A practical synthesis of optically active arylglycines via catalytic asymmetric Strecker reaction

Article abstract of DOI:10.1016/j.tet.2009.04.098

A practical procedure for catalytic asymmetric synthesis of optically active arylglycine derivatives via optically active α-aminonitriles has been developed. The N-benzhydryl α-arylaminonitrile intermediates were prepared in excellent yield (89-99%) and enantiomeric purity (96 to >98% ee) by enantioselective cyanation of aldimines with TMSCN/ⁱPrOH in the presence of 2.5 mol % of an easily prepared Ti/chiral amino alcohol complex at 0 °C, without requiring slow addition of the cyanating agent. The easily racemized α-aminonitrile intermediates were efficiently hydrolyzed by an aqueous HCl/TFA mixture to give the arylglycine derivatives in good yield (60-92%) and moderate to excellent enantiomeric purity (85-98% ee).

Full text of DOI:10.1016/j.tet.2009.04.098

Tetrahedron 65 (2009) 5849–5854
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A practical synthesis of optically active arylglycines via catalytic asymmetric
Strecker reaction
*
Vorawit Banphavichit, Woraluk Mansawat, Worawan Bhanthumnavin, Tirayut Vilaivan
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical procedure for catalytic asymmetric synthesis of optically active arylglycine derivatives via
Received 12 January 2009
Received in revised form 15 April 2009
Accepted 30 April 2009
optically active a-aminonitriles has been developed. The N-benzhydryl a-arylaminonitrile intermediates
were prepared in excellent yield (89–99%) and enantiomeric purity (96 to >98% ee) by enantioselective
cyanation of aldimines with TMSCN/iPrOH in the presence of 2.5 mol % of an easily prepared Ti/chiral
amino alcohol complex at 0 ꢀC, without requiring slow addition of the cyanating agent. The easily
Available online 8 May 2009
racemized a-aminonitrile intermediates were efficiently hydrolyzed by an aqueous HCl/TFA mixture to
give the arylglycine derivatives in good yield (60–92%) and moderate to excellent enantiomeric purity
(85–98% ee).
Keywords:
Asymmetric
Catalyst
Ó 2009 Elsevier Ltd. All rights reserved.
Imine
Hydrocyanation
1. Introduction
developed Ti/amino alcohol ligand catalyzed Strecker reaction.15
This is realized by the use of optimized reaction conditions that
Optically active arylglycines are important building blocks in
pharmaceutical industries as auxiliaries and intermediates for
synthesis of biologically active compounds.1 They can be obtained
by a variety of ways such as enzymatic resolution,2 chiral auxiliary
controlled,3 reagent-controlled,4 and catalyst-controlled5 asym-
metric syntheses. Among these, the catalytic asymmetric Strecker
reaction is perhaps the most direct and atom-economical process
allow a low catalyst loading (2.5 mol %) in conjunction with a new
hydrolysis protocol with minimized racemization.
2. Results and discussion
We have previously reported a highly enantioselective Ti-cata-
lyzed Strecker reaction of aromatic N-benzhydrylaldimines in the
presence of the structurally simple ligand 1 (Scheme 1).15 One of
the benefits of this system is that the reaction proceeded well at
0 ꢀC without the requirement of slow addition of the cyanating
agent. Nevertheless, the catalyst loading at 10 mol % was still too
high to be practically useful. In order to develop a more practical
system, the protocol for our previously reported asymmetric
for making optically active a-amino acids, especially a-arylglycines,
which are not accessible by other routes such as phase-transfer
catalyzed alkylation of glycine imines6 or asymmetric hydrogena-
tion of dehydroamino acids.7 A number of highly efficient catalyst
systems for asymmetric Strecker reactions have been designed and
evaluated during the past decade.8–11 However, the required
amount of the catalysts employed are generally quite high (10 mol %
are typical), which means that a large quantity of expensive chiral
ligands need to be consumed. Furthermore, it has previously been
Strecker reaction catalyzed by Ti/N-salicyl b-amino alcohol com-
plex was further optimized. It was reported earlier that a protic
additive is required to ensure complete and reproducible
results.12a,15a Screening of a variety of protic additive including
water, alcohols, and phenols revealed that 2-propanol (iPrOH) and
2,6-dimethylphenol were the best additives (Table 1, entries 3, 6, 8–
16). Since iPrOH is a volatile and non-toxic liquid, it was considered
more pleasant to handle than 2,6-dimethylphenol and was chosen
for further optimization. The ligand (S)-1a15a,b derived from (S)-
phenylalaninol was preferred due to its low cost and good crys-
tallinity despite the slightly lower ee compared to the more bulky
ligand (S)-1b (entries 3 and 9, 8 and 11). Pleasingly, it was found
that satisfactory ee could still be obtained at only 2.5 mol % catalyst
loading (entries 13–15). While over 90% ee was possible for certain
observed that direct hydrolysis of optically active a-aminonitriles
can result in deterioration of optical purity of the hydrolysis prod-
ucts.12 Instead of direct hydrolysis, a two-step hydrolysis via aryl-
glycine amides or imido-esters13 or temporary protection of the
arylaminonitriles by N-acylation14 have often been used to achieve
racemization-free hydrolysis. It is the objective of this work to
demonstrate a practical synthesis of arylglycines via our previously
* Corresponding author. Tel.: þ66 2 2187627; fax: þ66 2 2187598.
