Substituent effect on the stereoselectivity of acylation of racemic heterocyclic amines with N-phthaloyl-3-aryl-(S)-alanyl chlorides

Article abstract of DOI:10.1016/j.tetasy.2010.12.017

The acylative kinetic resolution of racemic 2-methyl-1,2,3,4- tetrahydroquinoline and 2,3-dihydro-3-methyl-4H-1,4-benzoxazine using acyl chlorides of N-phthaloyl-(S)-phenylalanine, N-phthaloyl-3-(4-nitrophenyl)-(S)- alanine and N-phthaloyl-O-methyl-(S)-tyrosine as chiral resolving agents has been carried out. It is shown that the effectiveness of an acylative kinetic resolution depends on the electronic effects of substituents in the phenyl fragment of the acylating agent and increases as the electron-donating properties of the para-substituent (OMe > H > NO₂) in phenyl fragment of N-phthaloyl-3-aryl-(S)-alanyl chlorides increase; conducting the process at a reduced temperature also contributes to an enhancement of the kinetic resolution.

Full text of DOI:10.1016/j.tetasy.2010.12.017

Tetrahedron: Asymmetry 22 (2011) 185–189
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Substituent effect on the stereoselectivity of acylation of racemic
heterocyclic amines with N-phthaloyl-3-aryl-(S)-alanyl chlorides
⇑
Galina L. Levit , Dmitry A. Gruzdev, Victor P. Krasnov, Evgeny N. Chulakov, Liliya Sh. Sadretdinova,
Marina A. Ezhikova, Mikhail I. Kodess, Valery N. Charushin
I. Ya. Postovsky Institute of Organic Synthesis of RAS (Ural Division), 22/20 S.Kovalevskoy/Akademicheskaya St., Ekaterinburg 620041, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The acylative kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2,3-dihydro-
3-methyl-4H-1,4-benzoxazine using acyl chlorides of N-phthaloyl-(S)-phenylalanine, N-phthaloyl-3-
(4-nitrophenyl)-(S)-alanine and N-phthaloyl-O-methyl-(S)-tyrosine as chiral resolving agents has been
carried out. It is shown that the effectiveness of an acylative kinetic resolution depends on the electronic
effects of substituents in the phenyl fragment of the acylating agent and increases as the electron-donat-
ing properties of the para-substituent (OMe > H > NO2) in phenyl fragment of N-phthaloyl-3-aryl-(S)-ala-
nyl chlorides increase; conducting the process at a reduced temperature also contributes to an
enhancement of the kinetic resolution.
Received 29 November 2010
Accepted 22 December 2010
Available online 2 February 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
However, the study of not only structural but also electronic fac-
tors is likely to be required for more fundamental understanding
Kinetic resolution has been widely used for preparation of
enantio pure compounds from the racemates.1 In particular, acyla-
tive kinetic resolution using enzymes,2 chiral acyl transfer cata-
lysts3 and chiral acylating agents4 is frequently applied for
obtaining enantiomerically pure amines and their derivatives.
We have shown that chiral acyl chlorides are efficient and con-
venient acylating resolving agents for the kinetic resolution of a
number of racemic heterocyclic amines, such as 2-methyl-
1,2,3,4-tetrahydroquinoline 1 and 2,3-dihydro-3-methyl-4H-1,4-
benzoxazine 2. It should be noted that enantiopure 2-substituted
1,2,3,4-tetrahydroquinolines5 and 3-substituted 2,3-dihydro-1,4-
benzoxazines6 are of special interest as the structural fragments
of naturally occurring substances and biologically active
compounds. It has been found that it is possible to achieve efficient
kinetic resolution with the acyl chlorides of (S)-naproxen,7 N-tosyl-
(S)-proline,8 N-phthaloyl-(S)-alanine9 and N-phthaloyl-(S)-phenyl-
alanine 3.10 Previously we have shown that the stereochemical
outcome of the kinetic resolution is determined by the structure
of the resolving agent. Thus, when the acyl chlorides of (S)-naprox-
en, N-phthaloyl-(S)-alanine and N-phthaloyl-(S)-phenylalanine
were used as resolving agents, the (S)-enantiomers of racemic
amines 1 and 2 reacted faster than the (R)-amines. In the case of
N-tosyl-(S)-prolyl chloride, (R)-1 and 2 formed products faster than
the (S)-enantiomers. By this means it provides a possibility for
preparative synthesis of both enantiomers of amines 1 and 2.
of kinetic resolution processes.
Herein we present the results of our studies on the effects of
substituents in the phenyl fragment of N-phthaloyl-3-aryl-(S)-ala-
nyl chlorides 3–5 on the stereochemical features of the kinetic res-
olution of racemic amines 1 and 2. Thereto, in addition to the
previously studied acyl chloride 310 we synthesised acyl chlorides
of N-phthaloyl-3-(4-nitrophenyl)-(S)-alanine 4 and N-phthaloyl-O-
methyl-(S)-tyrosine 5 differing in the electronic effects of a substi-
tuent in the para-position of the phenyl ring, which does not have
immediate steric effects.
2. Results and discussion
The acylation of heterocyclic amines with acyl chlorides 3–5
was carried out in various solvents at either +20 or ꢀ20 °C
(Scheme 1). In all cases, the formation of the mixtures of diastereo-
isomeric amides enriched with (S,S)-diastereoisomers was
observed, while unreacted amines were enriched with (R)-enanti-
omers (according to chiral HPLC). Individual (S,S)-amides 6 and 7
were previously isolated by the recrystallisation of the mixtures
of diastereoisomeric amides.10 However, in the cases of amides
8–11 we were unsuccessful in isolating the pure (S,S)-amides
either by recrystallisation or by column chromatography. There-
fore, we specially obtained (S,S)-amides 8–11 starting from enantio
pure amines (S)-110 and (S)-2.9
Based on the data for the kinetic resolution of amine 1 at +20 °C,
it was established that acyl chloride 4 (R = NO2) is a less selective
acylating agent in comparison with unsubstituted acyl chloride
⇑
Corresponding author.
E-mail address: ca512@ios.uran.ru (G.L. Levit).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.017

