Trifluoromethyl-modified dipeptides by ZrCl4-promoted aza-Henry reactions

Article abstract of DOI:10.1007/s00726-014-1749-4

Chiral (R)-1-phenylethylamine was successfully employed in a tandem aza-Henry addition-reduction reaction to give chiral β-nitro α-trifluoromethyl amines. A subsequent coupling reaction with N-Boc-protected amino acids leads to obtain optically pure CF

Full text of DOI:10.1007/s00726-014-1749-4

Amino Acids
DOI 10.1007/s00726-014-1749-4
ORIGINAL ARTICLE
Trifluoromethyl-modified dipeptides by ZrCl4-promoted
aza-Henry reactions
•
Stefania Fioravanti Alessia Pelagalli
•
•
Lucio Pellacani Fabio Sciubba
•
Maria Cecilia Vergari
Received: 24 February 2014 / Accepted: 10 April 2014
Ó Springer-Verlag Wien 2014
Abstract Chiral (R)-1-phenylethylamine was success-
fully employed in a tandem aza-Henry addition–reduction
reaction to give chiral b-nitro a-trifluoromethyl amines. A
subsequent coupling reaction with N-Boc-protected amino
acids leads to obtain optically pure CF3-modified dipep-
tides carrying two different N-protecting groups. These
peptidomimetic units are characterized by the presence of
the [CH(CF3)NH] group as mimetic of the natural [CONH]
peptidic bond and can be used for the synthesis of more
complex CF3-modified peptides after selective deprotection
of one of the two amine functions. 2D NMR spectral
analyses were employed to determine the absolute config-
urations of all newly synthesized chiral compounds.
reactivity (Cahard and Bizet 2014; O’Hagan 2013; Zhang
et al. 2012; Filler and Saha 2009; Couve-Bonnaire et al.
2007; Mu¨ller et al. 2007). Selective incorporation of fluo-
rinated residues into proteins is actually considered a
powerful strategy to modulate the properties of those pep-
tides which show great potential as highly active pharma-
ceuticals (Salwiczek et al. 2012; March et al. 2012; Merkel
and Budisa 2012; Buer and Marsh 2012; Mikami et al.
2011; Qiu and Qing 2011; Acena et al. 2010; Kukhar et al.
2009). The success of substitution with fluorine stems from
its unique properties: small size, very low polarizability and
strong inductive effect. As a consequence, the presence of
fluorine within a peptide often favorably modifies the bio-
physical, biological and chemical properties such as
hydrophobicity, acidity/basicity, reactivity and conforma-
tion. Numerous examples can be found where fluorine has
effectively replaced either hydrogen or oxygen in com-
pounds that have retained comparable activities, albeit with
different properties (Buer et al. 2012; McKinney and Urban
2010; Fustero et al. 2009; Molteni et al. 2004). An impor-
tant modification consists in the incorporation of a
[CH(CF3)NH] unit as a surrogate of the natural [CONH]
peptidic bond, due to the fact that the trifluoromethyl group
is an effective xenobiotic function for the peptide backbone
modification (Cho et al. 2013; Jagodzinska et al. 2009;
Zanda 2004; Sani et al. 2003; Molteni et al. 2003; Volon-
terio et al. 2002) (Fig. 1).
Keywords Amino acids ꢀ NMR techniques ꢀ
Organo-fluorine chemistry ꢀ Peptidomimetics
Introduction
The special nature of fluorine imparts a variety of properties
to certain molecules making them potential drug candi-
dates, including enhanced-binding interactions, metabolic
stability, changes in physical properties, and selective
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-014-1749-4) contains supplementary
material, which is available to authorized users.
Unfortunately, the synthetic accessibility of fluorinated
peptides is limited by the availability of appropriate
building blocks both for the liquid and for the solid-phase
synthesis.
S. Fioravanti (&) ꢀ A. Pelagalli ꢀ L. Pellacani ꢀ M. C. Vergari
`
Dipartimento di Chimica, Universita degli Studi di Roma ‘‘La
Sapienza’’, P.le Aldo Moro 5, 00185 Rome, Italy
e-mail: stefania.fioravanti@uniroma1.it
´
´
(E)-Trifluoromethyl aldimines (Begue et al. 2005), can
be easily synthesized through a solvent-free reaction
starting from commercial trifluoroacetaldehyde ethyl
hemiacetal (Gong and Kato 2004) and several primary
F. Sciubba
Istituto di Cristallografia, Consiglio Nazionale delle Ricerche
(CNR), Via Giovanni Amendola, 122/O, 70126 Bari, Italy
123

S. Fioravanti et al.
O
R'
O
R'
*
H
H
H
H
N
N
N
N
*
N
N
H
H
CF3
R
O
R
natural peptide
trifluoromethyl-modified peptide
Fig. 1 [CH(CF3)NH] unit as mimetic of natural [CONH] peptidic
bond
Scheme 2 One-pot synthesis of b-nitro a-trifluoromethyl amines
under solvent-free conditions
amines (Carroccia et al. 2010, 2011) and can be considered
interesting precursors for the construction of small fluori-
nated peptides, already containing both the CF3 group and
the nitrogen atom. Then, starting from our recent studies on
the ZrCl4-catalyzed aza-Henry addition of different nitro
alkanes on (E)-trifluoromethyl aldimines (Fioravanti et al.
