Synthesis of new trifluoromethylated hydroxyethylamine-based scaffolds

Article abstract of DOI:10.1002/ejoc.200900578

A very easy access to new trifluoromethyl-hydroxyethylamine (Tf-HEA) derivatives by epoxide ring opening with amino-containlng compounds, including aliphatic amines, aniline, aqueous ammonia, hydroxylamirie, hydrazine, amino acids and a dipeptide, is desc

Full text of DOI:10.1002/ejoc.200900578

FULL PAPER
DOI: 10.1002/ejoc.200900578
Synthesis of New Trifluoromethylated Hydroxyethylamine-Based Scaffolds
Christine Philippe,[a] Thierry Milcent,[a] Tam Nguyen Thi Ngoc,[a] Benoit Crousse,*[a] and
Danièle Bonnet-Delpon[a]
Keywords: Protease / Hydroxyethylamine / Fluorine / Epoxides / Amino acids / Peptidomimetics
A very easy access to new trifluoromethyl-hydroxyethyl-
amine (Tf-HEA) derivatives by epoxide ring opening with
amino-containing compounds, including aliphatic amines,
aniline, aqueous ammonia, hydroxylamine, hydrazine, amino
acids and a dipeptide, is described herein. The reactions
were carried out in protic solvents, without the use of any
catalyst or any other additive. A comparison of the efficiency
of water, fluorinated and non-fluorinated alcohols as solvents
is reported. Total regioselectivity is observed, and the stereo-
chemistry of the compounds is preserved.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
or a receptor. The ability of a trifluoromethyl group to
mimic a big lipophilic substituent (e.g. isobutyl or benzyl)
allows it to efficiently replace the side chain of several
amino acids (e.g. valine, leucine and phenylalanine) in-
volved in enzyme inhibitors.[22] Furthermore, the electron-
withdrawing effect of the trifluoromethyl group can de-
crease the pKa of the neighbouring amino group and,
thereby, increase its H-bond donating ability, leading to a
putative improvement in the interaction with the enzyme.
Considering that HEA is of great interest in protease inhibi-
tion and that the trifluoromethyl group offers interesting
properties, we developed some new trifluoromethylated
HEAs (Tf-HEAs, Figure 1). In this context, we focused our
efforts on the ring-opening reactions of epoxides 1 with sev-
eral nitrogen-containing compounds.
Introduction
A number of protease inhibitors contain in their struc-
ture a pattern able to mimic the transition state of the sub-
strate.[1] Among them, hydroxyethylamine (HEA) dipeptide
isosteres (Figure 1) have been widely used as inhibitors of
HIV-1 proteases,[2] metalloproteases,[3] plasmepsines,[4–7]
cathepsines D[8] and β-secretases.[9–12]
Results and Discussion
We synthesized epoxides 1 from trifluoromethyl imines
using an efficient procedure previously described by our
group (Scheme 1). Performing the same sequence with the
aldimine substituted with the methyl ether of (R)-phenylgly-
cinol, we obtained the epoxide 1b as a single enantiomer of
the (R,R) configuration.[23]
Figure 1. Replacement for the scissile peptide bond.
On the other hand, trifluoromethyl peptides and pepti-
domimetics play a crucial role in the development of ana-
logues of protease inhibitors.[13–16] Due to their specific
physico-chemical features (highly hydrophobic, electron–
rich and sterically demanding), the fluorinated groups can
greatly modify the behaviour of a molecule in a biological
environment.[17–21] Indeed, the incorporation of trifluoro-
methyl groups into peptides and peptidomimetics can im-
prove their resistance to metabolism and modify their struc-
tural properties and, hence, their binding with an enzyme
Scheme 1. Preparation of epoxides 1.
[a] BioCIS CNRS UMR 8076, Faculté de Pharmacie, Univ. Paris
Sud XI,
Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France
Fax: +33-1-46835740
Epoxide ring opening with amines as a route to β-amino
alcohols is widely described in the literature.[24,25] These re-
actions are usually carried out in protic solvents with an
E-mail: benoit.crousse@u-psud.fr
http://www.biocis.u-psud.fr
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B. Crousse et al.
FULL PAPER
excess of amine or at elevated temperatures. In the case of
poorly reactive aromatic amines,
a variety of acti-
vators[26–29] have been introduced to facilitate the ring-
opening reaction. Fluorinated alcohols have also been used
to promote this reaction,[30] and recently, Azizi et al. re-
ported epoxide ring opening with aliphatic amines in water
without any catalyst.[31]
Thus, we investigated ring opening reactions of epoxides
1 with amines in water without catalyst, using 1.1 equiv. of
the amines. In the case of aliphatic amines, we carried out
reactions at room temperature. Under these mild condi-
tions, we isolated the corresponding β-amino alcohols in
good yields (Table 1, Entries 1–3). In all cases, we obtained
only one regioisomer, resulting from the attack of the nu-
cleophile at the less-hindered carbon of the epoxide. With
aniline, no reaction occurred at room temperature. How-
ever, by heating the mixture at 60 °C, we produced the cor-
responding β-amino alcohol in good yield, albeit with a
Scheme 2. Epoxide ring opening with ammonia, hydroxylamine
and hydrazine.
long reaction time (2 d). In this latter case, reaction condi- reaction.[46–47] The second one has recently been published
tions could be improved by changing the solvent to hexa- by our group.[48] Reactions are simply performed in re-
fluoropropan-2-ol (HFIP, b.p. 58 °C). Due to its H-bond fluxing trifluoroethanol (TFE), which is a good H-bond do-
donating ability, HFIP can activate oxirane ring opening nor.
with aromatic amines but not with aliphatic ones (Table 1,
Considering the above results (Table 1), we first per-
formed the reaction in water on epoxide 1a using 2 equiv.
of glycine ethyl ester as the nucleophile. Under these condi-
tions at room temperature, no reaction occurred, and
switching to refluxing water offered no improvement.
Hence, we carried out the reaction in fluorinated alcohols.
HFIP proved to be unsatisfactory; 19F NMR spectroscopic
data indicated the formation of the desired 6a accompanied
with many side products. To maximize the yield, we stopped
the reaction before its completion (Table 2, Entry 1). We
made further attempts using refluxing TFE (b.p. 78 °C).[48]
Under these conditions, the reaction time was decreased,
and the crude product was cleaner (Table 2, Entry 2). Per-
forming the reaction at room temperature did not decrease
the amount of side products but significantly increased the
reaction time (Table 2, Entry 3). To compare TFE to its
non-fluorinated analogue, we investigated the epoxide ring
opening in refluxing EtOH (Table 2, Entry 4). Surprisingly,
Entries 4 and 5).[30]
Table 1. Epoxide ring opening with amines.
The efficiency of the reaction in water prompted us to we obtained product 6a as fast as in TFE. Furthermore,
perform the oxirane ring opening of 1a with an aqueous the crude product was very clean. The reaction was also
solution of ammonia (20%) and an aqueous solution of efficient using only 1 equiv. of glycine ethyl ester, but the
hydroxylamine (50%). These two reactions proceeded reaction time increased to 10 h (Table 2, Entry 5). This ob-
smoothly at room temperature and led to the corresponding servation is in accordance with our previous result.[48] With
β-amino alcohols 3 and 4 in quantitative yields (Scheme 2). the enantiopure epoxide 1b, we obtained similar results: re-
Solvolysis with hydrazine hydrate was also successful and action times in TFE and in EtOH were identical, but
provided the product 5 in quantitative yield.
chemoselectivity was higher in EtOH than in TFE (Table 2,
HEA-type inhibitors often require additional amino ac- Entries 6–7). Consequently, we found EtOH to be the best
ids for recognition of the active site of the enzymes. In this solvent for this reaction.
context, a direct ring opening with amino acids or peptides
We then explored the ring opening of epoxides 1 with
is an attractive route to elaborate HEA scaffolds. Only a other -amino acids in refluxing EtOH. In all cases, we used
few examples of amino acid ring opening of oxiranes are 2 equiv. of amino acid. However, when the ester group of
described in the literature, in contrast to the many examples the amino acid was not an ethyl ester, transesterification
with secondary amines. In most of these cases, yields and occurred to a non-negligible extent (Table 3).
the diversity of amino acids used were poor.[32–45] Currently,
To overcome this problem, we used only methyl- and
there are only two efficient methods for this reaction. The ethyl-ester-protected amino acids and carried out reactions
first one involves the use of Ca(OTf)2 as a promoter of the in MeOH or in EtOH, respectively. We used different amino
5216
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5215–5223

New Trifluoromethylated Hydroxyethylamine-Based Scaffolds
Table 2. Optimization of the reaction.[a]
Table 4. Epoxides ring opening with amino acids and dipeptide.
Sol-
vent
%
Yield
Entry
Epoxide
T [°C]
t [h]
Conv.
[%][b]
Entry
Epoxide Amino acid
t [h] Product % Yield
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
H-Gly-OEt
-H-Ala-OMe
-H-Phe-OMe
-H-Tyr(Bn)-OMe
-H-Met-OMe
-H-Asp(OMe)-OMe
-H-Phe--Ala-OMe
H-Gly-OEt
-H-Ala-OMe
-H-Phe-OMe
2
6.5
7.5
7
6a
7a
8a
77
65
87
84
76
89
45
76
67
94
78
80
75
38
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1b
1b
HFIP
TFE
TFE
58
78
r.t.