E-mail address: vtirayut@chula.ac.th (T. Vilaivan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.098

5850
V. Banphavichit et al. / Tetrahedron 65 (2009) 5849–5854
R
CHPh2
H
CHPh2
i
N
1-Ti(O
HN
Pr)4
N
H
OH
+ TMSCN
Ar
Ar
CN
OH
toluene, 0 °C
additive
1
2
3
3a: Ar = 4-MeOC6H4-
3b: Ar = 4-O2NC6H4-
3c: Ar = C6H5-
2a: Ar = 4-MeOC6H4-
2b: Ar = 4-O2NC6H4-
2c: Ar = C6H5-
(S)-1a: R = C6H5CH2-
i
(S)-1b: R = Pr-
Scheme 1.
Table 1
Effect of protic additive on yield and enantioselectivity of the Strecker reactiona
Entry
Substrate
Ligand (mol %)
Product
Additive (1 equiv)
Time (h)
%Conversionb
%eec
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
2a
2a
2b
2b
2c
2c
2c
2c
(S)-1a (10)
(S)-1a (10)
(S)-1a (10)
(S)-1a (10)
(S)-1a (10)
(S)-1a (10)
(S)-1a (10)
(S)-1a (10)
(S)-1b (10)
(S)-1b (10)
(S)-1b (10)
(S)-1b (10)
(S)-1a (10)
(S)-1a (5)
3a
3a
3a
3a
3a
3a
3a
3b
3a
3a
3b
3b
3c
3c
3c
3c
None
48
48
48
48
48
48
48
48
48
48
48
48
24
24
24
24
>99d
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
67
91
7
H2O
iPrOH
91
42
88
92
40
76
97
97
80
79
98
98
98
77
HFIP
PhOH
2,6-Dimethylphenol
2,4-Di-tert-butylphenol
iPrOH
9
iPrOH
10
11
12
13
14
15
16
2,6-Dimethylphenol
iPrOH
2,6-Dimethylphenol
iPrOH
iPrOH
iPrOH
iPrOH
>99
>99
>99
72
(S)-1a (2.5)
(S)-1a (1.0)
a
See Scheme 1 for other reaction parameters.
Measured by 1H NMR.
b
c
Determined by 1H NMR integration of the split Ha signals after addition of (S)-camphorsulfonic acid as chiral solvating agent.
>99% at 0.1 mmol scale, variable results were obtained at 1 mmol scale.
d
imine substrates such as 2c at 2 mol % catalyst loading, we prefer
the use of 2.5 mol %, which exhibited more substrate tolerance.
Even at such a low catalyst loading, there was no need to slowly add
TMSCN and the protic additive to the reaction, which greatly sim-
plified the reaction procedure compared to those employed with
other similar catalysts.12a,13b The optimal reaction temperature was
found to be 0 ꢀC. Attempts to decrease the temperature further
resulted in a very slow reaction rate and the ee was not improved
(data not shown). The reaction was usually complete within 24–
72 h, depending on the nature of substrates. The imines carrying
electron-withdrawing groups reacted more slowly than those
containing electron-donating groups. This suggests that the co-
ordination of the imino nitrogen atom to the catalyst is probably
the rate-limiting step. Nevertheless, all substrates tested reacted
more or less completely (>95% conversion according to 1H NMR
analysis) after 72 h.
aminonitrilesobtained are crystalline and the ee of these compounds
could be further enhanced by recrystallization from heptane, hex-
anes or their mixtures with ethyl acetate. Generally, 50–80% recovery
of the optically pure (98 to >99% ee) a-aminonitriles was easily
obtained after a single recrystallization of the materials obtained
Table 2
Yield and enantiomeric excess of Strecker products obtained under optimized
conditions
CHPh2
i
CHPh2
ligand 1 - Ti(OPr)4 (2.5 mol%)
HN
N
i
TMSCN (2 equiv), PrOH (1 equiv)
Ar
CN
3c-k
Ar
H
toluene, 0 °C, 72 h
2c-k
Entry Substrate Ligand Product Ar
% Yield % eea
[a]D (temp)
(c 1.0, CHCl3)
The new conditions were tested with a variety of N-benzhydryl
benzaldimine substrates containing alkyl and halogen substituents
at various positions on the aromatic ring. The reactions were carried
outata1 mmolscaleinscrew-cappedtesttubes, whichrequiredonly
6.4 mg of the ligand per reaction. Once all the reagents were com-
pletely added, the tube was capped and left at 0 ꢀC for 72 h. Under
theseconditions, thereactionproceeded smoothlytogivethedesired
1
2
3
4
5
6
7
8
2c
2c
2d
2e
2f
2g
2h
2i
(S)-1a (S)-3c
(R)-1a (R)-3c
(S)-1a (S)-3d
(S)-1a (S)-3e
(S)-1a (S)-3f
(S)-1a (S)-3g
(S)-1a (S)-3h
(S)-1a (S)-3i
(S)-1a (S)-3j
(S)-1a (S)-3k
(R)-1a (R)-3k
Ph–
Ph–
95
95
98
98
98
ꢁ63.0 (22 ꢀC)b
þ63.0 (22 ꢀC)c
ꢁ161.0 (24 ꢀC)
2-MeC6H4– 98
4-MeC6H4– 97
2-BrC6H4– 97
4-BrC6H4– 98
2-ClC6H4–
4-ClC6H4–
3-FC6H4–
>98 ꢁ54.0 (28 ꢀC)
>98 ꢁ121.0 (22 ꢀC)d
96
ꢁ32.9 (28 ꢀC)
98
94
99
>98 ꢁ118.0 (22 ꢀC)e
98
96
98
98
ꢁ34.6 (28 ꢀC)
ꢁ59.8 (28 ꢀC)
ꢁ186.0 (23 ꢀC)f
þ185.0 (23 ꢀC)
a-aminonitrile as the sole product. Certain a-aminonitriles including
9
10
11
2j
2k
2k
1-naphthyl (3k) and 4-bromo (3g) conveniently crystallized out of
the reaction mixture. In such cases, cold hexanes was added and the
precipitated products were collected by suction filtration. When the
product did not crystallize out, the solvent was removed (CAUTION:
toxic HCN vapor can evolve, use a well-ventilated fume hood!) and
the residue purified by column chromatography (basic Al2O3/10%
ethyl acetate in hexanesþ1% triethylaminedvide infra). The yield
and ee of the products obtained are shown in Table 2. All the
1-Naphthyl 91
1-Naphthyl 89
a
%ee of materials obtained from direct precipitation or column chromatography
(without additional recrystallization steps).