2012), the synthesis of N,N0-diprotected CF3-modified
Table 1 Results of the tandem Zr-catalyzed aza-Henry addition
Entry
2
R0
T (h)
Products
Yield
(%)a
Drb
1
2
a
H
3
3,30a
80
24
52
24
48
80:20
72:28
72:28
67:33
67:33
b
Me
18
syn-4,40b
anti-5,50b
syn-4,40c
anti-5,50c
dipeptides by
(Scheme 1).
a
short procedure was considered
3
c
Et
18
a
After flash chromatography on silica gel
Diastereomeric ratios by 19F NMR spectra performed on the crude
mixtures
Results and discussion
b
Chiral (R)-1-phenylethylamine (1) is considered as a suit-
able starting primary amine due to the presence of the
benzylic group that can be easily removed under mild
hydrogenolytic conditions. Considering that the imine
synthesis was performed under solvent-free conditions as
well as the aza-Henry addition, a one-pot reaction was
attempted. So, to the commercial amine 1 trifluoroacetal-
dehyde ethyl hemiacetal in equimolar ratio was added,
heating to 120 °C and the reaction was followed by 19F
NMR spectroscopy (4 h) (Carroccia et al. 2010). After
bringing the reaction to room temperature, ZrCl4 (50 % M)
and the appropriate nitro alkane 2 (5 eq) were added
directly in the same vessel (Scheme 2).
The aza-Henry reactions were followed by 19F NMR
spectroscopy and the results are reported in Table 1.
In all cases, complete disappearance of the CF3 signal of
the non-isolated intermediate imine was observed by 19F
NMR spectra and the expected b-nitro a-trifluoromethyl
amines were obtained in satisfactory yields after flash
chromatography on silica gel. In hope of enhancing the
stereoselective outcome, the reactions were repeated by
varying the temperature (0 and -20 °C), but no significant
changes in the diastereomeric ratios (dr) were determined
by the 19F NMR analysis performed on the crude mixtures.
As reported in Table 1, when using nitromethane 2a a
moderate diastereomeric ratio was observed (entry 1) and,
when the aza-Henry reactions were performed using nitro
alkanes 2b or 2c (entries 2 and 3), all the four possible
diastereomers were obtained, although in different ratios
(Fig. 2).
Nevertheless, we underline that complete stereoselec-
tivity can paradoxically result in a limitation in the stra-
tegic synthesis of CF3-modified dipeptides. In fact, it is
important to access each of the new diastereomeric pro-
ducts, because of the possible drastic difference of reac-
tivity in biological matrices among stereoisomers.
Fortunately, the diastereomers from the reaction mixture
could be easily separated by column chromatography to
obtain diastereomerically pure compounds.
To univocally assign the chirality of the newly formed
1
stereocenters, 2D NOESY H NMR spectra (Fig. 3) were
acquired on the purified 3a (a) and 30a (b).
These experiments permit to determine interproton dis-
tances through the measure of cross-peak volumes and thus
determine molecular geometry (Aliev et al. 2012; Falk
et al. 2001; Silvi et al. 2013; Carroccia et al. 2012; Aresu
et al. 2013b, c). In fact, as reported (Jeener et al. 1979)
starting from a reference cross peak whose interproton
Scheme 1 Procedure for the
synthesis of N,N0-diprotected
CF3-modified dipeptides
123

Trifluoromethyl-modified dipeptides
Fig. 2 19F NMR spectra
performed on the crude
mixtures of 3,30a and syn-4,40b
and anti-5,50b
Fig. 3 2D NOESY of 3a (a) and 30a (b). In both spectra the cross peaks corresponding to the interproton correlations Ha/Hb and Hb/Hc are
evidenced
distance is known, it is possible to calculate the distances
between other protons according to the following equation:
volume VR was set at 10 arbitrary units (au). Therefore, the
volumes relative to the cross peaks between Ha and Hb (VX)
were found to be 0.92 au for 3a and 1.37 au for 30a, and the
ꢀ
ꢁ
6
VX
VR
dR
dX
˚
corresponding interproton distances (3.96 and 3.70 A,
¼
;
respectively, with a confidence level of *3 %) (Jones
et al. 2011) were calculated. Thus, comparing the collected
data (Fig. 4), the absolute configurations of the new chiral
centers, S for 3a and R for 30a, were univocally assigned.
The results showed that the nucleophilic attack takes
place preferentially on the less hindered Si face of the
intermediate non-isolated (E,R)-trifluoromethyl imine I,
probably following the mechanism reported in Scheme 3
for the synthesis of the major isomer (R,S)-3a, that involves
the formation of the chiral metallic intermediate II.
in which VR is the volume of the reference cross peak, dR
is the corresponding interproton distance and VX is the
volume relative to the unknown distance dX.
Considering that the chiral center on the amine residue
is always in R configuration, the interproton distance
between Hb and the protons Hc in both 3 and 30a can be
considered as a fixed value and employed as a ruler to
determine the distance between Ha and Hb. On the basis of
˚
the optimized geometries of both diastereomers, 2.66 A
1
Finally, 2D NOESY H NMR spectra were performed
also on syn-4,40b,c anti-5,50b,c, and the absolute
was found as the medium value of the interproton distance
(dR) between Hb and the protons Hc and the corresponding
123

S. Fioravanti et al.
Fig. 4 Optimized geometries of (R,S)-3a and (R,R)-30a
Scheme 3 Proposed pathway
for the synthesis of the major
isomer (R,S)-3a
chromatography on silica gel (eluent: hexane/ethyl ace-
tate = 8:2). The absolute configurations were assigned on
the basis of NOESY analyses, following the above reported
methodology and choosing like distance ruler the one
between the proton of NH Boc-protected and the proton on
the L-Valine chiral center. Due to the presence of two
different N-protecting groups on the synthesized com-
pounds, on the basis of the planned synthetic strategy it is
possible to choose the further site of growth and molecular
diversification. In fact, a hydrogenolysis reaction permits to
remove the benzyl group, while an acidic hydrolysis leads
to remove the Boc group.