78
6.25
2
120
2
10
7.5
7
88
45
68
42
100
100
53
100
100
100
100
79
9a
6
7
18
7
10a
11a
12a
6b
EtOH
EtOH[c] 78
TFE
EtOH
78
78
100
100
9
18
18
18
18
18
72
7b
8b
9b
10b
11b
12b
10
11
12
13
14
[a] Reactions conditions: 0.5 mmol of epoxide, 1 mmol of glycine
ethyl ester. [b] Conversion was determined by 19F NMR spec-
troscopy. [c] The reaction was performed with 1 equiv. of glycine
ethyl ester.
-H-Tyr(Bn)-OMe
-H-Met-OMe
-H-Asp(OMe)-OMe
-H-Phe--Ala-OMe
Table 3. Transesterification.
1 equiv. of glycine ethyl ester. After 10 h, we submitted the
product directly to hydrogenation. Thus, we obtained prod-
uct 13, without any purification, in a 89% yield (Scheme 3).
Entry Epoxide Amino acid
t [h]
R2/Et
% Yield
1
2
3
4
5
1a
1a
1b
1b
1b
-H-Phe-OBn
-H-Met-OMe
-H-Phe-OBn
-H-Met-OMe
-H-Ala-OMe
18
6
18
18
18
79/21
86/14
84/16
72/28
70/30
72
87
81
71
71
Scheme 3. Ring opening and debenzylation in a one-pot process.
Conclusions
In summary, β-trifluoromethyl epoxide ring opening with
nitrogen-containing derivatives was achieved in water or
alcohol without any catalyst. Water proved to be very ef-
ficient with hydroxylamine, ammonia and aliphatic amines
but less so with aromatic amines, which reacted faster in
HFIP. With amino acids, reactions performed in water were
unsuccessful. Better results were obtained with fluorinated
alcohols; Tf-HEAs were always obtained accompanied by
a variable amount of side products. Finally, EtOH and
MeOH proved to be the most efficient solvents and pro-
moters for this reaction, leading to high yields of Tf-HEAs
without any additional catalyst. The corresponding fluori-
nated HEAs obtained are important building blocks for the
synthesis of fluorinated transition-state-analogue inhibitors
of proteases.
acids bearing an aliphatic, aromatic or functionalized side
chain. Starting epoxides 1a,b, C-protected amino acids, re-
action times, products 6–12 and yields are listed in Table 4.
With the epoxide 1a, reactions were complete in less than
8 h and led to a mixture of two diastereomers (1:1), as con-
firmed by 19F NMR spectroscopy. In most cases, 18 h were
needed for a complete reaction with epoxide 1b, probably
due to steric hindrance, and we obtained only one dia-
stereomer, indicating that no racemization occurred.
In all cases, the crude products were very clean.
Chromatography on silica gel was required only for the eli-
mination of the excess amino acid. Ring opening with
amino acids afforded Tf-HEAs in good yields ranging be-
tween 65 and 94%. Using the dipeptide -H-Phe--Ala-
(OMe) (Table 4, Entries 7 and 14), the reaction led to the
corresponding Tf-HEAs in moderate yields (45 and 38%,
respectively) and a longer reaction time.
Experimental Section
The debenzylation of 6a provided the product 13, which
can serve as a useful platform for further peptidic coupling.
Since this deprotection can be achieved in EtOH, we per-
formed a preliminary, one-pot, ring-opening/debenzylation
General: Melting points were measured on a Stuart® SMP10 appa-
ratus. 1H, 13C and 19F NMR spectra were recorded with a Bruker®
ARX 200 apparatus at 300, 75 and 188 MHz, respectively, in
with 1a. We placed this compound in refluxing EtOH with CDCl3 with TMS as an internal standard for 1H and 13C and
Eur. J. Org. Chem. 2009, 5215–5223
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5217

B. Crousse et al.
7.8 Hz, F) ppm.
C18H21F3N2O (338.37): calcd. C 63.89, H 6.26, N 8.28; found C
63.52, H 6.45, N 8.01.
FULL PAPER
CFCl3 as an internal standard for 19F NMR spectroscopy. Mass
spectra were recorded with a Bruker® Esquire-LC apparatus. IR
spectra were recorded with a Bruker® Vector 22 apparatus. Elemen-
tal analyses were carried out with an Ankersmit CAHN® 25 appa-
ratus. Optical rotations were measured with an Optical Activity
LTD Automatic polarimeter polAAr 32 apparatus at 589 nm. Col-
umn chromatography was performed on Merck® silica gel (60 µm)
with cyclohexane/AcOEt or ether/cyclohexane as a system eluent.
CDCl3, 25 °C):
δ
=
–71.6 (d, JF,H
=
3
3
3-(Benzylamino)-4,4,4-trifluoro-1-(phenylamino)butan-2-ol (2d): Ep-
oxide 1a (0.070 g, 0.30 mmol) and aniline (0.03 mL, 0.33 mmol)
gave, after 3 h of refluxing in HFIP (2 mL) and purification (ether/
cyclohexane, 4:6), the product 2d (0.095 g, 98%) as a yellow light
oil. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 2.75 (br. s, 2 H, NH),
2
3.05 (m, 1 H, H-3), 3.15 (m, 2 H, H-1), 3.78 (d, JH,H = 12.9 Hz,
General Procedure for the Synthesis of Products 2: Amine
(1.1 equiv.) was added to a solution of epoxide 1a (1 equiv.) in
water or in HFIP. The resulting solution was stirred at room tem-
perature or at reflux until the disappearance of the starting epoxide
(monitored by 19F NMR). The reaction medium was concentrated
under reduced pressure, and the resulting oil was then purified by
chromatography on silica gel.
2
1 H, CH2Ph), 3.94 (m, 1 H, H-2), 4.08 (d, JH,H = 12.9 Hz, 1 H,
CH2Ph), 6.47 (m, 2 H, Ar), 6.63 (m, 1 H, Ar), 7.17 (m, 7 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 46.9 (C-1), 52.1
2
1
(CH2Ph), 59.1 (q, JC,F = 28.8 Hz, C-3), 66.5 (C-2), 126.4 (q, JC,F
= 286.1 Hz, C-4), 113.1/118.0/127.6/128.6/129.2 (10 C, Ar), 138.9
(Ar), 147.7 (Ar) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ =
–71.5 (d, JF,H = 7.7 Hz, 3 F) ppm. IR: ν = 3385, 1603, 1506 cm–1.
3
˜
3-(Benzylamino)-4,4,4-trifluoro-1-(piperidin-1-yl)butan-2-ol
(2a):
C17H19F3N2O (324.34): calcd. C 62.95, H 5.90, N 8.64; found C
63.22, H 6.15, N 8.44.
Epoxide 1a (0.100 g, 0.43 mmol) and piperidine (0.040 g,
0.47 mmol) gave, after 4 h of stirring in water (3.5 mL) at room
temperature and purification (ether/cyclohexane, 4:6), the product
2a (0.121 g, 89%) as a light yellow oil. 1H NMR (200 MHz, CDCl3,
25 °C): δ = 1.43 (m, 6 H, piperidine), 2.09 (dd, JH,H = 4.3, JH,H
= 12.2 Hz, 1 H, H-1), 2.24 (m, 2 H, piperidine and H-1), 2.47 (m,
General Procedure for the Synthesis of Products 3–5: An excess of
the nitrogen-containing compound was added to epoxide 1a. The
resulting solution was vigorously stirred at room temperature until
the disappearance of the starting epoxide (monitored by 19F
NMR). The removal of the excess nitrogen-containing compound
was achieved under reduced pressure.
3
2
3
3
3 H, piperidine), 2.81 (qd, JH,H = 2.0, JH,F = 7.9 Hz, 1 H, H-3),
3.77 (d, 2JH,H = 13.2 Hz, 1 H, CH2Ph), 3.89 (ddd, 3JH,H = 2.0, 4.3,
2
10.0 Hz, 1 H, H-2), 4.01 (d, JH,H = 13.2 Hz, 1 H, CH2Ph), 7.22
1-Amino-3-(benzylamino)-4,4,4-trifluorobutan-2-ol (3): Epoxide 1a
(0.060 g, 0.26 mmol) and NH4OH (20%, 19.2 mL) gave, after 4 h
of vigorous stirring at room temperature, the product 3 (0.064 g,
(m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 24.1
(piperidine), 25.9 (2 C, piperidine), 52.1 (C-1), 54.4 (2 C, piperi-
2
1
dine), 59.4 (q, JC,F = 28.8 Hz, C-3), 60.8 (CH2Ph), 63.6 (C-2),
100%) as a light yellow oil. H NMR (200 MHz, CDCl3, 25 °C): δ
126.7 (q, 1JC,F = 286.4 Hz, C-4), 127.1 (Ar), 128.3 (4 C, Ar), 139.7
(Ar) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –71.90 (d, 3JF,H
= 7.9 Hz, 3 F) ppm. C16H23F3N2O (316.36): calcd. C 60.74, H 7.33,
N 8.85; found C 60.55, H 7.48, N 8.71.
