Efficient preparation of enantiomerically pure α-aryl-α- trifluoromethylglycines via Auto Seeded Programmed Polythermic Preferential Crystallization of 5-aryl-5-trifluoromethylhydantoins

Article abstract of DOI:10.1016/j.tetasy.2010.11.029

Both pure enantiomers of α-phenyl- (or α-(p-methoxyphenyl))- α-trifluoromethyl-glycine and their corresponding methyl esters were obtained on a preparative scale using the following four-step sequence: the preparation of 5-aryl-5-trifluoromethylhydantoins by a Buecherer-Bergs reaction starting from trifluoromethyl aryl ketones, optical resolution by Auto Seeded Programmed Polythermic Preferential Crystallization (AS3PC), basic hydrolysis of the enantiopure hydantoins by means of aqueous barium hydroxide, and esterification of the amino acids with trimethylsilyldiazomethane. Hydantoins 5 and 6 were proven to crystallize as conglomerates using first second harmonic generation and then X-ray powder diffraction. The absolute stereochemistry of (+)-5-phenyl-5-trifluoromethylhydantoin 5b was established to be (S) by X-ray diffraction analysis on a single-crystal.

Full text of DOI:10.1016/j.tetasy.2010.11.029

Tetrahedron: Asymmetry 22 (2011) 12–21
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient preparation of enantiomerically pure a-aryl-a-trifluoromethylglycines
via Auto Seeded Programmed Polythermic Preferential Crystallization
of 5-aryl-5-trifluoromethylhydantoins
Thibaut Martin, Cédrik Massif, Nicolas Wermester, Julie Linol, Séverine Tisse, Pascal Cardinael,
⇑
Gérard Coquerel, Jean-Philippe Bouillon
Laboratoire Sciences et Méthodes Séparatives, EA 3233 & FR 3038, Université de Rouen, IRCOF, F-76821 Mont-Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Both pure enantiomers of
a-phenyl- (or a-(p-methoxyphenyl))-a-trifluoromethyl-glycine and their
Received 22 October 2010
Accepted 26 November 2010
Available online 12 January 2011
corresponding methyl esters were obtained on a preparative scale using the following four-step sequence:
the preparation of 5-aryl-5-trifluoromethylhydantoins by a Bücherer–Bergs reaction starting from trifluo-
romethyl aryl ketones, optical resolution by Auto Seeded Programmed Polythermic Preferential Crystalliza-
tion (AS3PC), basic hydrolysis of the enantiopure hydantoins by means of aqueous barium hydroxide, and
esterification of the amino acids with trimethylsilyldiazomethane. Hydantoins 5 and 6 were proven to crys-
tallize as conglomerates using first second harmonic generation and then X-ray powder diffraction. The
absolute stereochemistry of (+)-5-phenyl-5-trifluoromethylhydantoin 5b was established to be (S) by X-
ray diffraction analysis on a single-crystal.
Dedicated to the memory of Professor Y. L.
Yagupol’skii (Institute of Organic Chemistry,
Kiev)
Ó 2010 Elsevier Ltd. All rights reserved.
NR1
1. Introduction
F3C
R2
a-Trifluoromethyl amino acids and their corresponding amino
esters are very attractive for the design of biologically active mole-
R1 = R2 = CO2Me
R1 = PMP, R2 = CO2tBu
Path A
ii
i
cules, especially in the application of peptides as pharmaceuticals.1
Among these compounds, fluorinated non-racemic
a,a-disubsti-
tuted -amino acids represent key targets in modern peptide chem-
a
O
istry,2 because of their remarkable properties. Their restricted
conformational flexibility is useful for well-defined secondary struc-
ture folding,3 their increased lipophilicity improves the in vivo
absorption rate and permeability through cellular membranes4
while their higher resistance toward enzymatic hydrolysis enhances
bioavailability.5
F3C
Ph
i
iii
Path B
ii
F3C
N
C
N
OH
NH2
O
ii
( ), (+) or (-)
S
iv
tBu
Path C
Several syntheses of racemic6 or enantiopure7
-amino acids have already been reported. Herein we wish to focus
on synthetic routes to enantiopure -disubstituted -trifluoro-
methyl -amino acids. There are two general methods described in
the literature: (a) the synthesis of racemic -amino acid derivatives
a-trifluoromethyl
a
F3C
Ph
a
,a
a
Scheme 1. Reagents and conditions: (i) PhMgX; (ii) HCl, HCO2Haq or (1) CANaq, (2)
a
HClaq; (iii) HCN; (iv) TMSCN.
a
based on reactions between N-protected imines derived from alkyl
trifluoropyruvate and various organometallic reagents,8 followed
by resolution using chiral agents or enzymes;5a,9 and (b) the diaste-
reoselective synthesis using chiral trifluoromethyl building blocks
(cyclic 2,5-diketopiperazine,10 b-sulfinylimines or b-iminosulfox-
ides,11
cleavage of the chiral auxiliary.
Among fluorinated -disubstituted
very few examples concerning -aryl-
derivatives. Only two racemic syntheses and one stereoselective
method have been reported (Scheme 1). In the first approach, -phe-
nyl- -trifluoromethylglycine was prepared from the reaction of a
non chiral trifluoropyruvate imine with a phenyl Grignard reagent
a
-CF3-imines, iminiums, and oxazolidines7,12), followed by
a,a
a-amino acids, there are
a
a-trifluoromethylglycine
a
a
⇑
Corresponding author. Tel.: +33 (0)2 35 52 24 22; fax: +33 (0)2 35 52 29 59.
E-mail address: jean-philippe.bouillon@univ-rouen.fr (J.-P. Bouillon).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.029

T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
13
followed by aqueous acid hydrolysis (Scheme 1: path A: R1 = R2 =
O
F3C
Ar
CO2Me)13 or oxidative removal of a p-methoxyphenyl (PMP) group
O
Method 1, 2 or 2'
by treatment with cerium ammonium nitrate (CAN) and acid
NH
t
hydrolysis (Scheme 1: path A: R1 = PMP, R2 = CO2 Bu).14 Another
HN
Ar
CF3
racemic synthesis involves a three-step sequence: the reaction of
trifluoroacetonitrile with phenyl Grignard reagent to afford the
corresponding ketimine; the addition of hydrogen cyanide leading
1-4
O
Ar = C6H5, pMeOC6H4,
pClC6H4, pBrC6H4
( )-5-8
to a-aminonitrile; and then aqueous hydrolysis with hydrochloric
acid (Scheme 1: path B).15
Scheme 3. Reagents and conditions. Method 1: KCN (3.0 equiv), (NH4)2CO3
(4.0 equiv), EtOH–H2O (50:50), autoclave, 110–120 °C, 38 h. Method 2 or 20: KCN
(1.2 equiv), (NH4)HCO3 (3.6 equiv), NH4OH (8.6 equiv), EtOH–H2O (50:50), 65 °C, 2–
4 days.
The non-racemic approach uses an asymmetric Strecker reaction
of chiral (R)-N-tert-butylsulfinylketimine with trimethylsilylcya-
nide followed by aqueous acid hydrolysis to remove the chiral aux-
iliary(Scheme 1: path C).16 These three syntheses suffer from several
drawbacks: the preparation of racemic mixtures (paths A, B) or the
use of a chiral auxiliary in stoichiometric amounts (path C).
repeated twice (heating 1 with 1.5 equiv of potassium cyanide
and 2.0 equiv of ammonium carbonate for 16 h, then the addition
of the same quantities of reagents and again heating for 22 h),
the yield of compound 5 reached 53% yield after purification by sil-
ica gel column chromatography (Table 1, Method 1: entry 1).
A second optimisation up to 72% yield was performed using the
procedure developed by Coquerel et al.21 starting from an aqueous
ammonium hydrogenocarbonate, ammonium hydroxide, and
potassium cyanide suspension (Scheme 3, Table 1, Method 2:
entry 2). This improvement can be reasonably explained by the in-
crease in reaction mixture solubility. Moreover, it was suspected
that ammonium carbamate (a side-product of ammonium carbon-
ate) might inhibit the Bücherer–Bergs reaction.