Fig. 5 Absolute configurations of syn-4,40b and anti-5,50b
configurations of all new chiral centers of diastereomeri-
cally pure b-nitro a-trifluoromethyl amines were assigned
(Fig. 5).
Then, the complete synthetic procedure was successfully
performed starting from the optically pure b-nitro a-tri-
fluoromethyl amines 3a and 30a to obtain directly optically
pure (R,S)-11 and (R,R)-110a (Scheme 5).
The obtained chiral b-nitro amines were considered in a
selective reduction reaction of the nitro group to form the
corresponding chiral b-diamines whose primary amine
group may give a coupling reaction with N-protected a-
amino acids under classical reaction conditions.
To test the procedure, the racemic mono-benzyl 1,2-
diamine 7, obtained from the corresponding b-nitro a-tri-
fluoromethyl amine 6 (Fioravanti et al. 2012), was con-
sidered in a coupling reaction with N-Boc-Gly or N-Boc-l-
Val performed in the presence of N,N0–dicyclohexylcar-
bodiimide (DCC) and 4-dimethylaminopyridine (DMAP)
(Scheme 4).
A subsequent hydrogenolysis reaction (Grishina et al.
2005) leadsto the corresponding (S)-12 and (R)-120a, aschiral
CF3-modified dipeptides, in which the presence of a primary
amine function can allow a further molecular growth.
Conclusion
In conclusion, the synthesis of optically pure trifluoro-
methyl-modified dipeptides has been reported here. The
process involves a tandem Zr-catalyzed aza-Henry addi-
tion–reduction reaction aiming to replace the natural
[CONH] peptidic bond with the [CH(CF3)NH] mimetic
unit. Starting from the commercially cheap (R)-1-
The use of N-Boc-l-Val leads to diastereomers (S,S)-9
and (R,S)-90 (Grishina et al. 2005) that were obtained as
optically pure CF3-modified dipeptides by flash
123

Trifluoromethyl-modified dipeptides
Scheme 4 Coupling reaction
with N-Boc-Gly or N-Boc-l-Val
Scheme 5 Synthetic procedure
for N-Boc-protected optically
pure CF3-modified dipeptides
phenylethylamine, a chiral metal complex was proposed as
an intermediate to explain the stereoselective reaction
outcome. The synthesis can be considered a green proce-
dure, the one-pot key step taking place under solvent-free
conditions. Moreover, the obtained compounds are suitable
for potential combinatorial applications and for industrial
use as building blocks for drug discovery, such as other
different peptidomimetic structures reported by us (Fio-
ravanti et al. 2010a, b; Aresu et al. 2013a).
recorded on a VARIAN XL-300 spectrometer at 282.2 MHz,
using CDCl3 as the solvent and C6F6 as the internal standard.
The NOESY experiments were performed by a Bruker
Avance III at400 MHz using CDCl3 as the solvent and CHCl3
as the internal standard and used to assist in structure eluci-
dation (Claridge 2009). HR-MS analyses were performed
using a Micromass Q-TOF Micro quadrupole-time of flight
(TOF) mass spectrometer equipped with an ESI source and a
syringe pump. The experiments were conducted in the posi-
tiveionmode. Optical rotationwasdeterminedat25 °C witha
JASCD DIP-370 polarimeter at a wavelength of 589 nm,
using a quartz cell of 1 cm length.
Experimental
IR spectra were recorded on a Perkin-Elmer 1600 FT/IR
spectrophotometer in CHCl3 as the solvent. 1H NMR and 13
C
One-pot synthesis of b-nitro a-trifluoromethyl amines
under solvent-free conditions: general procedure
NMR spectra were recorded on a VARIAN XL-300 spec-
trometer at 300 and 75 MHz or by a Bruker Avance III at 400
and 101 MHz, respectively, at room temperature. CDCl3 was
used as the solvent and CHCl3 and CDCl3 as the internal
standard for 1H and 13C, respectively. 19F NMR spectra were
A stirred equimolar solution (1 mmol) of trifluoroacetal-
dehyde ethyl hemiacetal (90 % aq. solution, 160 mg) and
(R)-1-phenylethylamine (122 mg) was heated at 120 °C
123

S. Fioravanti et al.
under solvent-free conditions in a flask fitted with a cal-
cium chloride tube. After 4 h, the reaction mixture was
cooled to room temperature and ZrCl4 (0.5 mmol, 116 mg)
and nitro compound 2 (5 mmol) were added under stirring.
(d, J = 6.8 Hz, 3H), 1.74 (br, 1H), 3.65–3.78 (m, 1H), 3.89
(q, J = 6.3 Hz, 1H), 4.55–4.45 (m, 1H), 7.16–7.28 (m,
5H). 13C NMR (101 MHz, CDCl3) d 12.5, 22.7, 55.9, 58.4
(q, J = 27.6 Hz), 80.4, 124.3 (q, J = 284.9 Hz), 127.1
(2C), 127.7, 128.6 (2C), 142.5. 19F NMR (282 MHz,
CDCl3) d -73.6 (d, J = 6.9 Hz). HR-MS (ESI/Q-TOF)
(m/z) calcd for C12H16F3N2O2 [M ? H]?: 277.1164, found
277.1159; (m/z) calcd for C12H15F3N2NaO2 [M ? Na]?:
299.0983, found 299.0978.
1
The reactions were followed by H and 19F NMR (3–18 h,
see Table 1). Then, after addition of water (5 mL), the
crude mixtures were extracted three times with Et2O. The
collected organic layers were dried over anhydrous Na2SO4
and the solvent was evaporated under vacuum. The crude
mixtures were purified by flash chromatography on silica
gel.
Synthesis of 3 and 30a. Yield: 80 % (210 mg). Separated
by flash chromatography on silica gel (eluent: hexane/ethyl
acetate = 9:1).