= 2.11 (br. s, 3 H, NH and NH2), 2.69 (d, 3JH,H = 5.7 Hz, 2 H, H-
3
3
1), 2.95 (qd, JH,H = 3.7, JH,F = 7.8 Hz, 1 H, H-3), 3.66 (m, 1 H,
2
2
H-2), 3.76 (d, JH,H = 13.1 Hz, 1 H, CH2Ph), 4.0 (d, JH,H
=
13.1 Hz, 1 H, CH2Ph), 7.22 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
2
CDCl3, 25 °C): δ = 44.5 (C-1), 52.1 (CH2Ph), 59.7 (q, JC,F
=
1-(4-Methoxyphenethylamino)-3-(benzylamino)-4,4,4-trifluorobutan-
2-ol (2b): Epoxide 1a (0.100 g, 0.43 mmol) and 2-(4-meth-
oxyphenyl)ethylamine (0.071 g, 0.47 mmol) gave, after 2 d of stir-
ring in water (3.5 mL) at room temperature and purification (ether/
petroleum spirit, 3:7), the product 2b (0.148 g, 90%) as a yellow
oil. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 2.40 (m, 1 H,
CH2PhOMe), 2.50 (m, 1 H, CH2PhOMe), 2.50 (m, 2 H, H-1), 2.60
1
25.8 Hz, C-3), 68.5 (C-2), 126.6 (q, JC,F = 286.0 Hz, C-4), 127.3
(Ar), 128.4 (4 C, Ar), 139.3 (Ar) ppm. 19F NMR (188 MHz,
3
CDCl3, 25 °C): δ = –71.6 (d, JF,H = 7.8 Hz, 3 F) ppm. MS (ESI):
m/z = 249 [M + H]+. IR: ν = 3350, 2924, 1454, 1261, 1129, 701,
˜
629 cm–1. C11H15F3N2O (248.24): calcd. C 53.22, H 6.09, N 11.28;
found C 53.55, H 5.80, N 10.99.
3
3
(m, 2 H, CH2CH2PhOMe), 2.82 (qd, JH,H = 4.0, JH,F = 7.8 Hz,
3-(Benzylamino)-4,4,4-trifluoro-1-(hydroxyamino)butan-2-ol
(4):
2
1 H, H-3), 3.53 (s, 3 H, OCH3), 3.70 (d, JH,H = 13.2 Hz, 1 H,
Epoxide 1a (0.130 g, 0.56 mmol) and aqueous hydroxylamine 50%
(2 mL) gave, after 16 h of vigorous stirring at room temperature,
the product 4 (0.148 g, 100%) as a yellow light oil. 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 2.64–2.98 (m, 3 H, H-1 and H-3),
CH2Ph), 3.75 (m, 1 H, H-2), 3.90 (d, 2JH,H = 13.2 Hz, 1 H, CH2Ph),
3
3
6.75 (d, JH,H = 6.5 Hz, 2 H, Ar), 6.97 (d, JH,H = 6.5 Hz, 2 H,
Ar), 7.20 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 35.3 (C-1), 50.7 (CH2CH2PhOMe), 51.9 (CH2PhOMe), 52.0
2
2
3.71 (d, JH,H = 13.0 Hz, 1 H, CH2Ph), 3.97 (d, JH,H = 13.0 Hz,
1 H, CH2Ph), 4.09 (m, 1 H, H-2), 7.23 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 51.8 (C-1), 56.5 (CH2Ph), 59.9
2
(CH2Ph), 54.8 (OCH3), 59.9 (q, JC,F = 25.8 Hz, C-3), 66.2 (C-2),
1
126.5 (q, JC,F = 286.2 Hz, C-4), 113.9/127.1/128.3/129.5 (9 C, Ar),
131.6 (Ar), 139.6 (Ar), 158.2 (Ar) ppm. 19F NMR (188 MHz,
2
1
(q, JC,F = 25.7 Hz, C-3), 64.9 (C-2), 126.5 (q, JC,F = 286.8 Hz,
3
C-4), 127.3 (Ar), 128.4 (4 C, Ar), 139.0 (Ar) ppm. 19F NMR
CDCl3, 25 °C):
δ
=
–71.6 (d, JF,H
=
7.8 Hz,
3
F) ppm.
3
C20H25F3N2O2 (382.42): calcd. C 62.81, H 6.59, N 7.33; found C
62.85, H 6.70, N 7.28.
(188 MHz, CDCl3, 25 °C): δ = –71.1 (d, JF,H = 7.5 Hz, 3 F) ppm.
MS (APCI): m/z = 265 [M + H]+. IR: ν = 3376, 2924, 1496, 1454,
˜
1258, 1118, 1078, 1020, 978, 895, 852, 823, 659 cm–1.
C11H15F3N2O2 (264.24): calcd. C 50.00, H 5.72, N 10.60; found C
50.38, H 5.63, N 10.43.
1,3-Bis(benzylamino)-4,4,4-trifluorobutan-2-ol (2c): Epoxide 1a
(0.060 g, 0.26 mmol) and benzylamine (0.03 mL, 0.286 mmol) gave,
after 2 d of stirring in water (1 mL) at room temperature and after
purification (ether/cyclohexane, 4:6), the product 2c (0.079 g, 99%)
3-Benzylamino-4,4,4-trifluoro-1-hydrazinobutan-2-ol (5): Epoxide
1a (0.0987 g, 0.427 mmol) and hydrazine (2 mL) gave, after 4 h of
1
as a yellow oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 3.25 (qd,
3JH,H = 3.2, JH,F = 7.8 Hz, 1 H, H-3), 3.96 (m, 2 H, H-1), 4.06 vigorous stirring at room temperature, the product 5 (0.1124 g,
3
100%) as a yellow oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
2
(m, 4 H, CH2Ph and H-2), 4.27 (d, JH,H = 13.1 Hz, 1 H, CH2Ph),
3
2
3
7.49 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
2.61 (dd, JH,H = 3.3, JH,H = 12.6 Hz, 1 H, H-1), 2.83 (dd, JH,H
2
2
3
3
49.9 (C-1), 51.5 (CH2Ph), 52.2 (CH2Ph), 59.9 (q, JC,F = 25.8 Hz,
= 8.7, JH,H = 12.6 Hz, 1 H, H-1), 2.90 (qd, JH,H = 3.3, JH,F
=
=
2
C-3), 66.4 (C-2), 126.8 (q, 1JC,F = 286.0 Hz, C-4), 127.4/128.3/128.5
7.8 Hz, 1 H, H-3), 3.53–3.76 (br. s, 3 H, NH), 3.73 (d, JH,H
(10 C, Ar), 139.1 (Ar), 139.5 (Ar) ppm. 19F NMR (188 MHz, 12.6 Hz, 1 H, CH2Ph), 3.97 (d, JH,H = 12.6 Hz, 1 H, CH2Ph),
2
5218
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5215–5223

New Trifluoromethylated Hydroxyethylamine-Based Scaffolds
3
3.95–4.00 (m, 1 H, H-2), 7.15–7.24 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 52.0 (C-1), 57.2 (CH2Ph), 59.9 (q,
NMR (188 MHz, CDCl3, 25 °C): δ = –71.44 (d, JF,H = 7.7 Hz, 3
3
F), –71.57 (d, JF,H = 7.7 Hz, 3 F) ppm. MS (APCI): m/z = 335.2
2JC,F = 25.6 Hz, C-3), 66.1 (C-2), 126.6 (q, JC,F = 284.6 Hz, C-4),
[M + H]+. IR: ν = 2950, 1737, 1650, 1454, 1260, 1128, 731, 698
1
˜
127.3 (Ar), 128.4 (4 C, Ar), 139.4 (Ar) ppm. 19F NMR (188 MHz,
cm–1. C15H21F3N2O3 (334.33): calcd. C 53.89, H 6.33, N 8.38;
3
CDCl3, 25 °C): δ = –71.35 (d, JF,H = 7.8 Hz, 3 F) ppm. IR: ν = found C 54.23, H 6.21, N 8.37.
˜
3341, 1664, 1261, 1130, 697 cm–1. C11H16F3N3O (263.26): calcd. C
(S)-Methyl 2-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutylamino]-
50.19, H 6.13, N 15.96; found C 50.57, H 5.75, N 15.70.
3-phenylpropanoate (8a): Epoxide 1a (0.1156 g, 0.5 mmol) and -H-
Phe-OMe (0.179 g, 1.0 mmol) gave, after 7.5 h of refluxing in
MeOH (1.25 mL) and purification (cyclohexane/AcOEt, 8:2), the
product 8a (0.178 g, 87%) as a colourless oil. 1H NMR (300 MHz,
General Procedure for the Synthesis of Products 6–11: The C-pro-
tected amino acid salt (1.5 mmol) and potassium carbonate
(2.5 mmol) were dissolved in water (3 mL). The free amino acid
was extracted with diethyl ether (3ϫ15 mL). The ethereal layer was CDCl3, 25 °C): δ = 1.65–2.04 (br. s, 2 H, NH), 2.35–2.42 (m, 2 H,
then dried with magnesium sulphate, filtered and concentrated un-
der reduced pressure at ambient temperature. The free amino acid
(2 equiv.) was immediately introduced to an alcoholic solution of
epoxide (1 equiv.). The reaction mixture was stirred at reflux until
the disappearance of the starting epoxide (monitored by 19F
NMR). The reaction medium was concentrated under reduced
pressure, and the resulting oil was then purified by chromatography
on silica gel. Products 6a–11a were obtained in the form of two
diastereomers in a 1:1 ratio, which was determined from the ratio
of integrals from 19F NMR spectra. Products 6b–11b were obtained
in the form of one diastereomer.