2. Results and discussion
2.1. Synthesis of ( )-hydantoins 5–8
The aim of our strategy was to develop an efficient three-step
method for the preparation of both (+)- and (ꢀ)-enantiomers of
a-aryl-a-trifluoromethylglycine derivatives. The key step is based
on an easy resolution of 5-aryl-5-trifluoromethylhydantoins by
Auto Seeded Programmed Polythermic Preferential Crystallization
(AS3PC).17 There are several advantages to this approach: there is
no need for the use of stoichiometric amounts of resolving agent;
it can be carried out on a large multigram scale, and both enantio-
mers are accessible in high enantiomeric excess (ee >98%).
When performing the same reaction on a large scale (Table 1,
entry 3), purification of compound 5 was difficult when using silica
gel column chromatography or direct recrystallization of the crude
mixture (due to solubility problems). Therefore, the crude mixture
According to Scheme 2, the two enantiomers of
a-aryl-a-CF3-
glycines could be obtained from aqueous basic hydrolysis of enan-
tiopure 5-aryl-5-CF3-hydantoins, which could be resolved by the
AS3PC method and prepared using a Bücherer-Bergs reaction from
the corresponding ketones.
was purified by precipitation of the ( )-a-methylbenzylamine
(
a
-MBA)ꢂ( )-hydantoin ammonium salt, filtration, and the release
of the corresponding ( ) hydantoin by simple heating (Table 1,
Method 20: entry 3) afforded 50% of pure compound 5. This purifi-
cation method has already been developed by Coquerel et al.21 for
non-fluorinated hydantoin derivatives.
The first step of our sequence was the one pot synthesis of 5-
aryl-5-trifluoromethylhydantoins. These compounds are known
to exhibit interesting biological activities such as anesthetic or
neuroprotective actions on the central nervous system.18a,b Two
main synthetic pathways to 5-aryl-5-CF3-hydantoins have previ-
ously been reported in the literature. The most general method is
based on a Bücherer–Bergs reaction19 starting from trifluoro-
methyl aryl ketones or the corresponding cyanohydrins with
ammonium carbonate and potassium cyanide.18 The second meth-
od involves the reaction of trifluoromethyl amino ester derivatives
with various substituted isocyanates followed by cyclization to the
corresponding hydantoins.20
Our methodology (Method 2 or 20) was then extended to vari-
ous p-substituted aryl trifluoromethyl ketones 2–4 (Scheme 3).
p-Methoxyphenyl hydantoin 6 was successfully prepared in good
yields using Method 2 or 20 (Table 1, entries 4 and 5). Nevertheless,
the reactions of p-chloro- and p-bromophenyl trifluoromethyl ke-
tones 3 and 4 were more complicated. Although reaction yields
were almost quantitative, the corresponding hydantoins 7 and 8
were obtained in 35% and 23% yields, respectively (Table 1, entries
6 and 7). Indeed, several other fluorinated by-products (which
were not characterized) were detected in the crude mixture by
19F NMR, indicating possible partial substitution of the halogen
or other competitive reactions.
We chose the Bücherer-Bergs reaction for the preparation of ( )
hydantoins 5–8 as their corresponding CF3-ketones 1–4 are com-
mercially available or easily prepared using
reaction.
a Friedel–Craft
It is worth noting that the aryl trifluoromethyl ketones 1–4
react differently compared to the non-fluorinated ones. Almost
The first experiment was to repeat the reported procedure18a
Table 1
starting from a,a,a-trifluoro-acetophenone 1 with ammonium car-
Synthesis of 5-aryl-5-(trifluoromethyl)hydantoins 5–8
bonate and potassium cyanide in a sealed container (Scheme 3).
Unfortunately, the conversion was not complete and a low yield
(ꢁ30–40%) of hydantoin 5 was obtained. When the reaction was
Entry
Ar
Ketone (scale)
Method
Conv.a (%)
Yieldb (%)
1
2
3
4
5
6
7
Ph
Ph
Ph
1 (5.7 mmol)
1 (5.7 mmol)
1 (345 mmol)
2 (23.8 mmol)
2 (107 mmol)
3 (3.6 mmol)
4 (4.1 mmol)
1
2
87
5 (53)c
5 (72)c
5 (50)d
6 (63)c
6 (65)d
7 (35)c
8 (23)c
ꢁ100
ꢁ100
ꢁ100
ꢁ100
ꢁ95e
ꢁ95e
20
2
O
pMeOC6H4
pMeOC6H4
pClC6H4
pBrC6H4
F3C
20
2
2
O
O
F3C
Ar
i
ii
Ar
iii
NH
Ar
CF3
HN
OH
Conversion was estimated by 19F NMR of the crude mixture.
Isolated pure compound.
Purification by silica gel column chromatography.
a
b
c
NH2
O
( )
(+) or (-)
d
e
Purification by crystallization with ( )-
aMBA.
Several other fluorinated by-products were detected in the crude mixture by 19
F
Scheme 2. Reagents and conditions: (i) aqueous basic hydrolysis; (ii) resolution by
AS3PC; (iii) Bücherer–Bergs reaction.
NMR.

14
T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
Table 2
quantitative conversion of 1–4 into hydantoins 5–8 was reached
after 2–4 days (in contrast, the corresponding 5-aryl-5-methyl-
hydantoins were obtained in good yields after only 5–10 h).21
Hydrogen bond lengths and angles
D–Hꢂ ꢂ ꢂA
d(D–H) (Å) d(Hꢂ ꢂ ꢂA) (Å) d(Dꢂ ꢂ ꢂA) (Å) Angle (DHA) (°)
N(1)–H(1)ꢂ ꢂ ꢂO(2) 0.86
N(2)–H(2)ꢂ ꢂ ꢂO(1) 0.86
1.99
1.99
2.838(2)
2.781(2)
169.3
153.1
2.2. Characterisation of hydantoins 5–8
All fluorinated ( )-hydantoins 5–8 were characterized using
spectroscopic experiments (19F, 1H, 13C NMR, and IR), mass spec-
trometry, and microanalyses. It was not possible to crystallize
the p-chloro- and p-bromophenylhydantoins 7 and 8. In contrast,
compounds 5 and 6 were easily obtained as solids and were sus-
pected to crystallize as conglomerates by means of first Second
Harmonic Generation (SHG) tests.22
Moreover, it was shown that the XRPD patterns of the racemic
mixtures and of the pure enantiomers were exactly superimpos-
able for hydantoins 5 and 6, respectively, thus confirming the full
chiral discrimination in the solid state. This important property
allowed us to perform the resolution of racemic hydantoins 5
and 6 by AS3PC experiments (vide infra).
Suitablesingle-crystals ofcompound5 wereobtainedbytheslow
evaporationof a saturated ether/MeOH/CH2Cl2 solution. The crystal-
line structure of hydantoin 5b was determined by single-crystal
X-ray diffraction in the P21 space group at 296 K. Structure represen-
tation (ORTEP drawing) is given in Figure 1. The (S)-configuration
wasassigned to a singlecrystal ofhydantoin 5b. ThecalculatedXRPD
pattern from single-crystal X-ray diffraction was consistent with the
experimental XRPD patterns. Therefore, the single-crystal used for
this structure study was representative of the bulk.
The stability of the crystalline packing was ensured by an exten-
sive network of hydrogen bonds (Table 2). The crystal structure
(see Cambridge Crystallographic Data Centre: Reference No.
684964) shows the usual H-bond network in the shape of a ribbon
and with a periodicity of 6.21 0.02 Å.23
therefore, determined from the resolution of the corresponding
ammonium salt. A batch of salt 9 was prepared from (R)-(+)-
a-
methylbenzylamine [(+)-a-MBA] and (+)-hydantoin 5b (obtained
from Pasteurian resolution,24 see Section 4). Several single-crystals
were obtained by slow evaporation of a petroleum ether/MeOH/
CH2Cl2 solution. The resolution of 9 was performed by single-crystal
X-ray diffraction and its configuration was the following: (R) for
(+)-a-MBA molecules and (S) for (+)-hydantoin molecules (Fig. 2).