(2R,3S)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]butan-2-amine (syn-40b)
Yellow oil (7 %, 21 mg). [a]2D5 -16.4 (c = 3, CHCl3). H
1
NMR (400 MHz, CDCl3) d 1.28 (d, J = 6.7 Hz, 3H), 1.42
(d, J = 7.7 Hz, 3H), 1.57 (br, 1H), 3.11–3.26 (m, 1H), 3.89
(q, J = 6.4 Hz, 1H), 4.50–4.59 (m, 1H), 7.08–7.17 (m,
5H). 13C NMR (101 MHz, CDCl3) d 16.1, 22.7, 56.1, 59.6
(q, J = 28.5 Hz), 82.2, 124.3 (q, J = 284.9 Hz), 126.5,
127.3 (2C), 127.8 (2C), 142.7. 19F NMR (282 MHz,
CDCl3) d -73.1 (d, J = 6.7 Hz). HR-MS (ESI/Q-TOF)
(m/z) calcd for C12H16F3N2O2 [M ? H]?: 277.1164, found
277.1171; (m/z) calcd for C12H15F3N2NaO2 [M ? Na]?:
299.0983, found 299.0986.
(2S)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]propan-2-amine (3a)
Yellow pale oil (64 %, 168 mg). IR: 3,328, 1,570 cm-1
.
[a]2D5 -79.0 (c = 4, CHCl3). H NMR (400 MHz, CDCl3)
d 1.36 (d, J = 6.4 Hz, 3H), 1.79 (br, 1H), 3.91–4.02 (m,
1H), 4.05 (q, J = 6.4 Hz, 1H), 4.45 (dd, J = 12.8, 7.8 Hz,
1H), 4.65 (dd, J = 12.8, 4.6 Hz, 1H), 7.27–7.39 (m, 5H).
13C NMR (101 MHz, CDCl3) d 23.22, 55.5, 56.03 (q,
J = 28.6 Hz), 73.9, 124.9 (q, J = 283.4 Hz), 126.6 (2C), 127.7,
128.6 (2C), 143.7. 19F NMR (282 MHz, CDCl3) d -77.3 (d,
J = 7.0 Hz). HR-MS (ESI/Q-TOF) m/z calcd for C11H14F3N2-
O2 [M ? H]? 263.1007, found 263.1011; m/z calcd for C11-
H13F3N2NaO2 [M ? Na]? 285.0827, found 285.0834.
1
(2S,3S)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]butan-2-amine (anti-5b)
Yellow oil (37 %, 105 mg). [a]2D5 -7.8 (c = 3, CHCl3). 1H
NMR (400 MHz, CDCl3) d 1.21 (d, J = 6.4 Hz, 3H), 1.52
(d, J = 6.8 Hz, 3H), 1.89 (br, 1H), 3.90 (q, J = 6.3 Hz,
1H), 4.12–4.01 (m, 1H), 4.58–4.67 (m, 1H), 7.17–7.28 (m,
5H). 13C NMR (101 MHz, CDCl3) d 12.4, 22.8, 55.8, 58.7
(q, J = 28.3 Hz), 80.6, 124.8 (q, J = 284.1 Hz), 126.7,
127.7 (2C), 128.6 (2C), 144.0. 19F NMR (282 MHz,
CDCl3) d -75.10 (d, J = 7.4 Hz). HR-MS (ESI/Q-TOF)
(m/z) calcd for C12H16F3N2O2 [M ? H]?: 277.1164, found
277.1168; (m/z) calcd for C12H15F3N2NaO2 [M ? Na]?:
299.0983, found 299.0977.
(2R)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]propan-2-amine (30a)
Yellow pale oil (16 %, 42 mg). [a]2D5 -15.3 (c = 3,
1
CHCl3). H NMR (400 MHz, CDCl3) d 1.32 (d, J = 6.5,
3H), 1.77 (br, 1H), 3.59–3.80 (m, 1H), 4.11 (q, J = 6.4,
1H), 4.29 (dd, J = 12.6, 9.3, 1H), 4.44 (dd, J = 12.6, 4.3,
1H), 7.15–7.38 (m, 5H). 13C NMR (101 MHz, CDCl3) d
24.8, 55.2 (q, J = 28.8 Hz), 55.9, 74.7, 125.3 (q,
J = 286.2 Hz), 127.0 (2C), 127.9, 128.7 (2C), 142.5. 19F
NMR (282 MHz, CDCl3) d -75.9 (d, J = 6.6 Hz). HR-
MS (ESI/Q-TOF) (m/z) calcd for C11H14F3N2O2
[M ? H]?: 263.1007, found 263.1002; (m/z) calcd for
C11H13F3N2NaO2 [M ? Na]?: 285.0827, found 285.0821.
Synthesis of syn-4,40b and anti-5,50b. Yield: 76 %
(210 mg). Separated by flash chromatography on silica gel
(2R,3R)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]butan-2-amine (anti-50b)
Yellow oil (15 %, 38 mg). [a]2D5 -8.0 (c = 3, CHCl3). H
1
NMR (400 MHz, CDCl3) d 1.24 (d, J = 6.5 Hz, 3H), 1.60 (d,
J = 8.0 Hz, 3H), 1.75 (br, 1H), 4.67–4.58 (m, 1H), 3.98 (q,
J = 6.4 Hz, 1H), 4.63–4.74 (m, 1H), 7.14–7.30 (m, 5H). 13
C
(eluent: hexane/ethyl acetate = 92:8). IR: 3,990, 1,550 cm-1
.