H-3), 2.63–2.77 (m, 4 H, H-3 and CH2CHOH), 2.83–2.93 (m, 4 H,
CH2CHOH and CHCF3), 3.31–3.38 (m, 2 H, H-2), 3.58 (s, 3 H,
CO2Me), 3.59 (s, 3 H, CO2Me), 3.63–3.71 (m, 4 H, CHOH and
2
CH2Ph), 3.93 (d, JH,H = 13.2 Hz, 2 H, CH2Ph), 7.03–7.06 (m, 4
H, Ar), 7.10–7.25 (m, 16 H, Ar) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 39.6 (C-3), 39.7 (C-3), 50.3 (CH2CHOH), 50.5
(CH2CHOH), 51.7 (CO2Me), 51.7 (CO2Me), 52.0 (CH2Ph), 52.0
2
2
(CH2Ph), 59.1 (q, JC,F = 25.8 Hz, CHCF3), 59.7 (q, JC,F
=
3
25.6 Hz, CHCF3), 62.4 (C-2), 63.0 (C-2), 66.2 (q, JC,F = 2.2 Hz,
3
1
CHOH), 67.0 (q, JC,F = 2.2 Hz, CHOH), 126.5 (q, JC,F
=
284.0 Hz, 2 C, CF3), 126.7/126.8/127.2/128.3/128.4/129.0 (20 C,
Ar), 137.0 (2 C, Ar), 139.4 (2 C, Ar), 174.7 (C-1), 174.7 (C-1) ppm.
19F NMR (188 MHz, CDCl3, 25 °C): δ = –71.38 (d, 3JF,H = 8.5 Hz,
3 F), –71.46 (d, 3JF,H = 7.5 Hz, 3 F) ppm. MS (APCI): m/z = 411.2
Ethyl 2-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutylamino]ace-
tate (6a): Epoxide 1a (0.1156 g, 0.5 mmol) and H-Gly-OEt (0.103 g,
1.0 mmol) gave, after 2 h of refluxing in EtOH (1.25 mL) and puri-
fication (cyclohexane/AcOEt, 6:4), the product 6a (0.128 g, 77%)
as a yellow solid; m.p. 43–44 °C. 1H NMR (300 MHz, CDCl3,
[M + H]+. IR: ν = 2931, 1734, 1454, 1261, 1129, 745, 698 cm–1.
˜
C21H25F3N2O3 (410.43): calcd. C 61.45, H 6.14, N 6.83; found C
61.57, H 6.31, N 6.66.
3
25 °C): δ = 1.21 (t, JH,H = 7.2 Hz, 3 H, CO2CH2CH3), 2.33–2.50
3
2
(br. s, 2 H, NH), 2.63 (dd, JH,H = 4.4, JH,H = 12.3 Hz, 1 H,
(S)-Methyl 2-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutylamino]-
3
2
CH2CHOH), 2.71 (dd, JH,H = 7.4, JH,H = 12.3 Hz, 1 H, 3-[4-(benzyloxy)phenyl]propanoate (9a): Epoxide 1a (0.1156 g,
CH2CHOH), 2.99 (qd, JH,H = 3.3, JH,F = 7.5 Hz, 1 H, CHCF3), 0.5 mmol) and -H-Tyr(Bn)-OMe (0.285 g, 1.0 mmol) gave, after
3
3
2
3.30 (s, 2 H, H-2), 3.75–3.82 (m, 1 H, CHOH), 3.77 (d, JH,H
=
7 h of refluxing in MeOH (1.25 mL) and purification (cyclohexane/
13.1 Hz, 1 H, CH2Ph), 4.02 (d, 2JH,H = 13.1 Hz, 1 H, CH2Ph), 4.12
AcOEt, 8:2), the product 9a (0.217 g, 84%) as a colourless oil. H
1
3
(q, JH,H = 7.2 Hz, 2 H, CO2CH2CH3), 7.18–7.30 (m, 5 H, Ar)
NMR (300 MHz, CDCl3, 25 °C): δ = 1.83–2.24 (br. s, 2 H, NH),
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 14.2 (CO2CH2CH3), 2.37–2.45 (m, 2 H, H-3), 2.65–2.95 (m, 8 H, H-3 and CH2CHOH
2
50.5 (CH2CHOH), 52.0 (C-2), 52.1 (CH2Ph), 59.7 (q, JC,F
=
and CHCF3), 3.28–3.35 (m, 2 H, H-2), 3.59 (s, 3 H, CO2Me), 3.59
2
25.8 Hz, CHCF3), 60.9 (CO2CH2CH3), 66.6 (CHOH), 126.6 (q,
1JC,F = 284.5 Hz, CF3), 127.3 (Ar), 128.4 (2 C, Ar), 128.4 (2 C,
Ar), 139.4 (Ar), 172.4 (C-1) ppm. 19F NMR (188 MHz, CDCl3,
(s, 3 H, CO2Me), 3.65–3.74 (m, 2 H, CHOH), 3.69 (d, JH,H =
12.9 Hz, 2 H, CH2Ph), 3.95 (d, 2JH,H = 12.9 Hz, 2 H, CH2Ph), 4.92
(s, 4 H, OCH2Ph), 6.80 (d, 3JH,H = 8.6 Hz, 4 H, Ar), 6.96 (d, 3JH,H
= 8.6 Hz, 4 H, Ar), 7.16–7.34 (m, 20 H, Ar) ppm. 13C NMR
3
25 °C): δ = –71.49 (d, JF,H = 7.5 Hz, 3 F) ppm. MS (ESI): m/z =
335.3 [M + H]+, 357.3 [M + Na]+. IR: ν = 2940, 1729, 1448, 1256, (75 MHz, CDCl3, 25 °C):
δ = 38.8 (C-3), 38.8 (C-3), 50.3
˜
1206, 1115, 862, 694 cm–1. C15H21F3N2O3 (334.33): calcd. C 53.89, (CH2CHOH), 50.5 (CH2CHOH), 51.7 (CO2Me), 51.8 (CO2Me),
H 6.33, N 8.38; found C 54.21, H 6.70, N 7.99.
52.0 (2 C, CH2Ph), 59.2 (q, 2JC,F = 25.9 Hz, CHCF3), 59.8 (q, 2JC,F
= 25.6 Hz, CHCF3), 62.5 (C-2), 63.2 (C-2), 66.2 (q, 3JC,F = 2.4 Hz,
(S)-Methyl 2-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutylamino]-
propanoate (7a): Epoxide 1a (0.1156 g, 0.5 mmol) and -H-Ala-
OMe (0.103 g, 1.0 mmol) gave, after 6.5 h of refluxing in MeOH
(1.25 mL) and purification (cyclohexane/AcOEt, 7:3), the product
7a (0.108 g, 65%) as a colourless oil. 1H NMR (300 MHz, CDCl3,
3
CHOH), 67.0 (q, JC,F = 2.4 Hz, CHOH), 69.9 (2 C, OCH2Ph),
1
126.6 (q, JC,F = 284.6 Hz, 2 C, CF3), 114.8/127.3/127.3/127.4/
127.9/128.3/128.4/128.4/128.5/130.1 (28 C, Ar), 129.2 (Ar), 129.3
(Ar), 136.9 (2 C, Ar), 139.4 (2 C, Ar), 157.7 (2 C, Ar), 174.7 (C-1),
174.8 (C-1) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –71.36
3
3
25 °C): δ = 1.19 (d, JH,H = 6.9 Hz, 3 H, H-3), 1.20 (d, JH,H
=
3
3
(d, JF,H = 7.5 Hz, 3 F), –71.45 (d, JF,H = 7.5 Hz, 3 F) ppm. MS
6.9 Hz, 3 H, H-3), 2.33–2.53 (br. s, 2 H, NH), 2.46–2.53 (m, 2 H,
CH2CHOH), 2.65–2.75 (m, 2 H, CH2CHOH), 2.92–3.04 (m, 2 H,
(APCI): m/z = 517.4 [M + H]+. IR: ν = 2925, 1734, 1511, 1454,
˜
1241, 1130, 1025, 735, 697 cm–1. C28H31F3N2O4 (516.55): calcd. C
65.10, H 6.05, N 5.42; found C 64.92, H 6.25, N 5.17.