2.4. Resolution of ( )-hydantoins 5 and 6 by Auto Seeded
Programmed Polythermic Preferential Crystallization
experiments
Preferential crystallization, also called entrainment, is a well-
known preparative resolution method25 applicable to racemic
mixtures crystallizing as stable conglomerates. This method con-
sists of alternate stereoselective crystallizations of each antipode
from a supersaturated mother liquor initially containing an excess
of one enantiomer. By means of successive recycling of the mother
liquor and the addition of the racemic mixture in order to maintain
the same initial concentration, the process quantitatively gave the
two enantiomers without the use of a resolving agent. A variant of
preferential crystallization known as AS3PC (Auto Seeded
Programmed Polythermic Preferential Crystallization),17,21 which
offers improved performances in comparison to the conventional
seeded method, was applied here.
2.3. Determination of the absolute configuration of hydantoin
5b
2.4.1. Resolution of ( )-5-phenyl-5-trifluoromethylhydantoin 5
Two batches of ( )-5-phenyl-5-trifluoromethylhydantoin
5
were resolved by two campaigns of preferential crystallization
(Scheme 4). Seven and twelve entrainments were carried out by
successive recycling of the mother liquor. The initial composition
The resolution of the crystalline structure of hydantoin 5b did
not allow us to unambiguously determine the absolute configura-
tion because the Flack parameter was not accurate enough. It was,
Figure 1. Visualisation of hydrogen bonds between hydantoin molecules (ORTEP drawing) of 5b. All non-hydrogen atoms are represented by their displacement ellipsoids
drawn at a 50% probability level. Hydrogen atoms are drawn with an arbitrary radius.

T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
15
Figure 2. Projections of the crystalline structure of the (R)-(+)-a-MBA salt 9 of (+)-(S)-hydantoin 5b along an axis.
O
F3C
Ar
of the system for the first attempts, the main AS3PC parameters,
and the results are collected in Tables 3 and 4, respectively. The
temperature ramp was from 30 °C to ꢀ10 °C for the first campaign
and from 30 °C to ꢀ15 °C for the second one (cooling rate = 0.67 °C/
min). The final temperature was held until the end (ꢃ24 h) show-
ing a strong entrainment effect. The evolution of the enantiomeric
excess (ee) was measured by using off line polarimetry and HPLC
with three or four samples of the mother liquor near completion
of the entrainment.
Ar = C6H5: (-)-(R)-5a
Ar = pMeOC6H4: (-)-6a
NH
O
HN
F3C
Ar
AS3PC17,21
O
O
NH
HN
F3C
Ar
O
Ar = C6H5: (+)-(S)-5b
NH
Ar = C6H5: ( )-5
Ar = pMeOC6H4: (+)-6b
HN
Ar = pMeOC6H4: ( )-6
An average mass of 1.2 g (crude crops) was collected with an
enantiomeric purity approximately 86% ee. Theoretically, the ee
value should be 100%; the lower value obtained is due to the fact
that the crystals were partially impregnated by the mother liquor
containing the remaining racemic mixture and no washing of the
filtration cake had been implemented. We noticed that the final
temperature TF for the second campaign was decreased from
ꢀ10 °C down to ꢀ15 °C in order to increase the driving force of
the crystallization. Subsequent purification by recrystallization
gave the pure enantiomer with an enantiomeric purity of 99% ee
with 87% yield. This result is consistent with the crystal structure
with a partial solid solution, that is, complete chiral discrimination
occurs in the solid state.
O
Scheme 4. AS3PC resolution of ( ) hydantoins 5 and 6.
from 0 °C down to ꢀ10 °C. Experimentally, the entrainment effect
remained unchanged because the same driving force (supersatura-
tion) was used.
During these entrainments, the crop mass values were scattered
because monitoring the mother liquor requires several samples,
thus causing a significant loss of material at this scale. An average
mass of 777 mg (crude crops) was collected with an enantiomeric
purity of approximately 86% ee. Recrystallization in ethanol gave
access to the pure enantiomers with an enantiomeric purity of
greater than 99% ee.
In conclusion, for these small scale AS3PC experiments, the di-
rect resolution of 5-phenyl-5-trifluoromethylhydantoin 5 was
characterized by a satisfactory entrainment effect.
2.5. Synthesis of a-aryl-a-trifluoromethylglycine derivatives
2.4.2. Resolution of ( )-5-(p-methoxyphenyl)-5-
(trifluoromethyl)hydantoin 6
The most general method for the transformation of hydantoins
into the corresponding -amino acids uses aqueous acid (H2SO4 or
The same AS3PC experiments were performed with ( ) 5-(p-
methoxyphenyl)-5-trifluoromethylhydantoin 6. Seven entrain-
ments were carried out by successive recycling of the mother
liquor. The initial composition of the system for the first attempt,
the main AS3PC parameters and the results are given in Table 5.
The temperature ramp was from 40 °C to 0 °C for the first four cy-
cles and from 40 °C to ꢀ10 °C for the following cycles (cooling
rate = 0.67 °C/min). The final temperature was held until the end
of entrainment (ꢃ48 h) in order to determine the end of the
entrainment effect.
a
HCl)26 or basic (NaOH, LiOH, or Ba(OH)2)27 hydrolysis. For non-
fluorinated hydantoins, several reactions have already been re-
ported in the literature. These transformations usually require
strong reaction conditions such as highly concentrated aqueous
acid (e.g., H2SO4 60%) or base (e.g., NaOH 2 M) solution, long reac-
tion time (12–48 h), high temperature (>120 °C), and give only
moderate yields (25–50%) of the amino acid derivatives.26,27 It is
worth noting that basic hydrolysis often gives slightly better yields.
On the contrary, there is only one publication that reports the
We noticed that after a certain number of crystallizations, sev-
eral impurities contained in the racemic mixture accumulated in
the mother liquor. These components introduced a shift in the
temperatures: the final temperatures TF progressively decreased
hydrolysis of (R)-5-difluoromethyl-5-methylhydantoin into (R)-a-
difluoromethylalanine hydrochloride (yield: 90%) by refluxing with
aqueous Ba(OH)2ꢂ8H2O and subsequent HCl acidification of the
reaction mixture.11b

16
T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
Table 3
Results of the preferential crystallization of ( )-5-phenyl-5-trifluoromethylhydantoin 5—first campaign
Mass of ethanol (g)
Mass of racemic mixture M( ) (g)
4.71
Mass of pure enantiomer Mp (g)
24.9
1
0.45
Cycle
2
3
4
5
6
7
Mass of crops (g)
0.766
89
0.682
6.7
1.645
40a
0.658
6.5
1.082
91
0.985
9.5
1.205
86
1.036
9.9
0.975
88
0.858
8.3
0.949
91
0.864
8.4
1.078
85
0.916
8.9
Enantiomeric excess by HPLC (% ee)
Mass of collected pure enantiomer (g)
eef (%)b
a
For this batch, nucleation of the antipode was detected before filtration.
eef stands for the final enantiomeric excess of the mother liquor at the end of the entrainment. eef
M
p =2
b
¼
.
