A practical asymmetric synthesis of homochiral α-arylglycines

Article abstract of DOI:10.1016/S0957-4166(01)00022-2

Enantioselective reduction of a series of substituted aryl trichloromethyl ketones with the CBS-catecholborane reagent afforded homochiral aryl trichloromethyl carbinols which have been elaborated to give homochiral α-arylglycines in high e.e.

Full text of DOI:10.1016/S0957-4166(01)00022-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 149–155
A practical asymmetric synthesis of homochiral a-arylglycines
Christelle Mellin-Morlie`re,a,b David J. Aitken,a,c,* Steven D. Bull,b,d Stephen G. Daviesb and
Henri-Philippe Hussona
aLaboratoire de Chimie The´rapeutique associe´ au CNRS, Faculte´ des Sciences Pharmaceutiques et Biologiques,
Universite´ Rene´ Descartes, Paris V, 4 Avenue de l’Observatoire, 75270 Paris cedex, France
bThe Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
cLaboratoire SEESIB-CNRS, De´partement de Chimie, Universite´ Blaise Pascal - Clermont-Ferrand II, 24 Avenue des Landais,
63177 Aubie`re cedex, France
dDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 12 December 2000; accepted 11 January 2001
Abstract—Enantioselective reduction of a series of substituted aryl trichloromethyl ketones with the CBS-catecholborane reagent
afforded homochiral aryl trichloromethyl carbinols which have been elaborated to give homochiral a-arylglycines in high e.e.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
a-arylglycines can prove problematical since this class of
a-amino acids are prone to racemisation at their a-stereo-
centre.6 As part of our studies directed towards the
synthesis of a small library of homochiral a-arylglycines,
we wished to determine whether the methodology first
developed by Corey and Link for the asymmetric syn-
thesis of aliphatic a-amino acids,7 based on the enan-
tioselective reduction of trichloromethyl ketones with
the CBS catalyst, could be employed for the asymmetric
synthesis of aryl a-amino acids. We wish to report herein
that a key modification to the reaction conditions orig-
inally described by Corey and Link7 has enabled us to
employ this methodology for the asymmetric synthesis
of a representative range of a-arylglycines in >97% e.e.
The development of methodology for the asymmetric
synthesis of homochiral a-arylglycines continues to
attract attention within the synthetic community due to
their potential pharmacological properties and their use
as precursors for the synthesis of chiral ligands and
novel oligopeptide structures.1 A range of strategies exist
for the enantioselective synthesis of this class of a-amino
acids, including asymmetric Strecker reactions,2 C-aryl-
ation of electrophilic chiral glycinates,3 electrophilic
amination of chiral benzylic enolates,4 and enantioselec-
tive carboxylation of metallated benzylamine deriva-
tives.5 In practice, however, the asymmetric synthesis of
Scheme 1. Reagents and conditions: (i) catecholborane, CBS catalyst 6, toluene, −78°C; (ii) 4 equiv. of NaOH, 2 equiv. of NaN3,
DME/H2O; (iii) H2, Pd/C, EtOAc.
* Corresponding author. Fax: +33-4-73-40-77-17; e-mail: aitken@chisg1.univ-bpclermont.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00022-2

150
C. Mellin-Morlie`re et al. / Tetrahedron: Asymmetry 12 (2001) 149–155
2. Results and discussion
carbinols 2a–g were not resolved. The absolute configu-
ration of the stereogenic centre of each homochiral aryl
trichloromethyl carbinol (−)-2a–g was assigned as R
using the previously established model for the CBS
reduction system in which reduction of trichloromethyl
ketones with the (S)-enantiomer of CBS catalyst 6
afforded (R)-trichloromethyl carbinols.11 These assign-
ments were confirmed for (−)-2,2,2-trichloro-1-
phenylethanol 2a by comparison of the sign of its
specific rotation of [h]D23=−36.0 with that of the known
(S)-enantiomer, (+)-2a ([h]2D5=+36.9, CHCl3).17
The original report by Corey and Link7 on the asym-
metric synthesis of homochiral aliphatic a-amino acids
relied on a strategy in which enantioselective reduction
of easily prepared alkyl trichloromethyl ketones 1 with
the chiral CBS catalyst
6
gave homochiral
trichloromethyl carbinols 2. Treatment of these com-
pounds with excess NaOH gave dichloroepoxide inter-
mediates 3, which underwent ring opening with an
azide anion to afford homochiral a-azido acids 4. Sub-
sequent hydrogenolysis of these a-azido acids afforded
homochiral a-amino acids 5 in very high e.e. (Scheme
1).