NMR (101 MHz, CDCl3) d 16.1, 22.7, 56.1, 59.3 (q,
J = 28.4 Hz), 82.9, 124.6 (q, J = 284.5 Hz), 126.7 (2C),
127.7, 128.6(2C), 144.1. 19FNMR(282 MHz, CDCl3)d-74.1
(d, J = 7.1 Hz). HR-MS (ESI/Q-TOF) (m/z) calcd for C12-
H16F3N2O2 [M ? H]?: 277.1164, found 277.1165; (m/z) calcd
for C12H15F3N2NaO2 [M ? Na]?: 299.0983, found 299.0984.
(2S,3R)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]butan-2-amine (syn-4b)
Yellow oil (17 %, 46 mg). [a]2D5 -8.8 (c = 3, CHCl3). H
NMR (400 MHz, CDCl3) d 1.26 (d, J = 6.5 Hz, 3H), 1.45
1
123

Trifluoromethyl-modified dipeptides
Synthesis of syn-4,40c and anti-5,50c. Yield: 72 %
(210 mg). Separated by flash chromatography on silica gel
(eluent: hexane/ethyl acetate = 92:8). IR: 3,350,
3.56–3.64 (m, 1H), 4.10 (q, J = 6.4, 1H), 4.57–4.62 (m,
1H), 7.31–7.37 (m, 5H). 13C NMR (101 MHz, CDCl3) d
10.5, 21.8, 22.0, 56.3, 59.4 (q, J = 28.6 Hz), 90.1, 124.9
(q, J = 284.2 Hz), 126.8 (2C), 127.8, 128.3 (2C), 144.3.
19F NMR (282 MHz, CDCl3) d -74.7 (d, J = 6.8 Hz).
HR-MS (ESI/Q-TOF) (m/z) calcd for C13H18F3N2O2
[M ? H]?: 291.1132, found 291.1139.
1,560 cm-1
.
(2S,3R)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]pentan-2-amine (syn-4c)
Yellow oil (16 %, 44 mg). [a]2D5 -14.5 (c = 3, CHCl3). 1H
NMR (400 MHz, CDCl3) d 0.93 (t, J = 7.3 Hz, 3H), 1.37
(d, J = 6.5, 3H), 1.56 (br, 1H), 1.95–2.07 (m, 2H),
3.56–3.62 (m, 1H), 4.05 (q, J = 6.4, 1H), 4.38–4.43 (m,
1H), 7.29–7.37 (m, 5H). 13C NMR (101 MHz, CDCl3) d
10.2, 24.2, 24.6, 55.9, 58.6 (q, J = 28.4 Hz), 88.5, 124.3
(q, J = 284.7 Hz), 126.5, 127.2 (2C), 128.7 (2C), 142.6.
19F NMR (282 MHz, CDCl3) d -75.7 (d, J = 7.4 Hz).
HR-MS (ESI/Q-TOF) (m/z) calcd for C13H18F3N2O2
[M ? H]?: 291.1132, found 291.1137.
Reduction reactions: synthesis of (R,S)-10a and (R,R)-
100a
To a solution of 3a or 30a (262 mg, 1 mmol) in anhydrous
MeOH, under an inert atmosphere (Ar), anhydrous
ammonium formate (310 mg, 5 mmol) and Pd/C 10 %
(95 mg) were added. The reaction mixture was kept at
reflux for 1.5 h and then filtered off to remove the catalyst.
The solvent was evaporated under vacuum and 5 mL of
water was added; the mixture was extracted three times
with Et2O. The collected organic layer was dried over
anhydrous Na2SO4 and the solvent evaporated under
vacuum.
(2R,3S)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]pentan-2-amine (syn-40c)
Yellow oil (8 %, 25 mg). [a]2D5 ?17.1 (c = 4, CHCl3). H
(2S)-3,3,3-Trifluoro-N2-[(1R)-1-phenylethyl]propane-1,2-
1
NMR (400 MHz, CDCl3) d 0.74 (t, J = 7.4 Hz, 3H), 1.30
(d, J = 6.5 Hz, 3H), 1.48 (br, 1H), 1.57–1.67 (m, 2H),
3.05–3.15 (m, 1H), 4.05 (q, J = 6.4 Hz, 1H), 4.40 (m, 1H),
7.18–7.30 (m, 5H). 13C NMR (101 MHz, CDCl3) d 10.2,
24.2, 24.7, 55.8, 58.0 (q, J = 27.8 Hz), 88.5, 124.3 (q,
J = 284.6 Hz), 127.5 (2C), 127.8, 128.6 (2C), 142.8. 19F
NMR (282 MHz, CDCl3) d -73.6 (d, J = 6.9 Hz). HR-
MS (ESI/Q-TOF) (m/z) calcd for C13H18F3N2O2
[M ? H]?: 291.1132, found 291.1128.
diamine [(R,S)-10a]
Yellow oil. Yield: 81 % (188 mg). Purified by flash chro-
matography on silica gel (eluent: hexane/ethyl ace-
tate = 8:2). [a]2D5 ?12.7 (c = 5, CHCl3). IR: 3,488,
3,395 cm-1 1H NMR (300 MHz, CDCl3) d 1.30 (d,
.
J = 6.4 Hz, 3H), 1.89 (br, 3H), 2.76 (dd, J = 13.4, 5.7 Hz,
1H), 2.87–3.03 (m, 2H), 3.97 (q, J = 6.4 Hz, 1H),
7.17–7.33 (m, 5H). 13C NMR (75 MHz, CDCl3) d 23.8,
39.4, 55.2, 57.9 (q, J = 26.1 Hz), 126.2 (q, J = 284.3 Hz),
126.7 (2C), 127.3, 128.5 (2C), 144.8. 19F NMR (282 MHz,
CDCl3) d -76.4 (d, J = 7.7 Hz). HR-MS (ESI/Q-TOF)
(m/z) calcd for C11H16F3N2 [M ? H]?: 233.1266, found
233.1272.