M
p =2þMðꢄÞ
Table 4
Results of preferential crystallization of ( )-5-phenyl-5-trifluoromethylhydantoin 5—second campaign
Mass of ethanol (g)
31.9
Mass of racemic mixture M( ) (g)
Mass of pure enantiomer Mp (g)
6.0
0.50
Cycle
1
2
3
4
5
6
7
8
9
10
11
12
Mass of crops (g)
1.084
88
0.953
7.3
1.146
80
0.917
7.1
1.641
80
1.313
9.9
1.617
90
1.471
10.9
1.166
91
1.061
8.1
1.124
87
0.978
7.5
1.349
88
1.187
9.0
1.505
89
1.339
10.0
1.391
93
1.293
9.7
1.389
95
1.319
9.9
1.317
91
1.198
9.1
0.977
94
0.918
7.1
Enantiomeric excess by HPLC (% ee)
Mass of collected pure enantiomer (g)
eef (%)
Table 5
Results of preferential crystallization of ( ) 5-(p-methoxyphenyl)-5-trifluoromethyl-hydantoin 6
Mass of ethanol (g)
Mass of racemic mixture M( ) (g)
Mass of pure enantiomer Mp (g)
21.5
1
3.2
0.35
Cycle
2
3
4
5
6
7
MEAN
Mass of crops (g)
1.070
58
0.621
8.8%
1.082
93
1.006
13.6%
0.534
95
0.508
7.3%
0.405
92
0.372
5.5%
0.845
86
0.723
10.1%
0.613
88
0.549
7.9%
0.892
89
0.794
11.0%
0.777
85.8
0.653
9.1%
Enantiomeric excess by HPLC (% ee)
Mass of collected pure enantiomer (g)
eef
As indicated in the literature11b as well in our first preliminary
experiment, it was necessary touse mildreaction conditionsin order
to avoid the loss of the trifluoromethyl group. The hydrolysis of 5-
aryl-5-trifluoromethylhydantoins 5 and 6 were performed using
Zanda’s reaction conditions, but hydrochloric acid was replaced by
sulfuric acid in order to increase the precipitation of inorganic salts
(BaSO4 is less soluble in water than BaCl2). Reactions were optimized
on racemic mixtures, then the transformations were extended to
both (+)- and (ꢀ)-enantiomers without the isolation of the
corresponding amino acid derivatives (see one pot procedure). Nev-
ertheless, we did not notice any variation in the chemical yields in
the racemic or enantiopure series. The best conditions were the fol-
O
F3C
Ar
O
O
1) i
F3C
Ar
F3C
Ar
NH
2) ii
OH
NH2
iv
HN
OMe
NH2
3) iii
O
( ), (+) or (-)
( ), (+) or (-)
( ), (+) or (-)
Ar = C6H5: 12 (70%)a
Ar = C6H5: 10 (~22%)
Ar = C6H5: 5
Ar = pMeOC6H4: 11 (~60%)
Ar = pMeOC6H4: 6
Ar = pMeOC6H4: 13 (76%)b
Scheme 5. Reagents and conditions: (i) Ba(OH)2ꢂ8H2O,
D, 3 days; (ii) H2SO4 (0.5 M);
(iii) DOWEX chromatography; (iv) TMSCHN2, MeOH–toluene, 25 °C. aOverall yield
of 12 from 5: 14%. bOverall yield of 13 from 6: 46%.
lowing: an aqueous suspension of hydantoin
5 or 6 and
and 13 were obtained in 70% and 76% yields, respectively. The chem-
ical purities of 12 and 13 were checked by microanalysis. However,
all attempts to verify the enantiomeric purity by chiral GC (station-
Ba(OH)2ꢂ8H2O (6 equiv) was refluxed for 3 days (reaction evolution
was monitored by 19F NMR of the crude reaction mixture). After
H2SO4 acidification (pH 1) and removal of the inorganic salts, the
ary phase: chirasil-
(stationary phase: Chirobiotic T or Chirobiotic V) were unsuccessful.
For the esterification of ( )- -amino acid 11, small amounts of
L-val or permethylated-b-cyclodextrin) or HPLC
resulting a-amino acid was obtained by chromatography on Dowex
50WX, in moderate (ꢁ22% for compound 10) to good (ꢁ60% for com-
a
pound 11) yields (Scheme 5).
N-methyl and N,N-dimethyl amino esters 14 and 15 (see Section 4)
were observed in the crude reaction mixture by NMR and GC–MS.
In order to increase the efficiency of our method, a one pot syn-
thesis of compounds 12 and 13 was performed starting from the
corresponding 5-aryl-5-trifluoromethylhydantoins 5 and 6; overall
yields of 14% and 46%, respectively, were obtained (Scheme 5).
a
-Amino acids 10 and 11 were characterized by NMR experi-
ments (19F, 1H, 13C), and mass spectrometry (MS, HRMS). Although
only one enantiomer of each -amino acid 10 or 11 was observed
a
usingchiralHPLCanalysis(stationaryphase:ChirobioticT), the sam-
ples were slightly contaminated by inorganic salts (as proved by
microanalysis). Therefore, compounds 10 and 11 were derivatized
As indicated in Scheme 5, yields of
and 11 (ꢁ60%) were quite different and this requires explanation.
It was hypothesized that after the formation of the -amino acids,
a
-amino acids 10 (ꢁ22%)
into the corresponding a-amino esters using a solution of trimethyl-
silyldiazomethane28 in an MeOH-toluene mixture (Scheme 5). After
a
easy purification by chromatography on silica gel, compounds 12

T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
17
in situ deprotonation of the carboxylic function of 10 or 11 could
be followed by a decarboxylation reaction leading to carbanion
16 (Scheme 6). The latter could then lose a fluoride anion (which
is a good leaving group) to give difluoroalkene 17. This highly reac-
tive intermediate could thus behave as a Michael type acceptor in
an aqueous basic medium to afford the corresponding phenylgly-
cine derivative 18 as the final product (Scheme 6). This proposition
was supported by the observation of compound 18 (R = H) in the
crude reaction mixture of hydantoin 5, using LC-MS analysis. On
the contrary, a p-methoxy substituent (which exhibits an elec-
tron-donating effect through phenyl conjugation) seems to have
a destabilising contribution on the anion 16, thus preventing the
loss of the fluoride anion and, therefore, the formation of p-meth-
oxyphenylglycine 18 (R = OMe).
enantiopure (+) hydantoins 5b and 6b were obtained using Pasteu-
-methylbenzylamine.24 Reac-
rian resolution starting from (ꢀ)-(S)-
a
tions were followed by thin layer chromatography (TLC) on silica gel
(Merck, Darmstadt, Germany) and revealed using UV light, using
either an ethanolic solution of phosphomolybdic acid or ninhydrin
solution (especially for amino acids and amino esters). Purification
of compounds5–8 (Table1) was carriedoutusingflash columnchro-
matography with silica gel (70–200 lm). The purity of the synthetic
products was established by HPLC/UV analysis and confirmed by
NMR spectroscopic data and MS analysis. HPLC: for hydantoins
5a,b and 6a,b: ThermoQuest P1500, UV Detector: k = 235 nm, chiral
stationary phase: Chiral Pack AD, mobile phase: ethanol, flow: 1 mL/
min; for a-amino acids 10a,b and 11a,b: ThermoQuest P1500, UV
Detector: k = 220 nm, chiral stationary phase: Chirobiotic T,
250 mmꢅ4.6 mm, mobile phase: 90% MeOH/10% water/0.1% acetic
acid, flow: 1 mL minꢀ1. MS: Thermo Finnigan, LCQ Advantage Max,
Electrospray Ionisation, Source heater T = 220 °C, capillary volt-
age = 33 V. High Resolution Mass Spectra (HRMS) were recorded
with a Q-TOF Micromass Instrument in the positive ESI (CV = 30 V)
mode. 1H (300 MHz), 19F (280 MHz), and 13C (75 MHz) NMR spectra
were recorded on a Bruker Advance DMX 300 instrument. All the
experiments were recorded using CDCl3 or CD3COCD3 or DMSO-d6
as solvent. TMS or the deuterated solvent signal was taken as inter-
nal reference for 1H and 13C spectra and the CFCl3 signal for 19F spec-
3. Conclusion
We have described a straightforward synthesis of both enantio-
mers of
a-phenyl- and a-(p-methoxyphenyl)-a-trifluoromethyl-
glycines 10 and 11, from commercially available or easily
accessible trifluoromethyl aryl ketones, using a three-step se-
quence. It is worth noting that there is only one publication which
reports the stereoselective synthesis of the a
-amino acid 10.16 The
main advantages of our methodology are the multigram scale syn-
thesis and the access to both the (+)- and (ꢀ)-enantiomers in high
enantiomeric excess, thanks to efficient resolution of 5-aryl-5-
trifluoromethylhydantoins 5 and 6 by the AS3PC process. The
tra. The enantiomeric purity of the ‘crops’ of hydantoins 5, 6 was
ꢇC
determined by chiral HPLC. Specific rotations (½a 25
ꢆ
589 nm) were mea-
sured with a Perkin–Elmer Model 341 polarimeter using the sodium
D line at 589 nm, at 25 °C. XRPD measurements were carried out
with a D5000matic SiemensÒ instrument with a Bragg Brentano
geometry, in theta–theta reflection mode. The instrument is
equipped with an X-ray tube (copper anticathode, 40 kV, 40 mA,
fluorinated
a,a-disubstituted a-amino acids 10 and 11 as well as
a
-amino esters 12 and 13 could be involved in new valuable pep-
tide couplings:29 these aspects are currently under investigation.