2.2. Enantioselective synthesis of a-arylglycines
With the desired homochiral aryl trichloromethyl
carbinols 2a–g in hand, our attention turned towards
their elaboration to the desired homochiral a-aryl-
glycines 5a–g. Since we were aware of the increased
capacity of the stereogenic centres of the intermediate
a-azido acids 4a–g to undergo racemisation under alka-
line conditions, we first optimised conditions for the
conversion of (R)-2,2,2-trichloro-1-phenylethanol 2a
into (S)-phenylglycine 5a (Scheme 3). Application of
the original Corey–Link conditions,7 involving treat-
ment of carbinol (−)-2a with four equivalents of NaOH
and two equivalents of NaN3 in aqueous
dimethoxyethane, gave a-azido acid 4a, which was
immediately reduced by catalytic hydrogenation (10%
Pd/C as catalyst) to afford racemic ( )-phenylglycine 5a
in 70% yield (Table 1, entry 1). Given that racemisation
was unlikely to have occurred during hydrogenolysis of
a-azido acid 4a to phenylglycine 5a,18 we investigated a
variety of basic conditions for the conversion of carbi-
nol (−)-2a to its corresponding (S)-a-azido acid 4a in
an effort to suppress the racemisation. Thus, treatment
of carbinol (−)-2a with either one or two equivalents of
NaOH afforded, after hydrogenolysis, enantiomerically
enriched (S)-phenylglycine 5a in 70% e.e. but in low
yield (12 and 49%, respectively; Table 1, entries 2 and
3). Similarly, when LiOH, K2CO3 and Cs2CO3 were
employed as bases, phenylglycine 5a was obtained, after
hydrogenolysis, in very low yield (18–37%) and in
65–70% e.e. (Table 1, entries 4–6). Attempts to employ
the organic bases Et3N and DABCO did not afford any
of the desired product (Table 1, entries 7 and 8). A
review of the literature revealed that DBU had previ-
ously been employed as an alternative to NaOH for the
base-promoted conversion of alkyl trichloromethyl
carbinols 2 into derivatives of a-azido acids 4.19 We
found that treatment of the aryl trichloromethyl carbi-
nol (−)-2a with exactly one equivalent of DBU and two
We decided to investigate the extension of this method-
ology to the asymmetric synthesis of a-arylglycine
derivatives, an application which had not been reported
previously.
2.1. Asymmetric synthesis of homochiral aryl
trichloromethyl carbinols
A series of commercially available ortho-, meta- and
para-substituted aryl aldehydes 7a–g were treated with
trichloromethyl anion, generated in situ by treatment of
chloroform with KOH in MeOH/DMF,8 to afford the
corresponding racemic aryl trichloromethyl carbinols
( )-2a–g in 67–96% yield (Scheme 2).9 Subsequent oxi-
dation of these aryl trichloromethyl carbinols ( )-2a–g
using 1 equivalent of sodium dichromate and two
equivalents of sulphuric acid in glacial acetic acid
afforded the desired aryl trichloromethyl ketones ( )-
1a–g in 60–95% yield.10 Reduction of aryl
trichloromethyl ketones 1a–g with (S)-CBS catalyst 6,
using catecholborane as the stoichiometric reducing
agent,7
gave
the
desired
homochiral
aryl
trichloromethyl carbinols (−)-2a–g in acceptable yield
(64–74%) and in >99% e.e. (Scheme 2).11–13
The
enantiomeric
excess
of
each
(−)-aryl
trichloromethyl carbinol 2a–g was shown to be >99%
by derivatisation using Alexakis’ chiral phosphoramide
methodology14 and comparison of the 31P NMR spec-
tra with those of authentic racemic standards. Interest-
ingly, the Mosher’s ester chiral derivatisation method,
previously employed to determine the enantiomeric
purity of both aryl methyl carbinols15 and aryl trifl-
uoromethyl carbinols,16 proved ineffective in this case,
1
since resonances in both the H and 19F NMR spectra
of the derivatives of racemic aryl trichloromethyl
Scheme 2. Reagents and conditions: (i) CHCl3, KOH, MeOH/DMF, −10°C; (ii) Na2Cr2O7, H2SO4/AcOH; (iii) catecholborane,
CBS catalyst 6 (10 mol%), toluene, −70 to 0°C.