(2S,3S)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]pentan-2-amine (anti-5c)
1
Yellow oil (32 %, 90 mg). [a]2D5 -9.8 (c = 4, CHCl3). H
NMR (400 MHz, CDCl3) d 1.03 (t, J = 7.3 Hz, 3H), 1.34
(d, J = 6.5, 3H), 1.69 (br, 1H), 1.92–2.05 (m, 2H),
3.79–3.89 (m, 1H), 4.05 (q, J = 6.4, 1H), 4.52–4.57 (m,
1H), 7.27–7.35 (m, 5H). 13C NMR (101 MHz, CDCl3) d
10.5, 22.8, 23.0, 56.1, 59.0 (q, J = 28.2 Hz), 88.0, 124.5
(q, J = 284.4 Hz), 126.8 (2C), 127.7, 128.7 (2C), 143.9.
19F NMR (282 MHz, CDCl3) d -75.7 (d, J = 7.4 Hz).
HR-MS (ESI/Q-TOF) (m/z) calcd for C13H18F3N2O2
[M ? H]?: 291.1132, found 291.1125.
(2R)-3,3,3-Trifluoro-N2-[(1R)-1-phenylethyl]propane-1,2-
diamine [(R,R)-100a]
Yellow oil. Yield: 80 % (186 mg). Purified by flash chro-
matography on silica gel (eluent: hexane/ethyl ace-
tate = 8:2). [a]D25 ?14.2 (c = 4.5, CHCl3). mmax 3,488,
3,395 cm-1 1H NMR (300 MHz, CDCl3) d 1.36 (d,
.
J = 6.5 Hz, 3H), 1.57 (br, 3H), 2.59 (dd, J = 12.3, 7.5 Hz,
1H), 2.68–2.85 (m, 2H), 4.09 (q, J = 6.3 Hz, 1H),
7.35–7.20 (m, 5H). 13C NMR (75 MHz, CDCl3) d 24.8,
40.9, 56.2, 58.2 (q, J = 25.7 Hz), 126.4 (q, J = 284.6 Hz),
127.0 (2C), 127.4, 128.5 (2C), 144.4. 19F NMR (282 MHz,
CDCl3) d -76.1 (d, J = 6.5 Hz). HR-MS (ESI/Q-TOF)
(m/z) calcd for C11H16F3N2 [M ? H]?: 233.1266, found
233.1258.
(2R,3R)-1,1,1-Trifluoro-3-nitro-N-[(1R)-1-
phenylethyl]pentan-2-amine (anti-50c)
Yellow oil (16 %, 50 mg). [a]2D5 -13.6 (c = 4, CHCl3). 1H
NMR (400 MHz, CDCl3) d 1.03 (t, J = 7.4 Hz, 3H), 1.32
(d, J = 6.6, 3H), 1.70 (br, 1H), 2.12–2.25 (m, 2H),
123

S. Fioravanti et al.
3,343, 1,710, 1,671 cm-1. H NMR (300 MHz, CDCl3) d
0.77 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.3 Hz, 3H), 1.38 (s,
9H), 2.13 (br, 1H), 3.02–3.19 (m, 1H), 3.64–3.98 (m, 6H),
4.89 (br, 1H), 6.31 (br, 1H), 7.15–7.33 (m, 5H). 13C NMR
(75 MHz, CDCl3) d 19.3 (2C), 28.3 (3C), 30.4, 37.6, 51.4,
57.7 (q, J = 26.9 Hz), 60.0, 80.1, 125.8 (q, J = 284.3 Hz),
127.5, 128.4 (2C), 128.6 (2C), 139.1, 155.8, 171.9. 19F
NMR (282 MHz, CDCl3) d -76.7 (d, J = 5.3 Hz). HR-
MS (ESI/Q-TOF) (m/z) calcd for C20H31F3N3O3
[M ? H]?: 418.2239, found 418.2242; (m/z) calcd for
C20H30F3N3NaO3 [M ? Na]?: 440.2137, found 440.2131.
1
Coupling reactions: general procedure
To a solution of 7 (33 Fioravanti et al. 2012), (R,S)-10a or
(R,R)-100a (0.5 mmol) in 10 mL of CH2Cl2 equimolar
amounts of a-amino acid N-Boc-protected, N,N0-dicyclo-
hexylcarbodiimide (DCC) and catalytic amounts of
4-dimethylaminopyridine (DMAP, 10 % M) were added.
After 24 h of stirring at room temperature, the crude mixture
was filtered off to remove the formed N,N0-dicyclohexylurea
(DCU) and the solvent was evaporated under vacuum.
tert-Butyl (2-{[2-(benzylamino)-3,3,3-
trifluoropropyl]amino}-2-oxoethyl)carbamate (8)
tert-Butyl (2-oxo-2-{(2S)-3,3,3-trifluoro-2-[(1R)-1-
phenylethylamino]propylamino}ethyl) carbamate
[(R,S)-11a]
White viscous oil. Yield: 90 % (202 mg). Purified by flash
chromatography on silica gel (eluent: hexane/ethyl ace-
tate = 85:25). mmax 3,450, 3,342, 1,718, 1,677 cm-1. 1H NMR
(300 MHz, CDCl3) d 1.45(s, 9H), 2.67(br, 1H), 3.07–3.31 (m,
2H), 3.57–4.12 (m, 5H), 5.06 (br, 1H), 6.48 (br, 1H), 7.15–7.44
(m, 5H). 13C NMR (75 MHz, CDCl3) d 24.8, 28.1 (3C), 44.2,
51.5, 57.7 (q, J = 27.0 Hz), 80.2, 125.9 (q, J = 283.8 Hz)
127.3 (2C), 128.2, 128.4 (2C), 139.1, 156.0, 170.2. 19F NMR
(282 MHz, CDCl3) d -76.8 (d, J = 5.9 Hz). HR-MS (ESI/Q-
TOF) (m/z) calcd for C17H25F3N3O3 [M ? H]?: 376.1770,
found 376.1778; (m/z) calcd for C17H24F3N3NaO3
[M ? Na]?: 398.1667, found 398.1659.