K
a
1 radiation: 1.540598 Å, K 2 radiation: 1.544426 Å), a nickel filter,
a
4. Experimental
and a scintillation detector. The diffraction patterns were collected
with steps of 0.04° (2-theta) over the angular range 3–30°, with a
counting time of 4 s per step. No internal standard was used but a
sample of quartz was analyzed as an external standard (data pro-
cessing by using software EVAÒ v 9.0.0.2). The crystal structures of
hydantoin 5b and ammonium salt 9 were determined from single-
crystal X-ray diffraction on a BrukerÓ SMART APEX diffractometer
4.1. General methods
Reagents and solvents were generally the best quality commer-
cial grade and used without further purification: a,a,a-trifluoroace-
tophenone (Acros, 99%), 1-(4-chlorophenyl)-2,2,2-trifluoroeth
anone (Aldrich, 99%), 1-(4-bromophenyl)-2,2,2-trifluoroethanone
(with MoK 1 radiation: 0.71073 Å). The structures were determined
a
(Aldrich, 99%), ( )-a-methylbenzylamine [( )-a-MBA, Acros, 99%],
by means of the direct methods and refined with the SHELXTLÓ
package.31 Single-crystals of 5b and 9 were obtained by a slow evap-
oration of a saturated solution of petroleum ether/MeOH/CH2Cl2.
TG/DSC measurements were performed with a STA 409 PC/PG (Net-
zschÒ) with aluminum crucibles and with a 2 K/min heating rate.
ethanol (Acros, absolute), KCN (Aldrich, 99%), NH4HCO3 (Prolabo,
Rectapur), NH4OH (Acros, for analysis, 28–30 wt % solution of NH3
in water), Ba(OH)2ꢂ8H2O (Acros, 98%). Ketone 2 was prepared and
purified according to the literature.30 Small amounts (ꢁ100 mg) of
4.2. General procedure for the synthesis of 5-(trifluoromethyl)-
hydantoins 5–8
R
R
The ( )-5-(trifluoromethyl)hydantoins 5–8 were prepared from
the appropriate ketones 1–4 using a Bücherer–Bergs reaction.
CF3
O
- CO2
Na+ -OH
- NaF
H
17
CF2
F
H2N
H2N
Na+
4.2.1. Typical procedure for Method 1 (Table 1, entry 1)
O
16
A solution of ketone 1 (5.74 mmol, 1 equiv) in ethanol (12 mL)
was added to a mixture of KCN (0.56 g, 8.61 mmol) and (NH4)2CO3
(1.65 g, 17.22 mmol) in water (12 mL). The suspension was heated
in an autoclave at 110–120 °C for 16 h. The course of the reaction
was controlled by 19F NMR of the crude mixture. After one night
of heating, the conversion was not complete. Next, KCN (0.56 g,
8.61 mmol) and (NH4)2CO3 (0.55 g, 5.74 mmol) were added. The
suspension was again heated at 110–120 °C for 22 h. At the end
of reaction, an excess of hydrochloric acid solution (37 wt %,
10 mL) was slowly added to obtain an acidic pH (pH 1–2). The
aqueous phase was extracted four times with diethyl ether
(4 ꢅ 30 mL). The combined organic extracts were dried over
MgSO4, filtered, and evaporated under reduced pressure. The crude
R = H: 10
R = OMe: 11
R
R
+ NaOH H3O+
- NaF
CF2
H2N
CO2H
Na+ -OH
H2N
18
17
R = H: observed
R = OMe: _
Scheme 6. Proposed mechanism explaining the low yield of a-amino acid 10.

18
T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
yellow solid was purified by silica gel column chromatography
(eluent: petroleum ether/AcOEt 70:30) affording the desired
hydantoin 5 (0.74 g, 53%).
(EI, %) m/z 274 [M+], 205, 134 (100), 91, 44. HRMS (ESI+) calcd for
11H9F3N2O3Na m/z 297.0463, found 297.0464.
C
4.2.6. ( ) 5-(p-Chlorophenyl)-5-(trifluoromethyl)hydantoin 7
( )-Hydantoin 7 was obtained in 35% yield (0.35 g) using Meth-
od 2 (Table 1, entry 6) after purification by silica gel column chro-
matography (eluent: petroleum ether/AcOEt 50/50). Oil. 1H NMR
(300 MHz, CD3COCD3) d: 7.1 (br s, 1H, NH), 7.4 (br s, 1H, NH),
4.2.2. Typical procedure for Method 2 (Table 1, entry 2)
A solution of ketone 1 (5.74 mmol, 1 equiv) in ethanol (23 mL)
was added to a mixture of KCN (4.67 g, 6.89 mmol) and (NH4)HCO3
(17.1 g, 20.66 mmol) in water (23 mL). A solution of NH4OH
(30 wt %, 17.7 mL) was added into the flask provided with a reflux
condenser. The mixture was heated at 65 °C for 3 days. At the end
of the reaction, an excess of hydrochloric acid solution (37 wt %,
20 mL) was slowly added to obtain an acidic pH (pH 1–2). The
same work-up and purification on silica gel column chromatogra-
phy as Method 1 afforded hydantoin 5 (1.01 g, 72%).
3
3
7.52 (d, JH,H = 8.7 Hz, 2H Ar), 7.86 (d, JH,H = 8.7 Hz, 2H Ar). 19F
NMR (280 MHz, CD3COCD3) d: ꢀ74.7 (s). 13C NMR (75 MHz, CDCl3)
d: 77.8 (q, 2JC,F = 29.3 Hz, C-5), 123.5 (q, 1JC,F = 286.1 Hz, CF3), 127.9
4
(q, JC,F = 1.5 Hz, 2 ꢅ CH Ar), 129.1 (s, 2 ꢅ CH Ar), 132.4 (s, Cq Ar),
136.0 (s, Cq Ar), 160.6 (s, C-2, CO), 170.1 (s, C-4, CO). MS (ESIꢀ)
m/z 279 [M-H], 277 [M-H]. HRMS (ESIꢀ) calcd for C10H535ClF3N2O2
m/z 276.9992, found 277.0000. Several other fluorinated by-prod-
ucts were detected in the crude mixture by 19F NMR but were
not separated and assigned.
4.2.3. Typical procedure for Method 20 (Table 1, entry 3)
A solution of ketone 1 (0.345 mol, 1 equiv) in ethanol (140 mL)
was added to a mixture of KCN (27.2 g, 0.418 mol) and (NH4)HCO3
(100 g, 1.260 mol) in water (140 mL).