C. Mellin-Morlie`re et al. / Tetrahedron: Asymmetry 12 (2001) 149–155
151
Scheme 3. Reagents and conditions: (i) base, 2 equiv. of NaN3, DME/H2O (see Table 1); (ii) H2, Pd/C, EtOAc.
equivalents
of
sodium
azide
in
aqueous
inversion at their stereogenic centre to afford (S)-a-
azido acids 4a–g; the configuration of these derivatives
is conserved on hydrogenolysis to the corresponding
(S)-a-arylglycines 5a–g. These stereochemical assign-
ments were confirmed for 5a and 5g, for which the
positive sign of the specific rotations of the (S)-enan-
tiomers are known from the literature.20
dimethoxyethane afforded, after hydrogenolysis,
phenylglycine (+)-5a in 62% yield and >99% e.e. (Table
1, entry 9). The importance of carrying out this trans-
formation with exactly one mole equivalent of DBU
was demonstrated by carrying out the conversion of 2a
to 4a in the presence of either 1.2 or 2 equivalents of
DBU, which resulted in partial racemisation and
afforded, after hydrogenolysis, enantiomerically
enriched 5a in 90 and 82% e.e., respectively, albeit in
improved yield (Table 1, entries 9 and 10). To the best
of our knowledge, this is the first demonstration of the
superiority of DBU over inorganic bases for the trans-
formation of non-racemic trichloromethyl carbinols 2
into a-azido acids 4 without racemisation.
3. Conclusions
In conclusion, we have demonstrated that a key modifi-
cation to the methodology first developed by Corey and
Link for the asymmetric synthesis of homochiral
aliphatic a-amino acids, based on enantioselective
reduction of alkyl trichloromethyl ketones with CBS
catalyst 6, has enabled us to prepare a representative
series of diversely substituted a-arylglycines in reason-
able yield and very high e.e. The strategy employed is
practical and straightforward, involves commercially
available materials, and should be applicable to the
preparation of a wide range of homochiral a-aryl
glycines.
Table 1. Transformation of carbinol (−)-2a into a-azido
acid 4a then (S)-phenylglycine 5a according to Scheme 3a
Base
Equiv. used
Yield of 5a (%)
E.e. of 5a (%)
NaOH
NaOH
NaOH
LiOH
K2CO3
Cs2CO3
Et3N
DABCO
DBU
DBU
4
2
1
4
5
6
5
1
70
49
12
37
20
18
0
0
70
70
70
60
65
–
4. Experimental
4.1. General
0
–
2
80
71
62
82
90
]99
1.2
1
Melting points were determined on a Thermovar
apparatus. 1H (300.13 MHz), 13C{1H} (75.43 MHz),
19F (282.39 MHz) and 31P (121.49 MHz) NMR spectra
were recorded on a Bruker AC-300 instrument. Chemi-
cal shifts (l) are given in ppm, coupling constants (J)
are given in hertz. IR spectra were recorded on a
Perkin–Elmer FTIR 1600 spectrometer as solutions in
CHCl3 or as dispersions in Nujol. Principal diagnostic
absorptions are reported in wavenumbers (cm−1). Opti-
cal rotations were measured on a Perkin–Elmer 141
MC polarimeter in a 1 dm cell. Electron impact mass
spectra (EIMS) and chemical ionisation mass spectra
(CIMS) were obtained on a Nermag R10-10C quadru-
pole spectrometer, using ammonia as the vector gas for
the latter technique. High resolution chemical ionisa-
tion mass spectra (HRMS) were recorded on a Kratos
MS-80 spectrometer using methane as the vector gas.
For simplicity, diagnostic peak data from mass spectra
are presented only for isotopes 35Cl and 79Br, although
the expected statistical isotopic distributions were
invariably observed.
DBU
a The intermediate a-azido acid was not isolated but was immediately
hydrogenated to give the amino acid 5a. Enantiomeric excesses were
determined by Mosher’s amide analysis.
As a consequence of these findings, the optimised con-
ditions employing a stoichiometric quantity of DBU
were then employed for the conversion of the series of
homochiral (R)-aryl trichloromethyl carbinols (−)-2b–g
into their corresponding (S)-a-arylglycines 5b–g, which
were isolated in overall yields of between 40 and 62%
yield and in ]97% e.e. in all cases (Scheme 4).
The enantiomeric excesses of the homochiral a-aryl-
glycines 5a–g prepared in this study were determined by
conversion to the corresponding Mosher’s amide
derivatives and comparison of the 19F NMR spectra
with those of authentic racemic standards. The absolute
configuration of the homochiral a-arylglycines 5a–g
was assigned as S on the basis of the following mecha-
nistic arguments: cyclisation of homochiral (R)-aryl
trichloromethyl carbinols 2a–g affords epoxide interme-
diates 3a–g, which are attacked by azide anion with
Elemental analyses were carried out at the Institut de
Chimie des Substances Naturelles du CNRS, Gif-sur-
Yvette, France. Flash chromatography was performed

152
C. Mellin-Morlie`re et al. / Tetrahedron: Asymmetry 12 (2001) 149–155
Scheme 4. Reagents and conditions: (i) 1 equiv. of DBU, 2 equiv. of NaN3, DME/H2O; (ii) H2, Pd/C, EtOAc.
using Merck Kieselgel 60 (230–400 mesh) as the station-
ary phase. Analytical TLC was carried out on Merck
Kieselgel 60 F254 plates of 0.2 mm thickness which were
developed using a 5% solution of phosphomolybdic
acid in ethanol. All Rf values are given for the solvent
system which was used for preparative chromatogra-
phy. CBS catalyst 6 was prepared as a solution in
toluene, as previously described.13a Chloroform, DMF,
methanol and toluene were dried and purified by stan-
dard procedures before use; other solvents and all
reagents were obtained commercially and used as
supplied.