Lit.12a
Lit.10d
Lit.12a
Lit.12a
Lit.12a
[
a
]
ꢁ64.2 (c 5.0, CHCl3) (97% ee).
þ75.0 (c 0.1, CHCl3) (81% ee).
ꢁ122.0 (c 5.0, CHCl3) (>99% ee).
ꢁ122.0 (c 3.5, CHCl3) (>99% ee).
ꢁ182.0 (c 2.0, CHCl3) (>99% ee).
b
c
d
e
f
24
D
24
[a]
D
24
[a]
D
24
[a]
D
[a]
D
22

V. Banphavichit et al. / Tetrahedron 65 (2009) 5849–5854
5851
100
80
60
40
20
0
protonation of the
of the resonance stabilized benzylic iminium ions, hence racemi-
zation is prohibited (Scheme 2).
a
-amino group, which suppresses the formation
MeOH
THF
TFE
In order to complete the synthesis, the optically active
nitriles were hydrolyzed to provide the arylglycines. Certain
glycines have been obtained in high optical purities by hydrolysis of
N-benzhydryl
-aminonitriles with 6 M aqueous HCl.12a In our hands,
it was difficult to successfully apply the hydrolysis conditions to all
substrates. Because of the poor solubility of the -aminonitriles in the
a-amino-
AcOH
MeOH + HCl
a-aryl-
a
a
reaction medium, most of the starting materials were recovered
unchanged. Better results were obtained when a water-miscible co-
solvent was used. Amongst the co-solvents tested (methanol, acetic
acid, trifluoroacetic acid), trifluoroacetic acid was shown to be the
-20
0
20
40
60
80
100
120
140
160
180
most effective. Complete hydrolysis of all a-aminonitriles tested was
t (min)
achieved in a 1:1 mixture of concentrated aqueous HCl and tri-
fluoroacetic acid within 12 h at 80 ꢀC (2 mL/mmol). Prolonged
heating caused partial racemization and inadequate reaction time
resulted in incomplete hydrolysis and/or incomplete cleavage of the
N-benzhydryl group. Evaporation of the solvents followed by Boc
protection under mildly basic conditions (Boc2O/aq NaHCO3) and
methylation with diazomethane gave the corresponding Boc-aryl-
glycine methyl esters, which were analyzed for enantiomeric purity
by chiral HPLC. The racemic samples were also analyzed inparallel. In
most cases, the enantiomeric purity of the hydrolysis product was
very good (Table 3), although significant deterioration of %ee was also
observed in certain cases (entries 6 and 9).
Figure 1. Relative rates of racemization of optically active aminonitrile 3c (initial
ee¼70%) in different solvents at a concentration of 10 mg/mL (0.035 M).
from the above reactions. The absolute configuration of the amino-
nitrile obtainedwasconfirmed bycomparison of theopticalrotations
with literature values (Table 2). Ligand (S)-1a consistently gave the
product with the (S)-configuration. As expected, ligand (R)-1a gave
the opposite enantiomer in similar yields and %ee.
It should be noted that optically active a-arylamino acetonitriles
are very prone to racemization. We demonstrate here that the ra-
cemization is catalyzed by weak acids including silica gel as shown
by a significant decrease of ee after purification by column chro-
matography. Fortunately, the racemization can be suppressed by
chromatography on basic alumina with addition of a base such as
triethylamine to the eluent. More seriously, the aminonitrile 3
could racemize upon standing in protic solvents like methanol. The
Due to the sensitivity of a-aminonitriles toward racemization in
weak acid as discussed above, the acids should be mixed well be-
fore addition of the nitrile. If the order of addition was changed, i.e.,
Table 3
susceptibility of the
ous solvents is shown in Figure 1. A solution of optically active
aminonitrile (S)-3c in methanol at a concentration of 0.035 M lost
its optical activity with a t1/2 of around 6 h at 20 ꢀC. The racemi-
zation of (S)-3c was complete after standing overnight as confirmed
by optical rotation measurement. The effect is more pronounced for
a-aminonitrile (S)-3c to racemization in vari-
CHPh2
a
-
HN
NHBoc
CO2Me
4c-k
a) 1:1 conc HCl/TFA 80 °C, 18 h
b) Boc2O, aq NaHCO3
c) CH2N2
Ar
CN
3c-k
Ar
28
Entry Substrate Product Ar
% Yield % ee
% ee
[a]
D
a
-aminoarylacetonitriles containing an electron-donating sub-
Substrate Product (c 1.0, CHCl3)
stituent on the aromatic ring (data not shown). The solution of (S)-
3c in THF did not change its optical activities, at least, over the same
period of time. Faster racemization was observed in more acidic
solvents like 2,2,2-trifluoroethanol (TFE). The ease of racemization
1
2
3
4
5
6
7
8
(S)-3c
(R)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3h
(S)-3i
(S)-3j
(S)-3k
(R)-3k
(S)-4c
(R)-4c
(S)-4d
(S)-4e
(S)-4f
(S)-4g
Ph–
Ph–
92
89
98
98
93
93
95
92
94
85
91
94
87
98
98
þ120.2a
ꢁ120.2b
þ132.1
þ129.2c
þ95.2
2-MeC6H4– 76
4-MeC6H4– 60
2-BrC6H4– 87
4-BrC6H4– 81
98
>98
>98
96
>98
98
96
98
98
of optically active
a-aminonitriles has a significant implication
þ102.6
þ117.1
since it precluded many operations, including chemical trans-
formations and recrystallization, to be performed in protic solvents.