3
3
CHCF3), 3.20 (q, JH,H = 6.9 Hz, 1 H, H-2), 3.24 (q, JH,H
=
6.9 Hz, 1 H, H-2), 3.65 (s, 3 H, CO2Me), 3.65 (s, 3 H, CO2Me),
3.72–3.83 (m, 2 H, CHOH), 3.76 (d, 2JH,H = 13.4 Hz, 2 H, CH2Ph),
(S)-Methyl 2-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutylamino]-
4-(methylthio)butanoate (10a): Epoxide 1a (0.1156 g, 0.5 mmol) and
2
4.01 (d, JH,H = 13.4 Hz, 2 H, CH2Ph), 7.18–7.27 (m, 10 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 19.0 (C-3), 19.2 (C- -H-Met-OMe (0.163 g, 1.0 mmol) gave, after 6 h of refluxing in
3), 50.3 (2 C, CH2CHOH), 51.8 (CO2Me), 51.9 (CO2Me), 52.1
MeOH (1.25 mL) and purification (cyclohexane/AcOEt, 8:2), the
product 10a (0.134 g, 76%) as a colourless oil. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 1.64–1.76 (m, 2 H, H-3), 1.81–1.93 (m, 2 H, H-
3), 2.00 (s, 6 H, SMe), 2.23–2.50 (br. s, 2 H, NH), 2.40–2.50 (m, 6
2
(CH2Ph), 52.1 (CH2Ph), 56.2 (C-2), 56.7 (C-2), 59.5 (q, JC,F
=
25.8 Hz, CHCF3), 60.0 (q, 2JC,F = 25.6 Hz, CHCF3), 66.4 (q, 3JC,F
= 2.4 Hz, CHOH), 67.0 (q, 3JC,F = 2.2 Hz, CHOH), 126.6 (q, 1JC,F
3
2
= 284.6 Hz, 2 C, CF3), 127.3 (Ar), 127.3 (Ar), 128.4/128.4/128.4 (8 H, H-4 and CH2CHOH), 2.73 (dd, JH,H = 4.2, JH,H = 12.2 Hz,
3
2
C, Ar), 139.4 (Ar), 139.4 (Ar), 175.8 (C-1), 175.8 (C-1) ppm. 19F 1 H, CH2CHOH), 2.77 (dd, JH,H = 6.9, JH,H = 12.2 Hz, 1 H,
Eur. J. Org. Chem. 2009, 5215–5223
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5219

B. Crousse et al.
FULL PAPER
CH2CHOH), 2.97 (qd, JH,H = 2.9, JH,F = 7.6 Hz, 1 H, CHCF3), MS (APCI): m/z = 379.1 [M + H]+. IR: ν = 2870, 1725, 1451, 1204,
3
3
˜
3.05 (qd, 3JH,H = 3.4, 3JH,F = 7.8 Hz, 1 H, CHCF3), 3.25 (dd, 3JH,H 1150, 1103, 865, 692, 679 cm–1. C17H25F3N2O4 (378.39): calcd. C
3
= 5.1, 8.6 Hz, 1 H, H-2), 3.28 (dd, JH,H = 5.4, 8.4 Hz, 1 H, H-2), 53.96, H 6.66, N 7.40; found C 54.22, H 6.78, N 7.21. [α]2D5 = –57
3.66 (s, 3 H, CO2Me), 3.66 (s, 3 H, CO2Me), 3.71–3.83 (m, 2 H,
(c = 1, CH2Cl2).
2
2
CHOH), 3.76 (d, JH,H = 13.4 Hz, 2 H, CH2Ph), 4.01 (d, JH,H
=
(S)-Methyl 2-{(2S,3R)-3-[(R)-2-Methoxy-1-phenylethylamino]-4,4,4-
trifluoro-2-hydroxybutylamino}propanoate (7b): Epoxide 1b
(0.1375 g, 0.5 mmol) and -H-Ala-OMe (0.103 g, 1.0 mmol) gave,
after 18 h of refluxing in MeOH (1.25 mL) and purification (cyclo-
13.4 Hz, 2 H, CH2Ph), 7.16–7.27 (m, 10 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 15.3 (SMe), 15.3 (SMe), 30.5 (2 C,
C-4), 32.4 (C-3), 32.5 (C-3), 50.5 (CH2CHOH), 50.5 (CH2CHOH),
51.9 (CO2Me), 51.9 (CO2Me), 52.1 (CH2Ph), 52.1 (CH2Ph), 59.0
hexane/AcOEt, 7:3), the product 7b (0.127 g, 67%) as a colourless
2
2
(q, JC.F = 25.8 Hz, CHCF3), 59.7 (C-2), 60.0 (q, JC,F = 25.6 Hz,
CHCF3), 60.3 (C-2), 66.4 (q, 3JC,F = 2.2 Hz, CHOH), 67.2 (q, 3JC,F
= 2.4 Hz, CHOH), 126.6 (q, 1JC,F = 284.9 Hz, CF3), 126.6 (q, 1JC,F
= 284.9 Hz, CF3), 127.3 (Ar), 127.3 (Ar), 128.4 (4 C, Ar), 128.4 (4
C, Ar), 139.3 (Ar), 139.3 (Ar), 175.1 (C-1), 175.2 (C-1) ppm. 19F
3
oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.25 (d, JH,H
=
3
2
7.2 Hz, 3 H, H-3), 2.59 (dd, JH,H = 4.5, JH,H = 12.0 Hz, 1 H,
3
CH2CHOH), 2.48–2.68 (br. s, 1 H, NH), 2.83 (dd, JH,H = 8.1,
3
3
2JH,H = 12.0 Hz, 1 H, CH2CHOH), 3.03 (qd, JH,H = 2.4, JH,F
=
8.2 Hz, 1 H, CHCF3), 3.28 (s, 3 H, CH2OMe), 3.30–3.38 (m, 3 H,
3
NMR (188 MHz, CDCl3, 25 °C): δ = –71.39 (d, JF,H = 7.6 Hz, 3
3
CH2OMe and H-2), 3.66 (s, 3 H, CO2Me), 3.87 (ddd, JH,H = 2.4,
3
F), –71.48 (d, JF,H = 7.8 Hz, 3 F) ppm. MS (APCI): m/z = 395.2
3
4.5, 8.1 Hz, 1 H, CHOH), 4.04 (dd, JH,H = 4.8, 7.8 Hz, 1 H,
[M + H]+. IR: ν = 2919, 1733, 1454, 1260, 1128, 732, 699 cm–1.
˜
CHPh), 7.16–7.31 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 19.1 (C-3), 50.5 (CH2CHOH), 51.8 (CO2Me), 56.0 (C-
C17H25F3N2O3S (394.45): calcd. C 51.76, H 6.39, N 7.10; found C
52.13, H 6.17, N 7.03.
2
2), 58.8 (CH2OMe), 58.8 (q, JC,F = 26.6 Hz, CHCF3), 61.9
3
(S)-Dimethyl
2-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutyl-
(CHPh), 67.3 (q, JC,F = 2.1 Hz, CHOH), 77.9 (CH2OMe), 126.1
(q, 1JC,F = 281.8 Hz, CF3), 127.8/128.4 (5 C, Ar), 140.0 (Ar), 175.8
(C-1) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –73.20 (d,
3JF,H = 8.2 Hz, 3 F) ppm. MS (APCI): m/z = 379.2 [M + H]+. IR:
amino]succinate (11a): Epoxide 1a (0.1156 g, 0.5 mmol) and -H-
Asp(OMe)-OMe (0.161 g, 1.0 mmol) gave, after 7 h of refluxing in
MeOH (1.25 mL) and purification (cyclohexane/AcOEt, 7:3), the
product 11a (0.175 g, 89%) as a colourless oil. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 2.03–2.40 (br. s, 2 H, NH), 2.48–2.56 (m, 4 H,
CH2CHOH and H-3), 2.60–2.69 (m, 2 H, CH2CHOH and H-3),
ν = 2926, 1736, 1454, 1266, 1136, 701 cm–1. C H F N O
˜
17 25
3
2
4
(378.39): calcd. C 53.96, H 6.66, N 7.40; found C 54.36, H 6.87, N
7.02. [α]2D5 = –65 (c = 1, MeOH).
