this interaction is expected
to open up new opportunities for the design of functional artificial
peptides.
or any functional group on the phenyl ring. The n–
p* absorption
band of 3a–3c was observed at 291–292 nm, and that of the ethyl
ester-lacking compound 4 was also at 293 nm, at shorter wave-
length than that (296 nm) of the CH3-analogue 5. On the other hand,
the absorption peak due to n–
p
* transition in the spectrum of
-amino acid 3f appeared at
N-methyl b-amino- -trifluoromethyl-
a
a
Acknowledgements
295 nm, which was similar to that of CH3-analogue 5. The slight
blue-shift of the absorption band for 3a–3c and 4 is attributed to
the lower HOMO energy level, which may be due to interaction of
the CF3 group with the NHb group.19 It appears that the CF3 group
This work was supported by Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
at the
interaction that stabilizes a particular molecular conformation.
Interestingly, b-phenylamino- -trifluoromethyl- -amino acid
3a showed a positive CD signal in the n– * absorption region at
a-position of these amino acids undergoes an intramolecular
a
a
Supplementary data
p
ca. 290 nm in CHCl3 solution (Fig. 2). This CD signal can be attrib-
uted to the chiral conformation of the aromatic moiety, which has
an optically active carbon at the a-position. The CD spectra of other
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
107.

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M. Waki et al. / Tetrahedron Letters 55 (2014) 6915–6918
11. (a) Aceña, J. L.; Sorochinsky, A. E.; Soloshonok, V. A. Synthesis 2012, 44, 1591–
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