Indeed, in more than one instance methanol had been used as
solvent for organocatalyzed asymmetric Strecker reactions. This
might also partly explain the variable results observed in different
studies.16 Surprisingly, despite its sensitivity toward racemization
in weak acids, the racemization of (S)-3c was completely sup-
pressed in stronger acidic media such as HCl at a concentration of
0.1 M in methanol or neat acetic acid. This can be rationalized by
(S)-4h 2-ClC6H4– 85
(S)-4i
(S)-4j
(S)-4k 1-Naphthyl 78
(R)-4k 1-Naphthyl 77
4-ClC6H4– 86
3-FC6H4– 91
þ102.3
þ100.4
þ160.2
ꢁ160.2d
9
10
11
Lit.17
Lit.18
Lit.19
Lit.5c
[a]
þ134.1 (c 0.8, CHCl3).
a
25
D
b
c
20
[a
]
ꢁ130.0 (c 1.0, CHCl3).
D
22
[a
]
þ128.9 (c 2.4, CHCl3) (>98% ee).
ꢁ144.0 (c 1.0, CHCl3) (>99% ee).
D
d
23
[a]
D
Me
Me
R
H
C
R
H
C
O
H
O
H
H
R
N
N
N
+
HCN
Ar
Ar
Ar
N
N
X
H+
H
N
Me
R
H
O
H
X
Ar
C
N
Scheme 2.

5852
V. Banphavichit et al. / Tetrahedron 65 (2009) 5849–5854
the nitrile was first dissolved in TFA followed by addition of HCl,
a significant racemization would take place.
spectroscopy in the presence of (S)-camphorsulfonic acid.15a
Physical and spectroscopic data of Strecker adducts 3 can be found
in Supplementary data.
3. Conclusion
4.3. General procedure for the preparation of N-Boc-
In conclusion, we have developed a practical and efficient
arylglycine methyl ester derivatives 4
method for synthesis of optically active
a-arylaminonitriles by
Strecker reaction using a Ti complex of the structurally simple
The optically pure a-aminonitrile (0.5 mmol) was dissolved in
chiral amino alcohol ligand 1a at low catalyst loading (2.5 mol %).
a 1:1 mixture of concentrated aqueous HCl and trifluoroacetic acid
(2 mL/mmol) in a screw-capped test tube. The reaction mixture was
heated at 80 ꢀC for 18 h. Upon completion of the reaction, the re-
action mixture was extracted with hexanes (3ꢂ1 mL) and the sol-
vents removed by evaporation to afford the crude arylglycine as
hydrochloride salt.
The ease of racemization of these
a-arylaminonitriles has been
noted and the conditions that facilitate the racemization have been
identified. In addition, an efficient protocol employing 1:1 HCl/TFA
mixture for hydrolysis of the
a-arylaminonitriles to provide opti-
cally active -arylglycines with minimal racemization has also been
a
developed. Good yields and excellent enantiomeric purity of pro-
tected arylglycines were obtained starting from simple aromatic
aldimines. It is expected that the methodology should be generally
applicable to the preparation of a range of arylglycine derivatives.
The only limitation is perhaps the strongly acidic conditions re-
quired for the final hydrolysis, which may not be compatible with
many acid sensitive functional groups. The availability of haloge-
nated arylglycines means that more complex arylglycine
derivatives should in principle be further elaborated by well-
documented transformations such as transition metal-catalyzed
cross-coupling with alkynes, boronic acids or heteroatom
nucleophiles.
The crude product obtained above was dissolved in water (2 mL)
and treated with 2 equiv of NaHCO3. To the stirred resulting mix-
ture was slowly added 1.2 equiv of Boc2O in BuOH (2 mL). The
t
homogeneous solution was vigorously stirred for 5 h. Upon com-
pletion of the reaction, the solvent was removed under reduced
pressure. The solution was acidified with 10% HCl to pH¼2 and
extracted with ethyl acetate (3ꢂ10 mL). The organic phase was
combined, dried over anhydrous Na2SO4, and the solvent was
evaporated in vacuo. The crude product was dissolved in a mini-
mum amount of ethyl acetate and treated with an excess amount of
diazomethane, which had been generated by treatment of DiazaldÒ
with aqueous sodium hydroxide (CAUTION: risk of explosion).
Upon completion of the reaction (monitored by TLC or permanent
color change), the solvent was removed by evaporation. The crude
product was purified by flash column chromatography using 5%
ethyl acetate in hexanes as eluent.