A solution of NH4OH
4.2.7. ( ) 5-(p-Bromophenyl)-5-(trifluoromethyl)hydantoin 8
( )-Hydantoin 8 was obtained in 23% yield (0.31 g) using Meth-
od 2 (Table 1, entry 7) after purification by silica gel column chro-
matography (eluent: petroleum ether/AcOEt 60/40). Oil. 1H NMR
(300 MHz, CD3COCD3) d: 7.1 (br s, 1H, NH), 7.4 (br s, 1H, NH),
(30 wt %, 104 mL) was then added. The mixture was heated at
65 °C for 3 days. At the end of the reaction, an excess of hydrochlo-
ric acid solution (37 wt %, 70 mL) was slowly added to an obtain
acidic pH (pH 1–2). The resulting hydantoin 5 was precipitated
and filtered off. The crude was purified by crystallization of ammo-
3
3
7.71 (d, JH,H = 8.5 Hz, 2H Ar), 7.85 (d, JH,H = 8.5 Hz, 2H Ar). 19F
NMR (280 MHz, CD3COCD3) d: ꢀ74.7 (s). 13C NMR (75 MHz, CDCl3)
d: 77.9 (q, 2JC,F = 29.1 Hz, C-5), 123.6 (q, 1JC,F = 286.0 Hz, CF3), 124.3
nium salt with ( )-
aMBA as a base. The crude solid (56 g) was dis-
solved in ethanol (60 mL) then ( )-
aMBA (27.8 g, 1.02 equiv) was
slowly added. The resulting ammonium salt was formed after
5 min and its solubility was decreased by the slow addition of
diethyl ether (100 mL) as an anti-solvent. The suspension was fil-
trated on a Büchner and the collected mass was around 40 g. The
solution was partially evaporated and the process of crystallization
was repeated several times. Four successive crystallization/filtra-
tion sequences allowed the collection of several fractions of salt.
For each crop, the solid was washed with diethyl ether (ꢁ20 mL).
All solid phases were combined to give 63 g of the ammonium salt.
The release of pure hydantoin was performed by simple heating of
the ammonium salt at 100–110 °C, in an oven for 48 h. When the
4
(s, Cq Ar), 128.2 (q, JC,F = 1.6 Hz, 2 ꢅ CH Ar), 132.0 (s, 2 ꢅ CH Ar),
132.8 (s, Cq Ar), 160.6 (s, C-2, CO), 170.2 (s, C-4, CO). MS (ESIꢀ)
m/z 323 [M-H], 321 [M-H]. HRMS (ESIꢀ) calcd for C10H579BrF3N2O2
m/z 320.9486, found 320.9489. Several other fluorinated by-prod-
ucts were detected in the crude mixture by 19F NMR but were not
separated and assigned.
4.3. Typical procedure for the Auto Seeded Programmed Poly
thermic Preferential Crystallization (AS3PC) of 5-phenyl-5-
(trifluoromethyl)hydantoin 5 (Scheme 4, Tables 3–5)
loss of mass was about 33% (corresponding to aMBA mass), the so-
Preferential crystallization (PC) using the Auto-Seeded variant
(AS3PC17,21) was performed in a thermostated double-wall tube.
Temperature was accurately controlled by a cryo/thermostat (Lau-
daÒ RE107). The initial system containing an excess of the (S)-
enantiomer was heated at temperature TB (TB = 30 °C for hydantoin
5 and TB = 40 °C for hydantoin 6) so that only the (R)-enantiomer
was completely dissolved. The slurry was composed of crystals of
the (S)-enantiomer in excess and in a thermodynamic equilibrium
with its saturated solution; the suspension was self-seeded by
crystals of the pure enantiomer. The auto-seeded preferential crys-
tallization was then ready to start. Thus, the suspension was sub-
mitted to an adapted cooling program (30 °C to ꢀ10 °C for
hydantoin 5—cooling rate = 0.67 °C/min; and 40 °C to 0 °C for
hydantoin 6—cooling rate = 0.67 °C/min) and magnetic stirring
without any need of additional seeds so that the crystal growth
was favoured instead of an uncontrolled second nucleation. The
course of the entrainment was monitored by off-line polarimetric
measurements of the mother liquor. At the end of the entrainment,
the crystals of the (S)-enantiomer were collected by filtration with
a Büchner and the enantiomeric purities of the crops were deter-
mined by chiral HPLC. The mother liquor containing an excess of
the (R)-enantiomer was heated until TB. A mass of ( )-hydantoin
5 [equal to the collected mass of (S) crystals] was then added to
the mother liquor. The slurry was thus composed of crystals of
the (R)-enantiomer and the same cooling program was applied in
order to collect a crop of the (R)-enantiomer. This process can be
repeated as many times as necessary, allowing alternative crystal-
lizations of S- and R-enantiomers, corresponding to the resolution
of the racemic mixture.
lid was kept at room temperature. ( )-5-Phenyl-5-(trifluoro-
methyl)hydantoin 5 was obtained (42 g, 50% yield) with a 99%
chemical purity.
4.2.4. 5-Phenyl-5-(trifluoromethyl)hydantoin 5 (Table 1, entries
1–3)
( ) Hydantoin 5: solid. Mp 220 °C. 1H NMR (300 MHz,
CD3COCD3) d: 7.4–7.6 (m, 3H Ph), 7.9–8.0 (m, 2H Ph), 8.7 (br s,
1H, NH), 10.2 (br s, 1H, NH). 19F NMR (280 MHz, CD3COCD3) d:
2
ꢀ75.0 (s). 13C NMR (75 MHz, CD3OD) d: 69.6 (q, JC,F = 30.0 Hz, C-
1
5), 124.2 (q, JC,F = 284.2 Hz, CF3), 127.8 (s, 2 ꢅ CH Ph), 129.8 (s,
2 ꢅ CH Ph), 131.0 (s, CH Ph), 131.7 (s, Cq Ph), 158.2 (s, C-2, CO),
170.1 (s, C-4, CO). GC-MS (EI, %) m/z 244 [M+], 175, 132, 104
(100), 77. HRMS (ESI+) calcd for C10H7F3N2NaO2 m/z 267.0357,
found 267.0359.
4.2.5. 5-(p-Methoxyphenyl)-5-(trifluoromethyl)hydantoin 6
( )-Hydantoin 6 was obtained in 63% yield (4.11 g) using Meth-
od 2 (purification by chromatography on silica gel, Table 1, entry 4)
and in 65% yield (17.0 g) using Method 20 (purification by crystal-
lization of ammonium salt, Table 1, entry 5). ( )-Hydantoin 6: so-
lid. Mp 230 °C. 1H NMR (300 MHz, CD3COCD3) d: 3.68 (s, 3H,
3
3
MeO), 6.89 (d, JH,H = 8.6 Hz, 2H Ar), 7.63 (d, JH,H = 8.6 Hz, 2H Ar),
8.6 (br s, 1H, NH), 10.2 (br s, 1H, NH). 19F NMR (280 MHz,
CD3COCD3) d: ꢀ75.3 (s). 13C NMR (75 MHz, CD3COCD3) d: 55.6 (s,
2
CH3O), 68.5 (q, JC,F = 29.9 Hz, C-5), 114.8 (s, 2 ꢅ CH Ar), 122.9 (s,
1
Cq Ar), 123.9 (q, JC,F = 283.9 Hz, CF3), 128.9 (s, 2 ꢅ CH Ar), 155.9
(s, C-2, CO), 161.7 (s, Cq, COMe), 168.9 (s, C-4, CO). IR (KBr, cmꢀ1
)
3226, 3019, 2963, 1797, 1751, 1614, 1513, 1403, 1249. GC–MS

T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
19
4.3.1. (ꢀ)-(R)- and (+)-(S)-Hydantoins 5a and 5b
was added slowly. The resulting salt was formed after 5 min and
its solubility was decreased by the slow addition of diethyl ether
(20 mL). The suspension was filtrated on a Büchner to afford
1.40 g (yield: 90%) of the corresponding ammonium salt 9.
Enantiopure hydantoins 5a, 5b were obtained by an AS3PC pro-
cedure and recrystallization in ethanol.
25
589
(ꢀ)-(R)-Hydantoin 5a: solid. Mp 257 °C. ½
aꢆ
¼ ꢀ34:8 (c 0.01 g/
mL, MeOH). HPLC: retention time: 5.3 min; enantiomeric purity:
99.3% e.e.