4.2.3. ( )-2,2,2-Trichloro-1-(2-methylphenyl)ethanol 2c.
A white solid, 83%. Rf 0.22; mp 60°C (petroleum ether);
IR (CHCl3): 3582br; CIMS: m/z 204 [MH−Cl]+; 1H
NMR (CDCl3): l 2.52 (s, 3H), 3.20 (d, J=4.5, 1H),
5.57 (d, J=4.5, 1H), 7.19–7.35 (m, 3H), 7.82 (dd,
J=6.5 and 2.6, 1H); 13C{1H} NMR (CDCl3): l 20.5,
79.9, 103.6, 126.0, 127.9, 129.5, 130.8, 134.2, 137.7.
Anal. calcd for C9H9Cl3O: C, 45.13; H, 3.79; Cl, 44.40.
Found: C, 45.21; H, 3.79; Cl, 44.36.
4.2.4. ( )-2,2,2-Trichloro-1-(2-bromophenyl)ethanol 2d.
A white solid, 95%. Rf 0.33; mp 50°C (petroleum ether);
1
IR (CHCl3): 3570br; CIMS: m/z 303 [MH]+; H NMR
(CDCl3): l 4.21 (s, 1H), 5.61 (s, 1H), 7.28 (ddd, J=7.9,
1.9 and 1.7, 1H), 7.32 (ddd, J=8.1, 7.9 and 1.4, 1H),
7.63 (dd, J=7.9 and 1.4, 1H), 7.90 (dd, J=8.1 and 1.7,
1H); 13C{1H} NMR (CDCl3): l 81.8, 102.7, 125.7,
127.3, 130.0, 130.9, 132.9, 135.0. Anal. calcd for
C8H6BrCl3O: C, 31.58; H, 1.97. Found: C, 31.46; H,
1.88.
4.2. Preparation of racemic aryl trichloromethyl
carbinols 2a–g. General procedure
A solution of KOH (1.12 g, 20 mmol) in MeOH (4 ml)
was added dropwise to a stirred solution of aryl alde-
hyde 7a–g (20 mmol) and chloroform (3.5 ml, 44 mmol)
in DMF (15 ml) at −10°C under an inert atmosphere.
After 1 h at this temperature, the reaction mixture was
treated with a 1 M HCl solution (4 ml) and toluene (4
ml). This vigorously stirred mixture was allowed to
warm to room temperature over 30 min. The organic
phase was collected and washed with water (2×4 ml),
stirred with active charcoal for 10 min and filtered
through Celite, washed with a 5% NaHCO3 solution (4
ml) and then water (4 ml). The organic phase was then
dried over MgSO4, filtered and evaporated. The crude
product thus obtained was purified by flash chromatog-
raphy using cyclohexane/CH2Cl2 (7:3) as the mobile
phase. Solid products were then recrystallised from
petroleum ether.
4.2.5. ( )-2,2,2-Trichloro-1-(3-methylphenyl)ethanol 2e.
A colourless oil, 73%. Rf 0.34; IR (CHCl3): 3584br;
1
CIMS: m/z 239 [MH]+; H NMR (CDCl3): l 2.44 (s,
3H), 3.78 (d, J=4.5, 1H), 5.18 (d, J=4.5, 1H), 7.25–
7.47 (m, 4H); 13C{1H} NMR (CDCl3): l 21.6, 84.6,
103.2, 126.5, 127.8, 129.8, 130.3, 134.9, 137.6. Anal.
calcd for C9H9Cl3O: C, 45.13; H, 3.79; Cl, 44.40.
Found: C, 45.44; H, 3.76; Cl, 45.08.
4.2.6. ( )-2,2,2-Trichloro-1-(4-methylphenyl)ethanol 2f.
A colourless oil, 96%. Rf 0.45; IR (CHCl3): 3384br;
1
CIMS: m/z 239 [MH]+; H NMR (CDCl3): l 2.36 (s,
3H), 3.34 (d, J=3.9, 1H), 5.15 (d, J=3.9, 1H), 7.18 (d,
J=8.1, 2H), 7.47 (d, J=8.1, 2H); 13C{1H} NMR
(CDCl3): l 21.2, 84.3, 103.2, 128.5, 129.0, 131.8, 139.4.