4. Experimental
4.1. General
Melting points were measured on an Electrothermal 9100
melting point apparatus and were uncorrected. Optical rotations
were measured on Jasco P-1010 polarimeter at ambient tempera-
ture. FTIR spectra were recorded on a Nicolet Impact 410 IR spec-
trometer. 1H and 13C nuclear magnetic resonance (NMR) spectra
were recorded on a Varian Mercury-400 plus spectrometer oper-
ating at 400 MHz (1H) and 100 MHz (13C), respectively. Unless
otherwise stated, the spectra were taken in CDCl3. HRMS were
recorded at Chulabhorn Research Institute (Bangkok) on a Bruker
MicrOTOF mass spectrometer in positive APCI mode. Normal phase
high performance liquid chromatographic (HPLC) separations were
performed on a Water 600Ô system equipped with a UV/VIS de-
tector using hexanes/iPrOH as eluent. A Daicel Chiralcel ODÒ,
a Chiralcel OJ-HÒ, or a Chiralpak AD-HÒ column was used for the
determination of enantiomeric compositions.
4.3.1. N-Boc-(S)-phenylglycine methyl ester [(S)-4c]17
Compound (S)-4c was prepared according to the general pro-
cedure using (S)-3c as a starting material. The product was obtained
as a white solid (123.3 mg, 92%), mp 103–105 ꢀC; Rf¼0.52 (20% ethyl
28
acetate in hexanes); [
a
]
þ120.2 (c 1.0, CHCl3); nmax (KBr) 3403 (N–
D
H), 3013, 2982, 1734 (C]O), 1700 (C]O), 1504, 1444, 1360, 1322,
1266,1169 cmꢁ1
;
dH (400 MHz, CDCl3) 7.33 (5H, m, Ar), 5.55 (1H, br d,
NHBoc), 5.31 (1H, d, J¼7.2 Hz, CHCO2Me), 3.72 (3H, s, OCH3),1.43 (9H,
s, C(CH3)3); dC (100 MHz, CDCl3) 171.7,154.8,136.8,128.9,128.4,127.1,
80.2, 57.6, 52.7, 28.3; HPLC analysis: ChiralCel ODÒ, isocratic (n-
hexane/2-propanol¼97:3), flow 0.5 mL/min, 225 nm; minor enan-
tiomer tR (R)¼14.8 min; major enantiomer tR (S)¼16.4 min, 93% ee.
4.3.2. N-Boc-(R)-phenylglycine methyl ester [(R)-4c]18
Compound (R)-4c was prepared according to the general pro-
cedure using (R)-3c as a starting material. The product was
4.2. General procedure for the synthesis of 3 by Ti-catalyzed
Strecker reaction
obtained as a white solid (122.1 mg, 89%), mp 103–105 ꢀC; Rf¼0.52
28
(20% ethyl acetate in hexanes); [
a
]
ꢁ120.2 (c 1.0, CHCl3); nmax
D
(KBr) 3402 (N–H), 3015, 2982,1734 (C]O), 1700 (C]O), 1503, 1444,
The chiral ligand, N-(20-hydroxyphenyl)methyl-(S)-2-amino-3-
phenyl-propanol, (S)-1a (6.43 mg, 0.025 mmol), or its enantiomer
(R)-1a was dissolved in anhydrous toluene (1.5 mL) in a dried
1359, 1321, 1266, 1169 cmꢁ1
;
dH (400 MHz; CDCl3) 7.35 (5H, m, Ar),
5.55 (1H, d, J¼5.6 Hz, NHBoc), 5.32 (1H, d, J¼7.2 Hz, CHCO2Me), 3.71
(3H, s, OCH3), 1.43 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 171.5, 154.8,
136.9, 128.9, 128.4, 127.1, 80.2, 57.6, 52.7, 28.3; HPLC analysis:
ChiralCel ODÒ, isocratic (n-hexane/2-propanol¼97:3), flow 0.5 mL/
min, 225 nm; major enantiomer tR (R)¼14.8 min; minor enantio-
mer tR (S)¼16.5 min, 93% ee.
screw-capped test tube. Ti(OiPr)4 (7.4
m
L, 0.025 mmol) was added to
the reaction and left for 10 min at ambient temperature (30 ꢀC) to
give a clear yellow solution. 2-Propanol (76.5 L, 1.0 mmol) was
m
added in one portion by a syringe and the reaction left for another
10 min. The imine (1.0 mmol) was then added to the pre-formed
catalyst solution and the solution cooled to 0 ꢀC in an ice-salt bath
4.3.3. N-Boc-(S)-2-methylphenylglycine methyl ester [(S)-4d]
Compound (S)-4d was prepared according to the general pro-
cedure using (S)-3d as a starting material. The product was
for 15 min. Finally, TMSCN (250 mL, 2.0 mmol) was quickly added in
one portion using a syringe. After 72 h at 0 ꢀC, toluene was removed
in vacuo (CAUTION: toxic HCN vapor can evolve, use a well-venti-
lated fume hood!) and the crude product was purified by passing
through a plug of basic alumina eluting with 10% ethyl acetate in
obtained as a colorless oil (107.6 mg, 76%); Rf¼0.42 (20% ethyl
28
acetate in hexanes); [
a]
¼þ132.1 (c 1.0, CHCl3); nmax (film) 3384
D
(N–H), 3061, 2977, 1747 (C]O), 1714 (C]O), 1498, 1443, 1365,
1211, 1167 cmꢁ1
dH (400 MHz, CDCl3) 7.19 (4H, m, Ar), 5.54 (1H, d,
J¼7.6 Hz, CHCO2Me), 5.43 (1H, br d, NHBoc), 3.71 (3H, s, OCH3),
hexanes plus 1% triethylamine to yield the corresponding
a-amino-
;
nitriles, which were analyzed for enantioselectivity by 1H NMR

V. Banphavichit et al. / Tetrahedron 65 (2009) 5849–5854
5853
2.47 (3H, s, ArCH3), 1.43 (9H, s, C(CH3)3); dC (100 MHz, CDCl3)
172.2, 154.9, 136.7, 135.4, 130.9, 128.4, 126.5, 126.3, 80.1, 54.2, 52.6,
28.3, 19.4; HRMS (APCIþ): M$Naþ, found 302.1354. C15H21NO4Na
requires 302.1368; HPLC analysis: ChiralPak AD-HÒ, isocratic (n-
hexane/2-propanol¼98:2), flow 0.5 mL/min, 225 nm; minor en-
antiomer tR (R)¼30.2 min; major enantiomer tR (S)¼35.3 min,
95% ee.