3
2.78–2.86 (m, 2 H, CH2CHOH and H-3), 2.96 (qd, JH,H = 3.0,
3JH,F = 7.8 Hz, 1 H, CHCF3), 3.01 (qd, 3JH,H = 3.6, 3JH,F = 8.1 Hz,
(S)-Methyl 2-{(2S,3R)-3-[(R)-2-Methoxy-1-phenylethylamino]-4,4,4-
trifluoro-2-hydroxybutylamino}-3-phenylpropanoate (8b): Epoxide
1b (0.1375 g, 0.5 mmol) and -H-Phe-OMe (0.179 g, 1.0 mmol)
gave, after 18 h of refluxing in MeOH (1.25 mL) and purification
(cyclohexane/AcOEt, 7:3), the product 8b (0.214 g, 94%) as a
3
1 H, CHCF3), 3.52 (dd, JH,H = 7.8, 14.4 Hz, 1 H, H-2), 3.54 (dd,
3JH,H = 7.5, 14.1 Hz, 1 H, H-2), 3.60 (s, 6 H, CO2Me), 3.67 (s, 6
H, CO2Me), 3.70–3.82 (m, 4 H, CH2Ph and CHOH), 4.00 (d, 2JH,H
= 13.5 Hz, 2 H, CH2Ph), 7.18–7.27 (m, 10 H, Ar) ppm. 13C NMR
1
colourless oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 2.52 (dd,
(75 MHz, CDCl3, 25 °C):
δ = 37.8 (C-3), 37.8 (C-3), 50.5
2
3JH,H = 4.5, JH,H = 12.3 Hz, 1 H, CH2CHOH), 2.38–2.55 (br. s, 1
(CH2CHOH), 50.7 (CH2CHOH), 51.9 (CO2Me), 51.9 (CO2Me),
52.1 (2 C, CH2Ph), 52.2 (CO2Me), 52.2 (CO2Me), 57.2 (C-2), 58.0
H, NH), 2.78–2.97 (m, 4 H, CH2CHOH and H-3 and CHCF3),
3.24 (s, 3 H, CH2OMe), 3.27–3.47 (m, 3 H, CH2OMe and H-2),
2
2
(C-2), 59.3 (q, JC,F = 25.8 Hz, CHCF3), 59.8 (q, JC,F = 25.7 Hz,
3
3
3
3.59 (s, 3 H, CO2Me), 3.75 (ddd, JH,H = 2.7, 4.5, 7.5 Hz, 1 H,
CHCF3), 66.4 (q, JC,F = 2.2 Hz, CHOH), 67.3 (q, JC,F = 2.1 Hz,
CHOH), 126.6 (q, JC,F = 285.3 Hz, 2 C, CF3), 127.3 (2 C, Ar),
1
CHOH), 3.95–4.02 (m, 1 H, CHPh), 7.07–7.26 (m, 10 H, Ar) ppm.
13C NMR (75 MHz, CDCl3, 25 °C):
(CH2CHOH), 51.7 (CO2Me), 58.7 (q, JC.F = 26.6 Hz, CHCF3),
δ = 39.6 (C-3), 50.5
128.3 (4 C, Ar), 128.4 (4 C, Ar), 139.4 (Ar), 139.4 (Ar), 171.2/171.2/
2
173.7/173.8 (4 C, C-1 and C-4) ppm. 19F NMR (188 MHz, CDCl3,
3
3
3
58.7 (CH2OMe), 61.8/62.1 (CHPh/C-2), 67.0 (q, JC,F = 1.6 Hz,
25 °C): δ = –71.37 (d, JF,H = 7.8 Hz, 3 F), –71.51 (d, JF,H
=
1
8.1 Hz, 3 F) ppm. MS (ESI): m/z = 415.1 [M + Na]+. IR: ν = 2924,
CHOH), 77.9 (CH2OMe), 126.0 (q, JC,F = 281.8 Hz, CF3), 126.8/
˜
1736, 1438, 1262, 1133, 702, 631 cm–1. C17H23F3N2O5 (392.37):
calcd. C 52.04, H 5.91, N 7.14; found C 52.40, H 5.71, N 6.87.
127.8/127.8/128.3/128.4/129.0 (10 C, Ar), 137.0 (Ar), 139.9 (Ar),
174.6 (C-1) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –73.15
3
(d, JF,H = 8.3 Hz, 3 F) ppm. MS (APCI): m/z = 455.1 [M + H]+.
Ethyl 2-{(2S,3R)-3-[(R)-2-Methoxy-1-phenylethylamino]-4,4,4-tri-
fluoro-2-hydroxybutylamino}acetate (6b): Epoxide 1b (0.4812 g,
1.75 mmol) and H-Gly-OEt (0.360 g, 3.5 mmol) gave, after 7 h of
refluxing in EtOH (4.4 mL) and purification (cyclohexane/AcOEt,
IR: ν = 2933, 1734, 1455, 1266, 1134, 700 cm–1. C H F N O
˜
23 29
3
2
4
(454.48): calcd. C 60.78, H 6.43, N 6.16; found C 60.41, H 6.54, N
5.79. [α]2D5 = –37 (c = 1, MeOH).
1:1), the product 6b (0.5044 g, 76%) as a yellow solid; m.p. 51–
(S)-Methyl 2-{(2S,3R)-3-[(R)-2-Methoxy-1-phenylethylamino]-4,4,4-
trifluoro-2-hydroxybutylamino}-3-[4-(benzyloxy)phenyl]propanoate
3
52 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.22 (t, JH,H
=
7.2 Hz, 3 H, CO2CH2CH3), 2.33–2.63 (br. s, 1 H, NH), 2.76 (dd, (9b): Epoxide 1b (0.1375 g, 0.5 mmol) and -H-Tyr(Bn)-OMe
2
3
3JH,H = 4.5, JH,H = 12.0 Hz, 1 H, CH2CHOH), 2.82 (dd, JH,H
=
(0.285 g, 1.0 mmol) gave, after 18 h of refluxing in MeOH
7.8, 2JH,H = 12.0 Hz, 1 H, CH2CHOH), 3.05 (qd, 3JH,H = 3.0, 3JH,F (1.25 mL) and purification (cyclohexane/AcOEt, 8:2), the product
= 8.3 Hz, 1 H, CHCF3), 3.29 (s, 3 H, CH2OMe), 3.34–3.42 (m, 2 H, 9b (0.217 g, 78%) as a colourless oil. 1H NMR (300 MHz, CDCl3,
CH2OMe), 3.37 (s, 2 H, H-2), 3.86 (ddd, 3JH,H = 3.0, 4.5, 7.8 Hz, 1
25 °C): δ = 2.26–2.56 (br. s, 1 H, NH), 2.53 (dd, 3JH,H = 4.5, JH,H
2
3
H, CHOH), 3.97–4.08 (m, 1 H, CHPh), 4.14 (q, JH,H = 7.2 Hz, 2 = 12.3 Hz, 1 H, CH2CHOH), 2.74–2.90 (m, 3 H, CH2CHOH and
H, CO2CH2CH3), 7.19–7.32 (m, 5 H, Ar) ppm. 13C NMR H-3), 2.96 (qd, JH,H = 2.4, JH,F = 8.3 Hz, 1 H, CHCF3), 3.26 (s,
3
3
(75 MHz, CDCl3, 25 °C):
δ
=
14.2 (CO2CH2CH3), 50.5
3 H, CH2OMe), 3.29–3.44 (m, 3 H, CH2OMe and H-2), 3.60 (s, 3
2
(CH2CHOH), 52.3 (C-2), 58.8 (q, JC,F = 26.8 Hz, CHCF3), 58.9 H, CO2Me), 3.77 (ddd, 3JH,H = 2.4, 4.5, 7.5 Hz, 1 H, CHOH), 3.98
3
(CH2OMe), 60.9 (CO2CH2CH3), 61.9 (CHPh), 67.6 (q, JC,F
=
(dd, 3JH,H = 4.5, 8.2 Hz, 1 H, CHPh), 4.94 (s, 2 H, OCH2Ph), 6.82
1.6 Hz, CHOH), 78.0 (CH2OMe), 126.1 (q, 1JC,F = 281.8 Hz, CF3),
127.8/127.9/128.4 (5 C, Ar), 140.0 (Ar), 172.4 (C-1) ppm. 19F NMR
(188 MHz, CDCl3, 25 °C): δ = –73.24 (d, 3JF,H = 8.3 Hz, 3 F) ppm.
(d, JH,H = 8.6 Hz, 2 H, Ar), 7.01 (d, JH,H = 8.6 Hz, 2 H, Ar),
3
3
7.15–7.36 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 38.8 (C-3), 50.5 (CH2CHOH), 51.8 (CO2Me), 58.8 (q, JC,F
2
=
5220
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5215–5223

New Trifluoromethylated Hydroxyethylamine-Based Scaffolds
26.5 Hz, CHCF3), 58.8 (CH2OMe), 61.9/62.2 (2 C, CHPh and C-
an atmosphere of H2. After 30 min of vigorous stirring, the mixture
was filtered over Celite, and the filtrate was concentrated under
reduced pressure. The -H-Phe--Ala-OMe thus obtained and ep-
oxide 1a (0.1156 g, 0.5 mmol, 1 equiv.) were dissolved in 1.25 mL
of MeOH. After 18 h of refluxing and purification (cyclohexane/
AcOEt, 8:2 then 1:1), the product 12a (0.107 g, 45 %, 2 dia-
stereomers, 1:1) was obtained as a yellow oil. 1H NMR (300 MHz,
3
2), 67.0 (q, JC,F = 1.7 Hz, CHOH), 69.9 (OCH2Ph), 77.9
1
(CH2OMe), 126.0 (q, JC,F = 281.6 Hz, CF3), 114.8/127.4/127.8/
127.9/128.4/128.5/130.1 (14 C, Ar), 129.2 (Ar), 136.9 (Ar), 139.9
(Ar), 157.7 (Ar), 174.7 (C-1) ppm. 19F NMR (188 MHz, CDCl3,
3
25 °C): δ = –73.14 (d, JF,H = 8.3 Hz, 3 F) ppm. MS (APCI): m/z
= 561.4 [M + H]+. IR: ν = 2923, 1734, 1511, 1454, 1240, 1136,
˜
1109, 734, 699 cm–1. C30H35F3N2O5 (560.60): calcd. C 64.27, H
6.29, N 5.00; found C 64.16, H 6.47, N 4.77. [α]2D5 = –30 (c = 1,
CH2Cl2).