Anal. calcd for C9H9Cl3O: C, 45.13; H, 3.79. Found: C,
45.23; H, 3.81.
4.2.1. ( )-2,2,2-Trichloro-1-phenylethanol 2a. A yellow
oil, 91%. Rf 0.42; IR (CHCl3): 3396br; CIMS: m/z 242
1
[MH+NH3]+, 259 [MH+2NH3]+; H NMR (CDCl3): l
3.30 (s, 1H), 5.21 (s, 1H), 7.39 (m, 3H), 7.61 (m, 2H);
13C{1H} NMR (CDCl3): l 84.4, 103.0, 127.8, 129.2,
129.5, 134.7. Anal. calcd for C8H7Cl3O: C, 42.61; H,
3.13. Found: C, 42.38; H, 3.27.
4.2.7. ( )-2,2,2-Trichloro-1-(4-fluorophenyl)ethanol 2g. A
colourless oil, 67%. Rf 0.28; IR (CHCl3): 3433br;
1
CIMS: m/z 260 [MH+NH3]+; H NMR (CDCl3): l 3.49
(s, 1H), 5.18 (s, 1H), 7.07 (m, 2H), 7.56 (m, 2H);
13C{1H} NMR (CDCl3): l 83.8, 103.2, 114.8 (d, J=
22.6), 129.8, 131.0 (d, J=7.5), 163.3 (d, J=242). Anal.
calcd for C8H6Cl3FO: C, 39.46; H, 2.48. Found: C,
39.88; H, 2.63.
4.2.2.
( )-2,2,2-Trichloro-1-(2-methoxyphenyl)ethanol
2b. An off-white solid, 91%. Rf 0.34; mp 45°C
(petroleum ether); IR (CHCl3): 3586br; CIMS: m/z 255
[MH]+; 1H NMR (CDCl3): l 3.89 (s, 3H), 4.21 (d,
J=6.9, 1H), 5.61 (d, J=6.9, 1H), 7.00 (m, 1H), 7.39
(dd, J=7.8 and 1.6, 2H), 7.62 (dd, J=7.7 and 1.5, 2H);
13C{1H} NMR (CDCl3): l 55.6, 80.1, 103.6, 111.4,
120.6, 123.7, 130.6, 130.8, 157.9. Anal. calcd for
C9H9Cl3O2: C, 42.30; H, 3.55. Found: C, 42.64; H, 3.44.
4.3. Oxidation of aryl trichloromethyl carbinols 2a–g.
General procedure
A solution of sodium dichromate dihydrate (1.49 g,
5.00 mmol) and concentrated sulphuric acid (0.54 ml,

C. Mellin-Morlie`re et al. / Tetrahedron: Asymmetry 12 (2001) 149–155
153
10.0 mmol) in glacial acetic acid (10 ml) was added
dropwise to stirred solution of racemic aryl
4.3.7. 2,2,2-Trichloro-1-(4-fluorophenyl)ethanone 1g. An
oil, 88%. Rf 0.85; IR (CHCl3): 1744; EIMS: m/z 240
a
1
trichloromethyl carbinol ( )-2a–g (5.00 mmol) in glacial
acetic acid (10 ml). The mixture was stirred at room
temperature for 1 h, then the excess oxidant was
destroyed by the addition of 2-propanol (1.5 ml). After
a further 10 min, a saturated NaCl solution (25 ml) was
added and the mixture was extracted with CH2Cl2
(2×15 ml). The combined organic extracts were washed
with a 5% NaHCO3 solution (12 ml) and then a satu-
rated NaCl solution (12 ml). The organic phase was
then dried over MgSO4, filtered and evaporated. The
crude product thus obtained was purified by flash chro-
matography using cyclohexane/CH2Cl2 (1:1) as the
mobile phase.
(M+), 123 (M+−CCl3); H NMR (CDCl3): l 7.18 (m,
2H), 7.32 (m, 2H); 13C{1H} NMR (CDCl3): l 94.9,
115.5 (d, J=21.6), 124.9, 134.6 (d, J=7.2), 165.9 (d,
J=257), 179.3; HRMS: [C8H4Cl3FO+H]+ requires
240.9389. Found: 240.9372.
4.4. Asymmetric reduction of aryl trichloromethyl
ketones 1a–g. General procedure
A solution of aryl trichloromethyl ketone 1a–g (5.00
mmol) in toluene (50 ml) was added to a 1 M solution
of catalyst 6 in toluene (0.50 ml, 0.50 mmol). This
mixture was cooled to −70°C and a 1 M solution of
catecholborane in THF (10 ml, 10 mmol) was added
slowly. The mixture was stirred at −70°C for 8 h and
then at room temperature for 16 h, then water (10 ml)
and EtOAc (10 ml) were added. The organic phase was
washed with a 1 M NaOH solution (3×10 ml) and then
with a 1 M HCl solution (2×10 ml), dried over MgSO4,
filtered and evaporated. The crude product thus
obtained was purified in the same manner as described
above for the racemic preparation (Section 4.2).