225 nm; minor enantiomer tR (R)¼25.9 min; major enantiomer tR
(S)¼28.1 min, 91% ee.
4.3.8. N-Boc-(S)-4-chlorophenylglycine methyl ester [(S)-4i]
Compound (S)-4i was prepared according to the general pro-
cedure using (S)-3i as a starting material. The product was obtained
as a white solid (129.0 mg, 86%), mp 79–80 ꢀC; Rf¼0.25 (20% ethyl
28
acetate in hexanes); [
a
]
þ102.3 (c 1.0, CHCl3); nmax (KBr) 3399 (N–
D
4.3.4. N-Boc-(S)-4-methylphenylglycine methyl ester [(S)-4e]19
Compound (S)-4e was prepared according to the general pro-
cedure using (S)-3e as a starting material. The product was obtained
H), 3011, 2987, 1736 (C]O), 1697 (C]O), 1594, 1502, 1445, 1344,
1305, 1256, 1165 cmꢁ1
;
dH (400 MHz, CDCl3) 7.31 (4H, m, Ar), 5.62
(1H, br d, NHBoc), 5.28 (1H, d, J¼6.8 Hz, CHCO2Me), 3.71 (3H, s,
OCH3), 1.42 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 171.2, 154.7, 135.6,
134.3, 129.0, 128.4, 80.4, 56.9, 52.9, 28.3; HRMS (APCIþ):
[(MꢁBoc)$Hþ], found 200.0470. C9H11ClNO2 requires 200.0478;
HPLC analysis: ChiralCel ODÒ, isocratic (n-hexane/2-prop-
anol¼99:1), flow 0.5 mL/min, 225 nm; minor enantiomer tR
(R)¼17.8 min; major enantiomer tR (S)¼19.2 min, 94% ee.
as a colorless oil (83.3 mg, 60%); Rf¼0.35 (20% ethyl acetate in
28
hexanes); [
a]
þ129.2 (c 1.0, CHCl3); nmax (film) 3395 (N–H), 3054,
D
2979, 1734 (C]O), 1700 (C]O), 1505, 1444, 1349, 1317, 1251,
1170 cmꢁ1
;
dH (400 MHz, CDCl3) 7.24 (2H, d, J¼8.0 Hz, Ar), 7.15 (2H,
d, J¼8.0 Hz, Ar), 5.50 (1H, br d, NHBoc), 5.27 (1H, d, J¼6.8 Hz,
CHCO2Me), 3.71 (3H, s, OCH3), 2.33 (3H, s, ArCH3), 1.43 (9H, s,
C(CH3)3); dC (100 MHz, CDCl3) 171.8, 154.8, 138.3, 133.9, 129.7, 127.0,
80.1, 57.3, 52.6, 28.3, 21.1; HPLC analysis: ChiralCel ODÒ, isocratic (n-
hexane/2-propanol¼99:1), flow 0.5 mL/min, 225 nm; minor enan-
tiomer tR (R)¼20.9 min; major enantiomer tR (S)¼22.3 min, 92% ee.
4.3.9. N-Boc-(S)-3-fluorophenylglycine methyl ester [(S)-4j]
Compound (S)-4j was prepared according to the general pro-
cedure using (S)-4j asa startingmaterial. The product wasobtained as
a white solid (132.6 mg, 91%), mp 77–79 ꢀC; Rf¼0.34 (20% ethyl ace-
28
4.3.5. N-Boc-(S)-2-bromophenylglycine methyl ester [(S)-4f]
Compound (S)-4f was prepared according to the general pro-
cedure using (S)-3f as a starting material. The product was obtained
tate in hexanes); [
a
]
þ100.4 (c 1.03, CHCl3); nmax (KBr) 3398 (N–H),
D
3015, 2987, 1736 (C]O), 1698 (C]O), 1594, 1501, 1445, 1344, 1306,
1255, 1165 cmꢁ1
;
dH (400 MHz, CDCl3) 7.32 (1H, m, Ar), 7.15 (1H, d,
as a colorless oil (152.4 mg, 87%); Rf¼0.30 (20% ethyl acetate in
J¼7.6 Hz, Ar), 7.07 (1H, d, J¼9.6 Hz, Ar), 7.00 (1H, m, Ar), 5.70 (1H, br d,
NHBoc), 5.32 (1H, d, J¼6.8 Hz, CHCO2Me), 3.73 (3H, s, OCH3),1.43 (9H,
s, C(CH3)3); dC (100 MHz, CDCl3) 171.1, 162.6 (1JC–F¼250.0 Hz, Ar),
154.7, 139.4, 130.4 (3JC–F¼8.2 Hz), 122.8, 115.4 (2JC–F¼21.1 Hz), 114.1
(2JC–F¼22.3 Hz), 80.4, 57.1, 52.9, 28.3; HRMS (APCIþ): M$Naþ, found
306.1112. C14H18FNO4Na requires 306.1112; HPLC analysis: ChiralCel
OJ-HÒ, isocratic (n-hexane/2-propanol¼95:5), flow 1.0 mL/min,
225 nm; major enantiomer tR (S)¼8.0 min; minor enantiomer tR
(R)¼9.7 min, 87% ee.