CDCl3, 25 °C): δ = 1.26 (d, JH,H = 7.5 Hz, 3 H, CHMe), 1.28 (d,
3
3JH,H = 7.5 Hz, 3 H, CHMe), 1.73–2.09 (br. s, 2 H, NH), 2.44–2.70
3
3
(m, 6 H, CH2CHOH and CHCH2Ph), 2.78 (qd, JH,H = 3.4, JH,F
3
3
= 7.7 Hz, 1 H, CHCF3), 2.91 (qd, JH,H = 3.4, JH,F = 7.7 Hz, 1
(S)-Methyl 2-{(2S,3R)-3-[(R)-2-Methoxy-1-phenylethylamino]-4,4,4-
trifluoro-2-hydroxybutylamino}-4-(methylthio)butanoate (10b): Ep-
oxide 1b (0.1375 g, 0.5 mmol) and -H-Met-OMe (0.163 g,
1.0 mmol) gave, after 18 h of refluxing in MeOH (1.25 mL) and
purification (cyclohexane/AcOEt, 8:2), the product 10b (0.176 g,
3
2
H, CHCF3), 3.06 (dd, JH,H = 4.2, JH,H = 14.0 Hz, 2 H,
CHCH2Ph), 3.19 (dd, JH,H = 4.2, 9.0 Hz, 1 H, CHCH2Ph), 3.25
(dd, JH,H = 4.2, 9.3 Hz, 1 H, CHCH2Ph), 3.60 (s, 3 H, CO2Me),
3
3
3.61 (s, 3 H, CO2Me), 3.64–3.73 (m, 3 H, CHOH and CH2Ph),
3.75–3.80 (m, 1 H, CHOH), 3.92 (d, 2JH,H = 12.6 Hz, 1 H, CH2Ph),
1
80%) as a colourless oil. H NMR (300 MHz, CDCl3, 25 °C): δ =
2
3
3.96 (d, JH,H = 13.2 Hz, 1 H, CH2Ph), 4.51 (qi, JH,H = 7.5 Hz, 2
1.76–1.88 (m, 1 H, H-3), 1.90–1.99 (m, 1 H, H-3), 2.03 (s, 3 H,
3
H, CHMe), 7.09–7.22 (m, 20 H, Ar), 7.60 (d, JH,H = 7.5 Hz, 1 H,
3
3
SMe), 2.55 (t, JH,H = 7.4 Hz, 2 H, H-4), 2.62 (dd, JH,H = 4.5,
2JH,H = 12.3 Hz, 1 H, CH2CHOH), 2.78–3.10 (br. s, 1 H, NH),
2.92 (dd, 3JH,H = 7.5, 2JH,H = 12.3 Hz, 1 H, CH2CHOH), 3.06 (qd,
3JH,H = 3.0, 3JH,F = 8.3 Hz, 1 H, CHCF3), 3.30 (s, 3 H, CH2OMe),
3.34–3.44 (m, 3 H, CH2OMe and H-2), 3.69 (s, 3 H, CO2Me), 3.92
(ddd, 3JH,H = 3.0, 4.5, 7.5 Hz, 1 H, CHOH), 4.04 (dd, 3JH,H = 4.7,
8.0 Hz, 1 H, CHPh), 7.19–7.31 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 15.3 (SMe), 30.5 (C-4), 32.2 (C-3),
50.8 (CH2CHOH), 52.1 (CO2Me), 58.8/59.6 (2 C, CH2OMe and
C-2), 59.0 (q, 2JC.F = 26.2 Hz, CHCF3), 61.8 (CHPh), 67.0 (q, 3JC,F
NHCO), 7.62 (d, JH,H = 7.5 Hz, 1 H, NHCO) ppm. 13C NMR
3
(75 MHz, CDCl3, 25 °C): δ = 18.1 (CHMe), 18.2 (CHMe), 39.2
(CHCH2Ph), 39.3 (CHCH2Ph), 47.4 (2 C, CHCH2Ph), 51.4/51.9/
52.1 (4 C, CH2CHOH and CH2Ph), 52.4 (2 C, CO2Me), 59.5 (q,
2
2JC,F = 26.1 Hz, CHCF3), 60.0 (q, JC,F = 25.8 Hz, CHCF3), 63.7
3
(CHMe), 63.9 (CHMe), 67.1 (q, JC,F = 1.7 Hz, CHOH), 67.4 (q,
1
3JC,F = 2.0 Hz, CHOH), 126.3 (q, JC,F = 282.9 Hz, CF3), 126.4
(q, 1JC,F = 282.1 Hz, CF3), 126.9 (Ar), 126.9 (Ar), 127.3 (Ar), 127.3
(Ar), 128.2 (2 C, Ar), 128.3 (2 C, Ar), 128.3 (2 C, Ar), 128.4 (2 C,
Ar), 128.6 (2 C, Ar), 128.7 (2 C, Ar), 129.0 (2 C, Ar), 129.0 (2 C,
Ar), 137.1 (Ar), 137.1 (Ar), 139.1 (Ar), 139.1 (Ar), 173.3/173.3/
173.7/173.7 (4 C, CO2Me and NHCO) ppm. 19F NMR (188 MHz,
CDCl3, 25 °C): δ = –71.48 (d, 3JF,H = 7.7 Hz, 3 F), –71.69 (d, 3JF,H
= 7.7 Hz, 3 F) ppm. MS (ESI): m/z = 482.3 [M + H]+, 504.3 [M +
1
= 1.6 Hz, CHOH), 78.0 (CH2OMe), 126.0 (q, JC,F = 282.3 Hz,
CF3), 127.8 (2 C, Ar), 127.9 (Ar), 128.4 (2 C, Ar), 139.9 (Ar), 174.6
(C-1) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –73.04 (d,
3JF,H = 8.3 Hz, 3 F) ppm. MS (APCI): m/z = 439.2 [M + H]+. IR:
ν = 2920, 1733, 1454, 1266, 1134, 1101, 701 cm–1. C H F N O S
˜
Na]+. IR: ν = 3330, 2930, 2019, 1867, 1742, 1581, 1356, 1132 cm–1.
19 29
3
2
4
˜
(438.51): calcd. C 52.04, H 6.67, N 6.39; found C 52.09, H 6.61, N
C24H30F3N3O4 (481.51): calcd. C 59.87, H 6.28, N 8.73; found C
59.49, H 6.24, N 8.37.
6.02. [α]2D5 = –55 (c = 1, MeOH).
(S)-Dimethyl 2-{(2S,3R)-3-[(R)-2-Methoxy-1-phenylethylamino]-
4,4,4-trifluoro-2-hydroxybutylamino}succinate (11b): Epoxide 1b
(0.1375 g, 0.5 mmol) and -H-Asp(OMe)-OMe (0.161 g, 1.0 mmol)
gave, after 18 h of refluxing in MeOH (1.25 mL) and purification
(cyclohexane/AcOEt, 8:2), the product 11b (0.163 g, 75%) as a yel-
Methyl N-((2S,3R)-4,4,4-Trifluoro-2-hydroxy-3-{[(1R)-2-methoxy-
1-phenylethyl]amino}butyl)-L-phenylalanyl-L-alaninate (12b): -Cbz-
Phe--Ala-OMe (768 mg, 1.0 mmol, 2 equiv.) was dissolved in
5 mL of MeOH. Pd/C (10% in mass, 0.077 g) was added. The mix-
ture was then placed under an atmosphere of H2. After 30 min of
vigorous stirring, the mixture was filtered over Celite, and the fil-
trate was concentrated under reduced pressure. The -H-Phe--Ala-
OMe thus obtained and epoxide 1b (0.1375 g, 0.5 mmol, 1 equiv.)