4.3.1. 2,2,2-Trichloro-1-phenylethanone 1a. An oil, 78%.
Rf 0.83; IR (CHCl3): 1654; EIMS: m/z 187 (M+−Cl),
1
105 (M+−CCl3); H NMR (CDCl3): l 7.49 (t, J=8.4,
2H), 7.63 (tt, J=8.3 and 1.6, 1H), 8.26 (dd, J=8.4 and
1.6, 2H); 13C{1H} NMR (CDCl3): l 96.0, 128.5, 129.1,
131.6, 134.4, 181.3. Anal. calcd for C8H5Cl3O: C, 43.07;
H, 2.26; Cl, 47.59. Found: C, 43.19; H, 2.31; Cl, 47.49.
4.3.2. 2,2,2-Trichloro-1-(2-methoxyphenyl)ethanone 1b.
An oil, 60%. Rf 0.77; IR (CHCl3): 1710; EIMS: m/z 252
(M+), 135 (M+−CCl3); 1H NMR (CDCl3): l 3.85 (s,
3H), 7.08 (m, 2H), 7.55 (t, J=7.4, 1H), 7.66 (d, J=6.4,
1H); 13C{1H} NMR (CDCl3): l 55.7, 95.8, 111.5, 120.1,
123.1, 129.1, 132.9, 157.4, 186.1. Anal. calcd for
C9H7Cl3O2: C, 42.64; H, 2.78. Found: C, 42.91; H, 2.65.
4.4.1. (R)-2,2,2-Trichloro-1-phenylethanol 2a. A yellow
oil, 73%. Spectral data as for racemic preparation;
[h]2D3=−36 (c 1.00, CHCl3); e.e. >98% (derivatisation
method A).
4.4.2.
(R)-2,2,2-Trichloro-1-(2-methoxyphenyl)ethanol
4.3.3. 2,2,2-Trichloro-1-(2-methylphenyl)ethanone 1c. An
oil, 76%. Rf 0.89; IR (CHCl3): 1710; EIMS: m/z 236
(M+), 119 (M+−CCl3); 1H NMR (CDCl3): l 2.47 (s,
3H), 7.35 (m, 3H), 7.95 (dd, J=6.4 and 2.1, 1H);
13C{1H} NMR (CDCl3): l 20.5, 96.0, 125.2, 128.4,
131.6, 131.8, 134.2, 134.6, 174.0. Anal. calcd for
C9H7Cl3O: C, 45.51; H, 2.97. Found: C, 45.23; H, 3.81.
2b. A pale yellow solid, 64%. Spectral data as for
racemic preparation; [h]2D3=−52 (c 0.26, CHCl3); e.e.
>98% (derivatisation method A).
4.4.3. (R)-2,2,2-Trichloro-1-(2-methylphenyl)ethanol 2c.
A white solid, 74%. Spectral data as for racemic prepa-
ration; [h]2D3=−72 (c 0.25, CHCl3); e.e. >98% (derivati-
sation method A).
4.3.4. 2,2,2-Trichloro-1-(2-bromophenyl)ethanone 1d. An
oil, 95%. Rf 0.83; IR (CHCl3): 1744; EIMS: m/z 183
(M+−CCl3); 1H NMR (CDCl3): l 7.40 (m, 2H), 7.68 (m,
2H); 13C{1H} NMR (CDCl3): l 94.8, 120.5, 126.8,
128.6, 132.1, 133.4, 135.7, 185.4. Anal. calcd for
C8H4BrCl3O: C, 31.77; H, 1.33. Found: C, 32.56; H,
1.38.
4.4.4. (R)-2,2,2-Trichloro-1-(2-bromophenyl)ethanol 2d.
A white solid, 67%. Spectral data as for racemic prepa-
ration; [h]2D3=−79 (c 0.26, CHCl3); e.e. >98% (derivati-
sation method A).
4.3.5. 2,2,2-Trichloro-1-(3-methylphenyl)ethanone 1e. An
oil, 83%. Rf 0.81; IR (CHCl3): 1706; EIMS: m/z 236
(M+), 119 (M+−CCl3); 1H NMR (CDCl3): l 2.44 (s,
3H), 7.44 (m, 2H), 8.06 (m, 2H); 13C{1H} NMR
(CDCl3): l 21.3, 95.6, 128.3, 128.8, 129.3, 132.1, 135.3,
138.6, 181.7. Anal. calcd for C9H7Cl3O: C, 45.51; H,
2.97. Found: C, 45.23; H, 2.68.
4.4.5. (R)-2,2,2-Trichloro-1-(3-methylphenyl)ethanol 2e.