Purified by flash chromatography on silica gel (eluent:
hexane/ethyl acetate = 8:2). White viscous oil. Yield:
91 % (212 mg). Purified by flash chromatography on
silica gel (eluent: hexane/ethyl acetate = 8:2). [a]D25
?10.4 (c = 3, CHCl3). mmax 3,450, 3,342, 1,708,
1,667 cm-1 1H NMR (300 MHz, CDCl3) d 1.26 (d,
.
J = 6.5 Hz, 3H), 1.85 (s, 9H), 1.86 (br, 1H), 3.66–3.86
(m, 4H), 3.96–4.02 (m, 2H), 5.29 (br, 1H), 6.64 (br, 1H),
7.18–7.31 (m, 5H). 13C NMR (75 MHz, CDCl3) d 24.2,
24.7, 28.2 (3C), 44.5, 55.3, 56.0 (q, J = 26.8 Hz), 80.4,
126.5 (q, J = 284.6 Hz), 126.8 (2C), 127.3, 128.5 (2C),
144.4, 156.1, 169.4. 19F NMR (282 MHz, CDCl3) d -
77.0 (d, J = 7.8 Hz). HR-MS (ESI/Q-TOF) (m/z) calcd
for C18H27F3N3O3 [M ? H]? 390.2005, found 390.1997;
(m/z) calcd for C18H26F3N3NaO3 [M ? Na]?: 412.1824,
found 412.1831.
tert-Butyl [(2S)-1-{[(2S)-2-(benzylamino)-3,3,3-
trifluoropropyl]amino}-3-methyl-1-oxobutan-2-
yl]carbamate (S,S-9)
Purified by flash chromatography on silica gel (eluent: hex-
ane/ethyl acetate = 8:2). White viscous oil. Yield: 42 %
(105 mg). [a]2D5 -14.1 (c = 3, CHCl3). mmax 3,440, 3,342,
1,708, 1,670 cm-1. 1H NMR (300 MHz, CDCl3) d 0.81 (d,
J = 6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 1.36 (s, 9H), 2.01
(br, 1H), 3.04–3.18(m, 1H), 3.63–4.00 (m, 6H), 4.96 (br, 1H),
6.29 (br, 1H), 7.15–7.33 (m, 5H). 13C NMR (75 MHz,
CDCl3) d 19.3 (2C), 28.2 (3C), 30.6, 37.5, 51.5, 57.1–59.0 (q,
J = 26.7 Hz), 60.1, 82.3, 125.6 (q, J = 284.1 Hz), 127.4,
128.2 (2C), 128.6 (2C), 139.1, 172.0, 179.5. 19F NMR
(282 MHz, CDCl3) d -76.6 (d, J = 5.0 Hz). HR-MS (ESI/
Q-TOF) (m/z) calcd for C20H31F3N3O3 [M ? H]?:
418.2239, found 418.2243; (m/z) calcd for C20H30F3N3NaO3
[M ? Na]?: 440.2137, found 440.2129.
tert-Butyl (2-oxo-2-{(2R)-3,3,3-trifluoro-2-[(1R)-1-
phenylethylamino]propylamino}ethyl) carbamate
[(R,R)-110a]
Purified by flash chromatography on silica gel (eluent:
hexane/ethyl acetate = 8:2). White viscous oil. Yield:
89 % (208 mg). Purified by flash chromatography on silica
gel (eluent: hexane/ethyl acetate = 8:2). [a]2D5 ?8.9
(c = 3, CHCl3). mmax 3,457, 3,352, 1,728, 1,668 cm-1. H
1
NMR (300 MHz, CDCl3) d 1.33 (d, J = 6.5 Hz, 3H), 1.45
(s, 9H), 1.89 (br, 1H), 3.50–3.77 (m, 4H), 3.96–4.12 (m,
2H), 5.13 (br, 1H), 6.46 (br, 1H), 7.41–7.17 (m, 5H). 13C
NMR (75 MHz, CDCl3) d 24.4, 24.9, 28.2 (3C), 44.2, 56.4
(q, J = 26.9 Hz), 60.3, 80.3, 126.8 (q, J = 284.5 Hz),
126.9 (2C), 127.6, 128.7 (2C), 144.1, 156.0, 169.7. 19F
NMR (282 MHz, CDCl3) d -77.2 (d, J = 5.6 Hz). HR-
MS (ESI/Q-TOF) (m/z) calcd for C18H27F3N3O3
[M ? H]?: 390.2005, found 390.1999; (m/z) calcd for
C18H26F3N3NaO3 [M ? Na]?: 412.1824, found 412.1819.
tert-Butyl [(2S)-1-{[(2R)-2-(benzylamino)-3,3,3-
trifluoropropyl]amino}-3-methyl-1-oxobutan-2-
yl]carbamate (R,S-90)
Purified by flash chromatography on silica gel (eluent:
hexane/ethyl acetate = 8:2). White viscous oil. Yield:
44 % (110 mg). [a]D25 -10.5 (c = 4, CHCl3). mmax 3,440,
123

Trifluoromethyl-modified dipeptides
synthesis of diaziridines from a-branched N,N0-dialkyl a-
diimines. New J Chem 37:4125–4129. doi:10.1039/c3nj00780d
Synthesis of N-Boc-protected CF3-modified dipeptides
(S)-12 and (R)-120a
´
´
Begue JP, Bonnet-Delpon D, Crousse B, Legros J (2005) The
chemistry of trifluoromethyl imines and related acetals derived
from fluoral. Chem Soc Rev 34:562–572. doi:10.1039/
B401707M
In a two-neck flask trifluoromethyl dipeptides (R,S)-11 and
(R,R)-110a (0.4 mmol) were dissolved in 5 mL of anhy-
drous MeOH and 60 mg of 10 % Pd/C were added. The
reaction mixtures were hydrogenated under atmospheric
pressure at room temperature for 24 h after which the crude
mixtures were filtered off to remove the catalyst and the
solvent was removed by evaporation at reduced pressure.