28
hexanes); [
a
]
¼þ95.2 (c 1.0, CHCl3); nmax (film) 3379 (N–H), 3062,
D
2978, 1743 (C]O), 1715 (C]O), 1498, 1439, 1366, 1311, 1249,
1167 cmꢁ1
dH (400 MHz, CDCl3) 7.57 (1H, d, J¼7.50 Hz, Ar), 7.27–
;
7.34 (2H, m, Ar), 7.18 (1H, m, Ar), 5.70 (1H, d, J¼7.2 Hz, CHCO2Me),
5.65 (1H, br d, NHBoc), 3.72 (3H, s, OCH3), 1.42 (9H, s, C(CH3)3); dC
NMR (100 MHz, CDCl3) 171.1, 154.8, 136.8, 133.5, 129.8, 129.7, 127.9,
123.7, 80.3, 57.5, 52.9, 28.3; HRMS (APCIþ): M$Naþ, found 366.0314.
C14H18BrNO4Na requires 366.0311; HPLC analysis: ChiralCel ODÒ,
isocratic (n-hexane/2-propanol¼99:1), flow 0.5 mL/min, 225 nm;
minor enantiomer tR (R)¼29.4 min; major enantiomer tR
(S)¼32.5 min, 94% ee.
4.3.10. N-Boc-(S)-1-naphthylglycine methyl ester [(S)-4k]
Compound (S)-4k was prepared according to the general
procedure using (S)-3k as a starting material. The product was
4.3.6. N-Boc-(S)-4-bromophenylglycine methyl ester [(S)-4g]
Compound (S)-4g was prepared according to the general pro-
cedure using (S)-3g as a starting material. The product was
obtained as a colorless oil (122.6 mg, 78%); Rf¼0.31 (20% ethyl
28
acetate in hexanes); [
a
]
¼þ160.2 (c 1.0, CHCl3); nmax (film) 3377
D
(N–H), 3047, 2981, 1741 (C]O), 1692 (C]O), 1516, 1438, 1369,
1330, 1249, 1164 cmꢁ1
dH (400 MHz, CDCl3) 8.18 (1H, d, J¼8.4 Hz,
obtained as a white solid (144.0 mg, 81%), mp 86–88 ꢀC; Rf¼0.32
;
28
(20% ethyl acetate in hexanes); [
a
]
D
¼þ102.6 (c 1.0, CHCl3); nmax
Ar), 7.86 (2H, m, Ar), 7.58 (1H, apparent t, J¼7.2 Hz, Ar), 7.52 (1H,
apparent t, J¼7.4 Hz, Ar), 7.44 (2H, m, Ar), 6.09 (1H, d, J¼7.6 Hz,
CHCO2Me), 5.55 (1H, d, J¼6.8 Hz, NHBoc), 3.72 (3H, s, OCH3), 1.45
(9H, s, C(CH3)3); dC (100 MHz, CDCl3) 172.3, 155.1, 134.1, 132.8,
131.0, 129.3, 128.9, 127.0, 126.1, 125.5, 125.3, 123.3, 80.3, 54.7, 52.7,
28.3; HRMS (APCIþ): M$Naþ, found 338.1361. C18H21NO4Na re-
quires 338.1363; HPLC analysis: ChiralPak AD-HÒ, isocratic (n-
hexane/2-propanol¼90:10), flow 0.5 mL/min, 225 nm; minor
enantiomer tR (R)¼18.7 min; major enantiomer tR (S)¼21.8 min,
98% ee.
(KBr) 3392 (N–H), 3011, 2982, 1741 (C]O), 1690 (C]O), 1515, 1436,
1367, 1305, 1252, 1168 cmꢁ1
;
dH (400 MHz, CDCl3) 7.24 (2H,
d J¼8.4 Hz, Ar), 7.23 (2H, d, J¼8.4 Hz, Ar), 5.62 (1H, br d, NHBoc),
5.27 (1H, d, J¼6.8 Hz, CHCO2Me), 3.71 (3H, s, OCH3), 1.42 (9H, s,
C(CH3)3); dC (100 MHz, CDCl3) 171.1, 154.7, 136.1, 132.0, 128.8, 122.5,
80.3, 56.9, 52.9, 28.3; HRMS (APCIþ): M$Naþ, found 366.0314.
C14H18BrNO4Na requires 366.0311; HPLC analysis: ChiralCel OJ-HÒ,
isocratic (n-hexane/2-propanol¼90:10), flow 1.0 mL/min, 225 nm;
minor enantiomer tR (R)¼7.3 min; major enantiomer tR
(S)¼8.7 min, 85% ee.