A colourless oil, 71%. Spectral data as for racemic
preparation; [h]2D3=−45 (c 1.00, CHCl3); e.e. >98%
(derivatisation method A).
4.4.6. (R)-2,2,2-Trichloro-1-(4-methylphenyl)ethanol 2f.
A colourless oil, 67%. Spectral data as for racemic
preparation; [h]2D3=−35 (c 1.00, CHCl3); e.e. >98%
(derivatisation method A).
4.3.6. 2,2,2-Trichloro-1-(4-methylphenyl)ethanone 1f. An
oil, 83%. Rf 0.82; IR (CHCl3): 1707; EIMS: m/z 236
(M+), 119 (M+−CCl3); 1H NMR (CDCl3): l 2.42 (s,
3H), 7.27 (d, J=8.3, 2H), 8.15 (d, J=8.3, 2H); 13C{1H}
NMR (CDCl3): l 21.8, 95.6, 126.1, 129.1, 131.7, 145.6,
180.8; HRMS: [C9H7Cl3O+H]+ requires 236.9641.
Found: 236.9647.
4.4.7. (R)-2,2,2-Trichloro-1-(4-fluorophenyl)ethanol 2g.
A colourless oil, 68%. Spectral data as for racemic
preparation; [h]2D3=−33 (c 1.00, CHCl3); e.e. >98%
(derivatisation method A).

154
C. Mellin-Morlie`re et al. / Tetrahedron: Asymmetry 12 (2001) 149–155
4.5. Preparation of (S)-arylglycines 5a–g. General
procedure
60.2, 126.1, 129.6, 129.8, 130.3, 132.1, 138.5, 169.8;
[h]2D3=+146 (c 0.20, 5 M HCl); e.e. ]99% (derivatisa-
tion method B).
A solution of DBU (0.31 g, 2.00 mmol) and sodium
azide (0.26 g, 4.00 mmol) in water (6 ml) was added to
4.5.6. (S)-(4-Methylphenyl)glycine 5f. A white solid,
41%. Mp >250°C; IR (Nujol): 1735; CIMS: m/z 166
[MH]+; 1H NMR (CD3OD): l 2.35 (s, 3H), 4.78 (s, 1H),
7.18 (d, J=8.1, 2H), 7.47 (d, J=8.1, 2H); 13C{1H}
NMR (CD3OD): l 21.1, 60.2, 128.5, 129.1, 131.3,
139.2, 170.5; [h]2D3=+149 (c 0.50, 1 M HCl); e.e. ]99%
(derivatisation method B).
a
vigorously
stirred
solution
of
(R)-2,2,2-
trichloromethyl-1-arylethanol (−)-2a–g (2.00 mmol) in
dimethoxyethane (5 ml) at 10°C. After 5 min the mix-
ture was warmed to room temperature and stirred for a
further 24 h. Ether (3 ml) was added, and the two
phases separated. The organic phase was extracted with
a 5% NaOH solution (3 ml), and the aqueous phases
combined. The resulting aqueous solution was cooled
to 0°C and was treated with a 1 M KH2PO4 solution
until pH 3 was attained. The solution was then
extracted with EtOAc (4×3 ml) and the combined
extracts were dried over MgSO4. The resulting solution
of a-azido acid 4a–g was concentrated to a volume of 7
ml, and 10% palladium on carbon (10 mg) was added.
This mixture was stirred vigorously under hydrogen at
atmospheric pressure for 24 h. The solid catalyst was
recovered by careful filtration and the filtrate discarded.
The solids were washed with a mixture of water (50 ml)
and EtOH (3 ml) at 70°C, and a clear solution was
obtained by filtration. Evaporation of this solution left
the required (S)-arylglycine 5a–g, which was purified by
passage through a column of Dowex 50X8 ion
exchange resin.
4.5.7. (S)-(4-Fluorophenyl)glycine 5g. A white solid,
60%. Mp >250°C; IR (Nujol): 1736; CIMS: m/z 170
1
[MH]+; H NMR (CD3OD): l 4.65 (s, 1H), 7.21 (m,
2H), 7.54 (m, 2H); 13C{1H} NMR (CD3OD): l 65.4,
131.1, 117.1 (d, J=22.7), 131.4 (d, J=8.0), 166.4 (d,
J=245), 170.6; [h]2D3=+131 (c 0.50, 1 M HCl); e.e.
]99% (derivatisation method B).