Buer BC, Marsh ENG (2012) Fluorine: a new element in protein
design. Protein Sci 21:453–462. doi:10.1002/pro.2030
Buer BC, Levin BJ, Marsh ENG (2012) Influence of fluorination on
the thermodynamics of protein folding. J Am Chem Soc
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Cahard D, Bizet V (2014) The influence of fluorine in asymmetric
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Carroccia L, Fioravanti S, Pellacani L, Tardella PA (2010) Solvent-
free stereoselective synthesis of (E)-trifluoromethyl imines and
hydrazones synthesis. Synthesis: 4096–4100. doi:10.1055/s-
0030-1258280
tert-Butyl (2-{[(2S)-2-amino-3,3,3-trifluoropropyl]amino}-
2-oxoethyl)carbamate [(S)-12a]
Carroccia L, Fioravanti S, Pellacani L, Sadun C, Tardella PA (2011)
Synthesis of optically active trifluoromethyl substituted diazir-
idines and oxaziridines. Tetrahedron 67:5375–5381. doi:10.
1016/j.tet.2011.05.097
Yellow pale oil. Yield: 95 % (150 mg). [a]2D5 –5.5
(c = 3.5, CHCl3). IR: 3,390, 3,342, 1,708, 1,667 cm-1. 1H
NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.75–3.85 (m,
4H), 4.05–4.30 (m, 1H), 5.13 (br, 2H), 6.60 (br, 2H). 13C
NMR (75 MHz, CDCl3) d 28.1 (3C), 33.6, 41.0, 53.6 (q,
J = 27 Hz), 80.3, 124.8 (q, J = 283.7 Hz), 156.8, 162.5.
19F NMR (282 MHz, CDCl3) d -76.3 (d, J = 3.9 Hz).
HR-MS (ESI/Q-TOF) (m/z) calcd for C10H18F3N3O3
[M ? H]?: 286.1300, found 286.1305; (m/z) calcd for
C10H18F3N3NaO3 [M ? Na]?: 308.1198, found 308.1205.
Carroccia L, Delfini M, Fioravanti S, Pellacani L, Sciubba F (2012)
1
Stereoselective synthesis and ROESY H NMR study of bidiaz-
iridines. J Org Chem 77:2069–2073. doi:10.1021/jo202618u
Cho J-I, Nishizono N, Iwahashi N, Saigo K, Ishida Y (2013) Stereo-
regulated synthesis of peptides containing a b-trifluoromethyl-b-
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Claridge TDW (2009) High-resolution NMR techniques in organic
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conformational and medicinal studies. Org Biomol Chem
5:1151–1157. doi:10.1039/b701559c
tert-Butyl (2-{[(2R)-2-amino-3,3,3-trifluoropropyl]amino}-
2-oxoethyl) carbamate [(R)-120a]
Falk M, Burton IW, Hu T, Walter JA, Wright JLC (2001) Assignment
of the relative stereochemistry of the spirolides, macrocyclic
toxins isolated from shellfish and from the cultured dinoflagel-
late Alexandrium ostenfeldii. Tetrahedron 57:8659–8665. doi:10.
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Filler R, Saha R (2009) Fluorine in medicinal chemistry: a century of
progress and a 60-year retrospective of selected highlights.
Future Med Chem 1:777–791. doi:10.4155/fmc.09.65
Fioravanti S, Gasbarri S, Morreale A, Pellacani L, Ramadori F,
Tardella PA (2010a) Short malonyl dehydro peptides as potential
scaffolds for peptidomimetics by an efficient Knoevenagel
reaction. Amino Acids 39:461–470. doi:10.1007/s00726-009-
0462-1
Yellow pale oil. Yield: 93 % (141 mg). [a]2D5 ?5.5 (c = 3,
CHCl3).
Acknowledgments We are grateful for financial support from the
`
Universita degli Studi di Roma ‘‘La Sapienza’’ and the Dipartimento
di Chimica of the same university.
Conflict of interest No conflicts of interest declared by any of the
authors.
Fioravanti S, Gasbarri S, Pellacani L, Ramadori F, Tardella PA
(2010b) Synthesis of epoxy and aziridino malonyl peptidomi-
metics. Tetrahedron 66:9401–9404. doi:10.1016/j.tet.2010.09.
097
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amines by a selective ZrCl4-catalyzed aza-Henry reaction of (E)-
trifluoromethyl aldimines. Org Biomol Chem 10:8207–8210.
doi:10.1039/c2ob26397a
Fustero S, Chiva G, Piera J, Sanz-Cervera JF, Volonterio A, Zanda M,
Ramirez de Arellano C (2009) New fluorinated peptidomimetics
through tandem aza-Michael addition to a-trifluoromethyl
acrylamide acceptors: synthesis and conformational study in
solid state and solution. J Org Chem 74:3122–3132. doi:10.1021/
jo9001867
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ethyl hemiacetal for the synthesis of trifluoromethylated com-
pounds. Curr Org Chem 8:1659–1675. doi:10.2174/
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123