4.6.1. (+)-(R)-
(trifluoromethyl)hydantoin ammonium salt 9
a
-Methylbenzylamineꢂ(+)-5-phenyl-5-
25
589
(+)-(S)-Hydantoin 5b: solid. Mp 257 °C. ½
aꢆ
¼ þ34:7 (c 0.01 g/
mL, MeOH). HPLC: retention time: 3.3 min; enantiomeric purity:
White solid. Mp 190 °C. IR (KBr, cmꢀ1) 3184, 2982, 1792, 1741,
1602, 1452, 1389, 1257. HRMS (ESI+) calcd for C18H19F3N3O2 m/z
366.1429, found 366.1438. The solid was recrystallized in petro-
leum ether/MeOH/CH2Cl2 giving suitable single-crystal for X-ray
99.2% e.e.
The X-ray crystal structure determination of compound 5b
(Fig. 1). C10H7F3N2O2, Mr = 244.18, monoclinic, P21, a = 7.4111(1),
b = 6.1865(1), c = 11.3615(1) Å, b = 106.043(2)°, V = 500.6 Å3, Z = 2,
Dx = 1.620 g cmꢀ3. A total of 3876 reflections were collected at
diffraction analysis.
C18H18F3N3O2, Mr = 365.35, orthorhombic,
P212121, a = 6.2300(5), b = 16.1133(1), c = 18.5094(1) Å, V = 1858.1
293 K using MoK
a radiation (k = 0.71073 Å); 2041 independent
Å3, Z = 4, Dx = 1.306 g cmꢀ3. A total of 14998 reflections were col-
reflections (Rint = 0.0238). The structure was solved by direct
methods with SHELXTL and refined by least square using F2 values
and anisotropic thermal parameters for non hydrogen atoms.31
There was one independent molecule in the asymmetric unit
(151 parameters). The final reliability values for 2041 unique
reflections and 154 parameters are R1 = 0.0521, wR2 = 0.1176 for
1059 reflections with I > 2r(I) and R1 = 0.0587 and wR2 = 0.1176
for all data. The data have been deposited at the Cambridge Crys-
tallographic Data Centre (Reference N° 684964).
lected at 293 K using MoK
a radiation (k = 0.71073 Å); 2205 inde-
pendent reflections (Rint = 0.0475). The structure was solved by
direct methods with SHELXTL and refined by least square using F2
31
values and anisotropic thermal parameters for non hydrogen
atoms. There is one independent molecule (one
and one hydantoin molecule) in the asymmetric unit (237 param-
eters). The final R values for the 2205 unique reflections and 237
parameters are R1 = 0.0405, wR2 = 0.0926 for 1563 reflections with
aMBA molecule
I > 2r(I) and R1 = 0.0663 and wR2 = 0.1019 for all data. The data
have been deposited at the Cambridge Crystallographic Data Cen-
tre (Reference No. 684965). X-ray diffraction analysis is presented
in Figure 2.
4.3.2. (ꢀ) and (+) Hydantoins 6a and 6b
Enantiopure hydantoins 6a and 6b were obtained by an AS3PC
procedure (Table 5) and recrystallized in ethanol.
25
589
(ꢀ)-Hydantoin 6a: solid. Mp 261 °C. ½
a
ꢆ
¼ ꢀ32:8 (c 0.01 g/mL,
EtOH). HPLC: retention time: 6.3 min. Enantiomeric purity: 99.6%
4.6.2. (+)-(R)-a-Methylbenzylamine.(+)5-(p-methoxyphenyl)-5-
(trifluoromethyl)hydantoin ammonium salt
It was not possible to obtain a suitable single-crystal for X-ray
diffraction analysis in order to determine the absolute configura-
tion of 6a or 6b. White solid. Mp 224 °C. IR (KBr, cmꢀ1) 3232,
2985, 1797, 1745, 1615, 1515, 1403, 1249. HRMS (ESI+) calcd for
e.e.
25
589
(+) Hydantoin 6b: solid. Mp 261 °C. ½
a
ꢆ
¼ þ32:8 (c 0.01 g/mL,
EtOH). HPLC: retention time: 3.7 min. Enantiomeric purity: 99.7%
e.e.
4.4. General procedure for obtaining enantiopure 5-aryl-5-
(trifluoromethyl)-hydantoins 5, 6 by recrystallization of AS3PC
crops
C19H21F3N3O3 m/z 396.1535, found 396.1550.
4.7. Typical procedure for the preparation of
a-aryl-a-
trifluoromethylglycines 10 and 11 (Scheme 5)
In a single operation, each crude enantiomer of hydantoins 5 or
6 (enantiomeric purity ꢁ80% ee) can be purified to > 99.9% ee.
For a typical example: 5 g of hydantoin 5b (from AS3PC crops)
were dissolved in ethanol (3.44 g). The mixture was heated up (T
ꢁ 60 °C) in order to obtain a clear solution. Then, the temperature
was progressively decreased to 30 °C. The system was kept at this
temperature for 2 h. A filtration of the mixture was carried out on a
glass filter n°4 to afford 4.34 g of pure enantiomer (yield: 87%,
99.9% ee).
A
suspension
of
( )-5-(p-methoxyphenyl)-5-(trifluoro-
methyl)hydantoin
6
(1.00 g, 3.64 mmol) and Ba(OH)2ꢂ8H2O
(6.90 g, 21.89 mmol) in water (40 mL) was refluxed for 3 days.
The evolution of the reaction was followed by 19F NMR of the crude
mixture. After cooling at room temperature, the reaction mixture
was acidified with aqueous sulfuric acid solution (0.5 M, 15 mL)
until pH 1 (BaSO4 salt precipitated). The suspension was filtered
on a Büchner and the resulting filtrate was chromatographed on
an ion-exchange DOWEX 50WX8-100 (H+ form, 280 mL) eluting
first with water (ꢁ200 mL) until pH 5–6 and then with 10% aque-
ous ammonia (ꢁ300 mL). Solvent removal at reduced pressure of
the collected ammonia fractions, afforded ꢁ600 mg (ꢁ 60%) of
the free ( )-amino acid 11 as a white powder.
4.5. Typical procedure for Pasteurian resolution of hydantoins 5
and 6
A
solution of ( )-5-phenyl-5-(trifluoromethyl)hydantoin
5
(2.00 g, 8.19 mmol) and (ꢀ)-(S)-
a
-methylbenzylamine (0.99 g,
8.19 mmol) in ethanol (44 mL) was stirred in a thermostated bath
at 20 °C for 16 h. The ammonium salt was filtered and washed with
ethanol (2 mL). The crude was then poured into a solution of
hydrochloric acid (50 mL) and stirred at room temperature for
22 h. The resulting solid was filtered to afford 0.54 g (yield: 25%)
of enantiopure hydantoin 5b (99.8% ee).
4.7.1.
a-(p-Methoxyphenyl)-a-trifluoromethylglycine 11
a
( )-
-Amino acid 11: Mp 230 °C (sublimation). 1H NMR
3
(300 MHz, DMSO-d6) d: 3.73 (s, 3H, OCH3), 6.88 (d, JH,H = 8.8 Hz,
3
2H Ar), 7.62 (d, JH,H = 8.8 Hz, 2H Ar). 19F NMR (280 MHz, DMSO-
d6) d: ꢀ71.3 (s). 13C NMR (75 MHz, DMSO-d6) d: 55.1 (s, OCH3),
2
66.1 (q, JC,F = 24.2 Hz, C-2), 112.8 (s, 2 ꢅ CH Ar), 126.7 (q,
1JC,F = 283.3 Hz, CF3), 128.6 (s, 2 ꢅ CH Ar), 132.0 (s, Cq Ar), 158.5
(s, Cq, COMe), 169.7 (s, COOH). MS (ESIꢀ): m/z 248 [M-H]. HRMS
(ESI+) calcd for C10H11F3NO3 m/z 250.0691, found 250.0692.
The same procedure was applied to both the (ꢀ)- and (+)-enan-
tiomers 6a and 6b, but the corresponding amino acids 11a and 11b
were directly engaged in the esterification step.