186
G. L. Levit et al. / Tetrahedron: Asymmetry 22 (2011) 185–189
proceeded in a similar way (Table 1, entries 17–28). In all cases the
O
best stereochemical results were obtained in either dichlorometh-
ane or acetonitrile. A decrease in de(S,S)-amide, C and s values was
observed when the kinetic resolution experiments were carried
NPhth
Cl
NH
+
out in benzene or toluene. It is knownthat aromatic p–pinteractions
X
were strongly manifested in polar solvents, however benzene and
toluene molecules are supposed to solvate the aryl groups of the
dissolved substances more effectively, thus preventing the
Me
R
1 equiv.
0.5 equiv.
1
: X = CH2
p–p
interactions.11,12
3
: R = H (Phe)
2 :X = O
4
: R = NO2 (4-NO2-Phe)
In all cases, lowering the reaction temperature led to an increase
5: R = OMe (O-Me-Tyr)
o
in the acylation stereoselectivity (Table 1, entries 11–16 and 23–28).
Thus, for example, when the acylation of amine 1 with acyl chloride
5 was carried out in dichloromethane de(S,S)-10 was 70.7% and 75.5%
(s 9.7 and 13.7) at +20 and ꢀ20 °C, respectively(Table 1, entries 9 and
16). The kinetic resolution of amine 2 with chiral acyl chlorides in
dichloromethane at +20 °C also demonstrated stereoselectivity in
the order 4 < 3 < 5, thus providing s values 4.2, 6.0 and 6.3, respec-
tively (Table 1, entries 19, 17 and 21).
The decrease in the stereoselectivity of the acylation of heterocy-
clic amines 1 and 2 with the resolving agent 4 with an electron-with-
drawing substituent R = NO2 as compared with 3 (R = H), and the
increase when using methoxy-substituted derivative 5 (R = OMe)
solvent, T C, 6 h
O
NPhth
N
+
NH
X
Me
X
Me
R
X = CH2, (R)-1
X = O, (R)-2
(S,S)-6: X = CH2, R = H
7
(S,S)- : X = O, R = H
8
(S,S)- : X = CH2, R = NO2
(S,S)-9: X = O, R = NO2
(S,S)-10: X = CH2, R = OMe
(S,S)-11: X = O, R = OMe
can be considered as an argument in favour of specific p–p aromatic
interactions contributing to the process of enantiomeric differentia-
tion. It also indicates that both electronic and steric effects are
involved in the acylative kinetic resolution. This should be taken into
consideration when designing new chiral resolving agents.
Scheme 1. Acylative kinetic resolution of racemic amines 1 and 2 with chiral acyl
chlorides 3–5.
3; however compound 5 (R = OMe) exhibited a somewhat greater
stereoselectivity than 3 (Table 1, entries 1–16).
3. Conclusion
For example, when the acylation was carried out in dichloro-
methane at +20 °C the selectivity factor s was 8.9, 6.9 and 9.7 for
acyl chlorides 3, 4 and 5, respectively. Acylation of amine 2
In conclusion, the acylative kinetic resolution of racemic
2-methyl-1,2,3,4-tetrahydroquinoline and 2,3-dihydro-3-methyl-
4H-1,4-benzoxazine using acyl chlorides of N-phthaloyl-(S)-phen-
Table 1
Results for the kinetic resolution of racemic amines 1 and 2 using acyl chlorides 3–5a
Entry
Racemic amine
Resolving agent
T (°C)
Solvent
(S,S)-Amide, deb (%)
Unreacted (R)-amine, eec (%)
Conversion, Cd (%)
Selectivity factor, se
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
3
3
4
4
4
4
5
5
5
5
3
3
4
4
5
5
3
3
4
4
5
5
3
3
4
4
5
5
+20
+20
+20
+20
+20
+20
+20
+20
+20
+20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
+20
+20
+20
+20
+20
+20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
Toluene
CH2Cl2
Toluene
Benzene
CH2Cl2
MeCN
Toluene
Benzene
CH2Cl2
MeCN
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
48.8
67.1
42.2
54.3
62.0
65.3
54.0
64.4
70.7
68.7
68.9
74.4
54.5
69.0
69.4
75.5
59.2
59.8
47.8
52.6
60.5
60.2
64.3
67.4
63.0
62.8
63.8
69.4
33.3
56.9
33.1
36.3
50.4
60.6
34.6
47.9
51.3
54.2
33.3
60.4
37.2
59.2
32.8
63.6
47.5
48.7
40.9
46.1
46.1
45.6
46.4
46.2
44.0
43.1
52.3
47.6
40
46
44
40
45
48
39
43
42
44
33
45
41
46
32
46
45
45
46
47
43
43
42
41
41
41
45
41
4.110
8.910
3.3
4.8
6.9
8.6
4.6
7.2
9.7
9.2
7.610
12.510
4.8
9.9
7.6
13.7
6.010
6.310
4.2
5.0
6.3
6.2
7.210
8.110
6.7
6.6
7.5
8.8
CH2Cl2
MeCN
a
b
c
Average values for 2–4 parallel runs are presented.
Determined by HPLC (see Section 4).
Determined by chiral HPLC (see Section 4).
d
e
C = eeamine unreacted ꢁ 100%/(eeamine unreacted + deamide formed).1a
s = ln(1 ꢀ C) ꢁ (1 ꢀ eeamine unreacted)/ln(1 ꢀ C) ꢁ (1 + eeamine unreacted).1a