4.6. Determination of enantiomeric purity of carbinols
2 (derivatisation method A)
In an NMR tube, (1S,2S)-N,N%-dimethyl-1,2-bis[3-
(trifluoromethyl)phenyl]-1,2-ethanediamine (10 mg, 27
mmol) was dissolved in CDCl3 (0.6 ml). Pyridine (11 ml,
136 mmol) was added, followed by PCl3 (3 ml, 34 mmol),
then the aryl trichloromethyl carbinol 2a–g (27 mmol).
After 5 min, the sample was analysed by 31P NMR
spectroscopy. For all compounds 2a–g studied here, the
(R)-enantiomer gave a derivative having a 31P NMR
signal at l 140.0 ( 5.0) ppm, while the (S)-enantiomer
gave a lower field signal at l 145.0 ( 5.0) ppm; baseline
resolution was always achieved. The detection limit was
established using 2a, by incremental contamination of
enantiomerically pure material with racemic material,
and was found to be an enantiomeric ratio of 99:1 (i.e.
at e.e.=98%).
4.5.1. (S)-Phenylglycine 5a. A white solid, 62%. Mp
1
>250°C; IR (Nujol): 1730; CIMS: m/z 152 [MH]+; H
NMR (CD3OD): l 4.86 (s, 1H), 7.32–7.60 (m, 5H);
13C{1H} NMR (CD3OD): l 56.6, 128.0, 129.6, 130.3,
131.5, 170.8; [h]2D3=+154 (c 0.50, 5 M HCl); e.e. ]99%
(derivatisation method B).
4.5.2. (S)-(2-Methoxyphenyl)glycine 5b. A white solid,
40%. Mp >250°C; IR (Nujol): 1740; CIMS: m/z 182
[MH]+; 1H NMR (CD3OD): l 3.87 (s, 3H), 4.83 (s, 1H),
7.02 (m, 2H), 7.36 (m, 2H); 13C{1H} NMR (CD3OD): l
55.7, 56.1, 108.5, 112.2, 121.9, 130.6, 131.4, 131.7,
168.9; [h]2D3=+163 (c 0.10, 5 M HCl); e.e.=97%
(derivatisation method B).
4.7. Determination of enantiomeric purity of aryl-
glycines 5a–g (derivatisation method B)
Chiral derivatisation of each arylglycine 5a–g with (R)-
MTPA-Cl was carried out essentially according to
Williams’ procedure3 on a 70 mmol scale. The resulting
(R)-MTPA-amide was dissolved in CDCl3 (0.6 ml) and
analysed by 19F NMR spectroscopy. For all com-
pounds 5a–g studied here, the (R)-enantiomer gave a
derivative having a 19F NMR signal at l 8.75 ( 0.05)
ppm, while the (S)-enantiomer gave a lower field signal
at l 9.00 ( 0.05) ppm; baseline resolution was always
achieved. The detection limit was established using 5a,
by incremental contamination of enantiomerically pure
material with racemic material, and was found to be an
enantiomeric ratio of 99.5:0.5 (i.e. at e.e.=99%).
4.5.3. (S)-(2-Methylphenyl)glycine 5c. A white solid,
45%. Mp >250°C; IR (Nujol): 1744; CIMS: m/z 166
[MH]+; 1H NMR (CD3OD): l 2.49 (s, 3H), 4.56 (s, 1H),
7.24 (m, 2H), 7.41 (m, 2H); 13C{1H} NMR (CD3OD): l
19.6, 56.1, 123.6, 127.7, 128.2, 129.9, 132.0, 136.2,
169.2; [h]2D3=+91 (c 0.10, 5 M HCl); e.e. ]99%
(derivatisation method B).
4.5.4. (S)-(2-Bromophenyl)glycine 5d. A white solid,
55%. Mp >250°C; IR (Nujol): 1740; CIMS: m/z 230
1
[MH]+; H NMR (CD3OD): l 4.92 (s, 1H), 7.02–7.25
(m, 4H); 13C{1H} NMR (CD3OD): l 56.8, 127.0, 127.3,
128.0, 129.1, 129.6, 134.2, 171.2; [h]2D3=+67 (c 0.25, 5
M HCl); e.e.=98% (derivatisation method B).
Acknowledgements
4.5.5. (S)-(3-Methylphenyl)glycine 5e. A white solid,
49%. Mp >250°C; IR (Nujol): 1738; CIMS: m/z 166
[MH]+; 1H NMR (CD3OD): l 2.35 (s, 3H), 4.52 (s, 1H),
7.08–7.25 (m, 4H); 13C{1H} NMR (CD3OD): l 21.3,
This work was supported by the Rectorat des Univer-
site´s de Paris and the University of Oxford through the

C. Mellin-Morlie`re et al. / Tetrahedron: Asymmetry 12 (2001) 149–155
155
Paris–Oxford exchange scheme by award of a grant (to
C.M.-M.).
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