4.6. Typical procedure for the formation of (+)-(R)-a-MBA. (+)-5-
Phenylhydantoin ammonium salt 9; determination of its
absolute configuration by X-ray diffraction analysis (Fig. 2)
(+)-Hydantoin 5b (1.00 g, 4 mmol) was dissolved in ethanol
(20 mL), after which enantiopure (+)-(R)-a-MBA (0.50 g, 4 mmol)

20
T. Martin et al. / Tetrahedron: Asymmetry 22 (2011) 12–21
(ꢀ)-
a
-Amino acid 11a: Solid. HRMS (ESI+) calcd for C10H11F3NO3
2H Ar). 19F NMR (280 MHz, DMSO-d6) d: ꢀ69.6 (s). GC-MS (EI,%)
m/z 277 [M+], 218 (100), 148, 134, 110.
m/z 250.0691, found 250.0694. HPLC: retention time: 4.35 min.
Enantiomeric purity: 98.1% ee.
( )-N,N-Dimethyl a-(p-Methoxyphenyl)-a-trifluoromethylgly-
(+)-a
-Amino acid 11b: Solid. HRMS (ESI+) calcd for C10H11F3NO3
cine methyl ester 15. Selected data: 1H NMR (300 MHz, DMSO-
d6) d: 2.35 (s, 6H, N(CH3)2), 3.77 (s, 3H, COOCH3), 3.84 (s, 3H,
m/z 250.0691, found 250.0692. HPLC: retention time: 3.90 min.
Enantiomeric purity: 98.3% ee.
3
3
OCH3), 6.98 (d, JH,H = 8.8 Hz, 2H Ar), 7.29 (d, JH,H = 8.8 Hz, 2H
Ar). 19F NMR (280 MHz, DMSO-d6) d: ꢀ62.9 (s). GC-MS (EI,%) m/z
291 [M+], 232 (100), 148, 133, 110.
4.7.2. ( ) a-Phenyl-a-trifluoromethylglycine 10
( )-Amino acid 10 was obtained in ꢁ22% yield (ꢁ169 mg) using
the above described procedure. White powder. Mp 245 °C (sublima-
tion). 1H NMR (300 MHz, DMSO-d6) d: 7.27 (m, 3H Ph), 7.74 (m, 2H
Ph). 19F NMR (280 MHz, DMSO-d6) d: ꢀ70.8 (s). 13C NMR (75 MHz,
4.8.2. a-Phenyl-a-trifluoromethylglycine methyl ester 12
( )-Amino ester 12 was obtained in 70% yield (ꢁ185 mg)
using the procedure described above. Oil. 1H NMR (300 MHz,
DMSO-d6) d: 3.08 (s, 2H, NH2), 3.74 (s, 3H, OCH3), 7.43 (m, 3H
Ph), 7.54 (m, 2H Ph). 19F NMR (280 MHz, DMSO-d6) d: ꢀ73.4
(s). 13C NMR (75 MHz, DMSO-d6) d: 53.0 (s, OCH3), 67.6 (q,
2
1
DMSO-d6) d: 66.6 (q, JC,F = 23.6 Hz, C-2), 126.7 (q, JC,F = 282.3 Hz,
CF3), 127.1 (s, CH Ph), 127.3 (s, 2 ꢅ CH Ph), 127.4 (s, 2 ꢅ CH Ph),
140.3 (s, Cq Ph), 168.7 (s, COOH). MS (ESIꢀ): m/z 218 [M-H]. HRMS
(ESIꢀ) calcd for C9H7F3NO2 m/z 218.0429, found 218.0430.
1
2JC,F = 26.3 Hz, C-2), 124.6 (q, JC,F = 284.4 Hz, CF3), 126.9 (s,
The same procedure was applied to both the (ꢀ)-(R)- and (+)-
(S)-enantiomers 5a and 5b but the corresponding amino acids
10a and 10b were directly engaged in the esterification step.
2 ꢅ CH Ph), 128.4 (s, 2 ꢅ CH Ph), 129.0 (s, CH Ph), 135.1 (s, Cq
Ar), 169.5 (s, COOCH3). IR (film, cmꢀ1): 3402, 3339, 3011, 3001,
2958, 1748, 1604, 1501. GC–MS (EI,%) m/z 233 [M+], 174 (100),
104, 96, 79. HRMS (ESI+) calcd for C10H11F3NO2 m/z 234.0742,
(ꢀ)-(R)-
a
-Amino acid 10a: Solid. HRMS (ESIꢀ) calcd for
C9H7F3NO2 m/z 218.0429, found 218.0434. HPLC retention time:
found 234.0746.
25
589
4.06 min. Enantiomeric purity: 98.4% e.e.
(ꢀ)-(R)-Amino ester 12a. Oil.
½
aꢆ
¼ ꢀ3:05 (c 0.01 g/mL,
(+)-(S)-a
-Amino acid 10b: Solid. HRMS (ESIꢀ) calcd for
MeOH). HRMS (ESI+) calcd for C10H11F3NO2 m/z 234.0742, found
C9H7F3NO2 m/z 218.0429, found 218.0432. HPLC: retention time:
4.98 min. Enantiomeric purity: 98.2% e.e.
234.0744. C10H10F3NO2 (233.19): calcd. C 51.51, H 4.32, N 6.01;
found C 51.62, H 4.39, N 6.12.
25
589
(+)-(S)-Amino ester 12b. Oil. ½
a
ꢆ
¼ þ3:3 (c 0.01 g/mL, MeOH).
HRMS (ESI+) calcd for C10H11F3NO2 m/z 234.0742, found 234.0745.
It was not possible to determine the enantiomeric purity of
these amino esters by chiral GC or HPLC.
4.8. Typical procedure for the preparation of a-aryl-a-
trifluoromethylglycine methyl esters 12 and 13 (Scheme 5)
A solution of trimethylsilyldiazomethane (0.21 g, 1.8 mmol) in
diethyl ether (4 mL) was added dropwise to a solution of ( )-amino
acid 11 (0.30 g, 1.2 mmol) in a mixture of (3/2) toluene/methanol
(10 mL). The reaction mixture (slightly yellow) was stirred at room
temperature for 30 min. After solvent removal at reduced pressure,
the crude was purified by silica gel column chromatography (elu-
ent: petroleum ether/AcOEt 70/30) to afford the desired ( )-amino
ester 13 (0.20 g, 76%). It is worth noting that small amounts of N-
methyl and N,N-dimethyl amino esters 14 and 15 were detected in
the crude mixture by 1H, 19F NMR and GC-MS.
Acknowledgments
The authors would like to thank S. Colombel for her help in the
synthesis of hydantoins 7 and 8, Dr. D. Harakat for HRMS analyses,
Dr. M.-N. Petit for XRPD measurements; Dr. M. Sanselme and Dr. S.
Coste for X-ray of compounds 5b and 9; Dr. Y. Cartigny for TG/DSC
measurements, and Dr. K. Plé with the writing of this Letter.
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The same procedure was also applied to both the (+)- and (ꢀ)-
enantiomers 11a and 11b.
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3JH,H = 8.8 Hz, 2H Ar), 7.46 (d, JH,H = 8.8 Hz, 2H Ar). 19F NMR
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25
589
(ꢀ)-Amino ester 13a. Oil. ½
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ꢆ
¼ ꢀ2:2 (c 0.01 g/mL, MeOH).
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found C 50.24, H 4.69, N 5.29.
25
589
(+)-Amino ester 13b. Oil. ½
aꢆ
¼ þ2:1 (c 0.01 g/mL, MeOH).
HRMS (ESI+) calcd for C11H13F3NO3 m/z 264.0848, found 264.0841.
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these amino esters by chiral GC or HPLC.
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a-(p-Methoxyphenyl)-a-trifluoromethylglycine
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3
3H, OCH3), 6.97 (d, JH,H = 8.8 Hz, 2H Ar), 7.33 (d, JH,H = 8.8 Hz,

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