4.3.11. N-Boc-(R)-1-naphthylglycine methyl ester [(R)-4k]5c
Compound (R)-4k was prepared according to the general pro-
cedure using (R)-3k as a starting material. The product was
4.3.7. N-Boc-(S)-2-chlorophenylglycine methyl ester [(S)-4h]
Compound (S)-4h was prepared according to the general pro-
cedure using (S)-3h as a starting material. The product was
obtained as a colorless oil (121.4 mg, 77%); Rf¼0.31 (20% ethyl ac-
28
obtained as a colorless oil (125.5 mg, 85%); Rf¼0.34 (20% ethyl ac-
etate in hexanes); [
a]
ꢁ160.2 (c 1.0, CHCl3); nmax (film) 3383 (N–
D
28
etate in hexanes); [
a
]
þ117.1 (c 1.0, CHCl3); nmax (film) 3376 (N–H),
H), 3051, 2977, 1746 (C]O), 1710 (C]O), 1501, 1443, 1367, 1333,
1246, 1164 cmꢁ1
dH (400 MHz, CDCl3) 8.18 (1H, d, J¼8.4 Hz, Ar),
D
3066, 2978, 1747 (C]O), 1717 (C]O), 1498, 1439, 1365, 1313, 1249,
;
1168 cmꢁ1
;
dH (400 MHz, CDCl3) 7.37 (2H, m, Ar), 7.26 (2H, m, Ar),
7.86 (2H, m, Ar), 7.60 (1H, apparent t, J¼7.6 Hz Ar), 7.54 (1H, ap-
parent t, J¼6.8 Hz, Ar), 7.43 (2H, m, Ar), 6.05 (1H, d, J¼7.6 Hz,
CHCO2Me), 5.54 (1H, br d, NHBoc), 3.72 (3H, s, OCH3), 1.45 (9H, s,
C(CH3)3); dC (100 MHz, CDCl3) 172.3, 155.0, 133.9, 132.8, 131.0, 129.3,
129.0, 127.0, 126.0, 125.5, 125.3, 123.5, 80.3, 54.7, 52.7, 28.3; HPLC
analysis: ChiralPak AD-HÒ, isocratic (n-hexane/2-propanol¼90:10),
5.68 (2H, m, CHCO2Me and NHBoc), 3.73 (3H, s, OCH3), 1.43 (9H, s,
C(CH3)3); dC (100 MHz, CDCl3) 171.1, 154.8, 135.2, 133.6, 130.1, 129.8,
129.6, 127.2, 80.3, 55.6, 52.9, 28.3; HRMS (APCIþ): M$Hþ, found
300.1003. C14H19ClNO4 requires 300.0997; HPLC analysis: ChiralCel
ODÒ, isocratic (n-hexane/2-propanol¼97:3), flow 0.3 mL/min,

5854
V. Banphavichit et al. / Tetrahedron 65 (2009) 5849–5854
7. Monograph: Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, NY, 2000; Chapter 1.
flow 0.5 mL/min, 225 nm; major enantiomer tR (R)¼19.1 min; mi-
nor enantiomer tR (S)¼22.0 min, 98% ee.
8. Reviews: (a) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875–877; (b) Gro¨ger, H.
Chem. Rev. 2003, 103, 2795–2828; (c) Spino, C. Angew. Chem., Int. Ed. 2004, 43,
1764–1766; (d) Connon, S. J. Angew. Chem., Int. Ed. 2008, 47, 1176–1178.
9. Recent examples of metal catalysts: (a) Wu¨nnemann, S.; Fro¨hlich, R.; Hoppe, D.
Eur. J. Org. Chem. 2008, 684–692; (b) Negru, M.; Schollmeyer, D.; Kunz, H. Angew.
Chem., Int. Ed. 2007, 46, 9339–9341; (c) Blacker, J.; Clutterbuck, L. A.; Crampton,
M. R.; Grosjean, C.; North, M. Tetrahedron: Asymmetry 2006, 12, 1449–1456.
10. Recent examples of organocatalysts: (a) Wen, Y.; Gao, B.; Fu, Y.; Dong, S.; Liu, X.;
Feng, X. Chem.dEur. J. 2008, 14, 6789–6795; (b) Pan, S. C.; Zhou, J.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 612–614; (c) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.;
Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468–8470; (d) Wen, Y.; Xiong, Y.;
Chang, L.; Huang, J.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72, 7715–7719; (e) Jiao, Z.
G.; Feng, X. M.; Liu, B.; Chen, F. X.; Zhang, G. L.; Jiang, Y. Z. Eur. J. Org. Chem. 2003,
3818–3826; (f) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,124,10012–10014.
11. Chiral phase transfer catalyzed variants of asymmetric Strecker reactions have
recently been reported: (a) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc.
2006, 128, 2548–2549; (b) Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.;
Maruoka, K. Tetrahedron Lett. 2007, 48, 1337–1340; (c) Herrera, R. P.; Sgarzani,
V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem. 2006, 71, 9869–9872;
Acknowledgements
This work was supported by the Thailand Toray Science Foun-
dation (T.V.) and the Royal Golden Jubilee Ph.D. Project (V.B.). Ad-
ditional financial support from Rachadapiseksompoj Endowment
Fund from Chulalongkorn University (OSRU) is also acknowledged.
We thank Mr. Nitirat Chimnoi for obtaining HRMS data.
Supplementary data
Spectroscopic data of compounds 3c–3k, copies of 1H and 13C
NMR spectra of compounds 4c–4k, and chiral HPLC chromatograms
of compounds 4c–4k are available. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2009.04.098.
However, none of the examples includes a-aryl substrates presumably due to
their ease of racemization under basic conditions required for the PTC reactions.
See also: (d) Banphavichit, V.; Chaleawlertumpon, S.; Bhanthumnavin, W.; Vi-
laivan, T. Synth. Commun. 2004, 34, 3147–3160.
12. (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284–4285; (b) Wang,
X. J.; Zhang, F.; Liu, J. T. Tetrahedron 2008, 64, 1731–1735.
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