were dissolved in 1.25 mL of MeOH. After 72 h of refluxing and
purification (cyclohexane/AcOEt, 8:2 then 1:1), the product 12b
(0.100 g, 38%, 1 diastereomer) was obtained as a yellow oil. 1H
1
low oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 2.32–2.73 (br. s,
3
1 H, NH), 2.54–2.73 (m, 1 H, CH2CHOH), 2.58 (dd, JH,H = 7.8,
2JH,H = 15.9 Hz, 1 H, H-3), 2.70 (dd, 3JH,H = 5.1, 2JH,H = 15.9 Hz,
3
2
1 H, H-3), 2.93 (dd, JH , H = 8.1, JH , H = 12.3 Hz, 1 H,
3
3
CH2CHOH), 3.02 (qd, JH,H = 3.0, JH,F = 8.3 Hz, 1 H, CHCF3),
3.28 (s, 3 H, CH2OMe), 3.33–3.38 (m, 2 H, CH2OMe), 3.58 –3.62
(m, 1 H, H-2), 3.62 (s, 3 H, CO2Me), 3.68 (s, 3 H, CO2Me), 3.87
3
NMR (300 MHz, CDCl3, 25 °C): δ = 1.31 (d, JH,H = 7.5 Hz, 3 H,
3
(ddd, JH,H = 3.0, 4.2, 8.1 Hz, 1 H, CHOH), 4.00–4.05 (m, 1 H,
CHMe), 1.90–2.34 (br. s, 1 H, NH), 2.61–2.75 (m, 3 H, CH2CHOH
CHPh), 7.16–7.30 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3,
3
3
and CHCH2Ph), 3.06 (qd, JH,H = 3.0, JH,F = 8.3 Hz, 1 H,
25 °C): δ = 37.8 (C-3), 50.7 (CH2CHOH), 51.9 (CO2Me), 52.2
CHCF3), 3.13 (dd, 3JH,H = 3.9, JH,H = 13.8 Hz, 1 H, CHCH2Ph),
2
2
(CO2Me), 56.9/58.7 (2 C, CH2OMe and C-2), 58.8 (q, JC,F
=
3.22 (s, 3 H, CH2OMe), 3.30–3.35 (m, 3 H, CHCH2Ph and
CH2OMe), 3.65 (s, 3 H, CO2Me), 3.68–3.73 (m, 1 H, CHOH), 4.00
3
26.5 Hz, CHCF3), 61.8 (CHPh), 67.1 (q, JC,F = 1.8 Hz, CHOH),
77.9 (CH2OMe), 126.0 (q, 1JC,F = 281.8 Hz, CF3), 127.8 (Ar), 127.8
(2 C, Ar), 128.3 (2 C, Ar), 140.0 (Ar), 171.2/173.7 (2 C, C-1 and
C-4) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –72.75 (d,
3JF,H = 8.3 Hz, 3 F) ppm. MS (ESI): m/z = 459.2 [M + Na]+. IR:
3
3
(dd, JH,H = 5.4, 7.2 Hz, 1 H, CHPh), 4.55 (qi, JH,H = 7.5 Hz, 1
3
H, CHMe), 7.15–7.28 (m, 10 H, Ar), 7.67 (d, JH,H = 7.5 Hz, 1 H,
NHCO) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 18.1
(CHMe), 39.4 (CHCH2Ph), 47.4 (CHCH2Ph), 52.0 (CH2CHOH),
52.4 (CO2Me), 58.7 (CH2OMe), 58.8 (q, 2JC,F = 26.3 Hz, CHCF3),
ν = 2954, 1736, 1438, 1267, 1138, 704, 630 cm–1. C H F N O
˜
19 27
3
2
6
(436.42): calcd. C 52.29, H 6.24, N 6.42; found C 52.67, H 6.14, N
3
61.3 (CHPh), 63.7 (CHMe), 68.3 (q, JC,F = 1.6 Hz, CHOH), 78.1
(CH2OMe), 126.2 (q, JC,F = 276.7 Hz, CF3), 127.0 (Ar), 127.7 (2
6.24. [α]2D5 = –27 (c = 0.5, MeOH).
1
Methyl N-[3-(Benzylamino)-4,4,4-trifluoro-2-hydroxybutyl]-
L
-phen-
C, Ar), 127.9 (Ar), 128.4 (2 C, Ar), 128.7 (2 C, Ar), 129.1 (2 C,
ylalanyl- -alaninate (12a): -Cbz-Phe--Ala-OMe (768 mg,
1.0 mmol, 2 equiv.) was dissolved in 5 mL of MeOH. Pd/C (10%
in mass, 0.077 g) was added. The mixture was then placed under
L
Ar), 137.2 (Ar), 139.9 (Ar), 173.3/173.8 (2 C, CO2Me and NHCO)
3
ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –73.24 (d, JF,H
=
8.3 Hz, 3 F) ppm. MS (ESI): m/z = 548.3 [M + Na]+. IR: ν = 3324,
˜
Eur. J. Org. Chem. 2009, 5215–5223
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5221

B. Crousse et al.
FULL PAPER
2930, 1742, 1653, 1520, 1454, 1209, 1136, 732, 700 cm–1.
C26H34F3N3O5 (525.56): calcd. C 59.42, H 6.52, N 8.00; found C
59.11, H 6.45, N 7.67. [α]2D5 = –58 (c = 1, CH2Cl2).
Mullins, D. B. Prince, D. J. Paddock, A. G. Tomasselli, G. Win-
terrowd, Bioorg. Med. Chem. Lett. 2007, 17, 73–77.
[11] J. N. Freskos, Y. M. Fobian, T. E. Benson, J. B. Moon, M. J.
Bienkowski, D. L. Brown, T. L. Emmons, R. Heintz, A. La-
borde, J. J. McDonald, B. V. Mischke, J. M. Molyneaux, P. B.
Mullins, D. B. Prince, D. J. Paddock, A. G. Tomasselli, G. Win-
terrowd, Bioorg. Med. Chem. Lett. 2007, 17, 78–81.
[12] M. C. Maillard, R. K. Hom, T. E. Benson, J. B. Moon, S.
Mamo, M. Bienkowski, A. G. Tomasselli, D. D. Woods, D. B.
Prince, D. J. Paddock, T. L. Emmons, J. A. Trucker, M. S.
Dappen, L. Brogley, E. D. Thorsett, N. Jewett, S. Sinha, V.
John, J. Med. Chem. 2007, 50, 776–781.
Ethyl 2-(3-Amino-4,4,4-trifluoro-2-hydroxybutylamino)acetate (13):
Epoxide 1a (115.6 mg, 0.5 mmol, 1 equiv.) and H-Gly-OEt
(51.5 mg, 0.5 mmol, 1 equiv.) were dissolved in EtOH (1.25 mL).
After 10 h of refluxing, Pd(OH)2 (30% in mass, 50 mg) and EtOH
(15.75 mL) were added to the mixture, which was then placed under
an atmosphere of H2. After one night of vigorous stirring, the mix-
ture was filtered over celite. The filtrate was concentrated under
reduced pressure and gave product 13 (108.7 mg, 89%) as white
[13] M. Sani, A. Volonterio, M. Zanda, ChemMedChem 2007, 2,
1
needless; m.p. 60–62 °C. H NMR (300 MHz, CDCl3, 25 °C): δ =
1693–1700.
3
1.27 (t, JH,H = 7.2 Hz, 3 H, CO2CH2CH3), 1.59–2.51 (br. s, 3 H,
[14] H. Meng, K. Kumar, J. Am. Chem. Soc. 2007, 129, 15615–
15622.
CH2CHOH), 2.86 (dd, JH,H = 8.1, JH,H = 12.6 Hz, 1 H, [15] I. Ojima, K. Kato, F. A. Jameison, J. Conway, Bioorg. Med.
3
2
NH and NH2), 2.80 (dd, JH,H = 4.5, JH,H = 12.6 Hz, 1 H,
3
2
3
3
Chem. Lett. 1992, 2, 219–222.
CH2CHOH), 3.11 (qd, JH,H = 2.4, JH,F = 8.1 Hz, 1 H, CHCF3),
3
[16] I. Ojima, F. A. Jameison, Bioorg. Med. Chem. Lett. 1991, 1,
3.42 (s, 2 H, H-2), 3.89–3.93 (m, 1 H, CHOH), 4.19 (q, JH,H
=
7.2 Hz, 2 H, CO2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 14.1 (CO2CH2CH3), 50.5 (CH2CHOH), 52.1 (2-C), 55.4
581–584.
[17] J. P. Bégué, D. Bonnet-Delpon, J. Fluorine Chem. 2006, 127,
992–1012.
2
3
(q, JC,F = 27.6 Hz, CHCF3), 60.9 (CO2CH2CH3), 66.2 (q, JC,F
=
[18] C. Isanbor, D. O’Hagan, J. Fluorine Chem. 2006, 127, 303–319.
[19] K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013–1029.
[20] J. P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal
Chemistry of Fluorine, John Wiley & Sons, Hoboken, 2008.
[21] P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactiv-
ity, Applications, Wiley-VCH, Weinheim, 2004.
[22] M. Zanda, New J. Chem. 2004, 28, 1401–1411.
[23] N. T. N. Tam, G. Magueur, M. Ourevitch, B. Crousse, J. P.
Bégué, D. Bonnet-Delpon, J. Org. Chem. 2005, 70, 699–702.
[24] D. M. Hodgson, A. R. Gibbs, G. P. Lee, Tetrahedron 1996, 52,
14361–14384.
1.7 Hz, CHOH), 126.1 (q, 1JC,F = 280.7 Hz, CF3), 172.4 (1-C) ppm.
19F NMR (188 MHz, CDCl3, 25 °C): δ = –76.28 (d, 3JF,H = 8.1 Hz,
3 F) ppm. MS (ESI): m/z = 245 [MH]+, 267 [M + Na]+. IR: ν =
˜
3309, 1726, 1661, 1260, 1110, 1023, 796 cm–1. C8H15F3N2O3
(244.21): calcd. C 39.35, H 6.19, N 11.47; found C 39.74, H 5.93,
N 11.13.
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Central Glass is thanked for the kind gift of fluoral hydrate and
HFIP. DSM company is also thanked for the donation of (R)-phen-
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érieur et de la Recherche (MESR) for awarding a PhD student
fellowship. We thank A. Solgadi for performing mass spectra analy-
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