G. L. Levit et al. / Tetrahedron: Asymmetry 22 (2011) 185–189
187
ylalanine, N-phthaloyl-3-(4-nitrophenyl)-(S)-alanine and
N-phthaloyl-O-methyl-(S)-tyrosine as chiral resolving agents was
carried out. It has been shown that the effectiveness of acylative ki-
netic resolution depends on the electronic effects of substituents in
the phenyl fragment of the acylating agent and increases as the
electron-donating properties of the para-substituent (OMe > H > -
NO2) in the phenyl fragment of N-phthaloyl-3-aryl-(S)-alanyl chlo-
rides increase.
4.8, H-2), 6.73 (2H, m, Ar), 7.06 (2H, m, Ar), 7.85 (4H, m, Phth),
13.35 (1H, br s, COOH).
4.3. Acyl chlorides. General procedure
Oxalyl chloride (0.175 mL, 2 mmol) was added to a stirred sus-
pension of N-phthaloyl-(S)-amino acid (1 mmol) in a mixture of
benzene/n-hexane 6:4 (8 mL) at room temperature and then
DMF (2 lL) was added to the reaction mixture. The reaction mix-
4. Experimental
4.1. General
ture was stirred for 6 h at room temperature, and then the reaction
solution was evaporated to dryness under reduced pressure. The
residue was treated with n-hexane to give acyl chlorides 4 and 5.
Freshly prepared acyl chlorides were used for further syntheses
without additional purification.
Solvents were dried and purified by standard methods. 3-(4-
Nitrophenyl)-(S)-alanine13 and O-methyl-(S)-tyrosine14 were
obtained according to known procedures. Compounds 3, 6 and 7
were described previously.10 Enantiomerically pure amines (S)-
4.3.1. 3-(4-Nitrophenyl)-N-phthaloyl-(S)-alanyl chloride 4
Pale-yellow oil (0.344 g, 96%). 1H NMR (400 MHz; CDCL3): d
3.69 (1H, dd, J 14.4 and 10.6, HB-3), 3.75 (1H, dd, J 14.4 and 5.6,
HA-3), 5.36 (1H, dd, J 10.6 and 5.6, H-2), 7.35 (2H, m, Ar), 7.78
(2H, m, Phth), 7.86 (2H, m, Phth), 8.09 (2H, m, Ar).
1
10 and (S)-29 were prepared as described previously. All other re-
agents were of commercial quality. Melting points were obtained
using an SMP3 apparatus (Barloworld Scientific, UK) and are
uncorrected. Optical rotations were measured at a sodium D line
with Perkin Elmer M 341 polarimeter. 1H and 13C NMR spectra
were recorded on Bruker DRX-400 or Bruker Avance 500 spectrom-
eters with tetramethylsilane as an internal standard. J values are
given in Hz. 1H and 13C NMR spectra of amides 8–11 were recorded
in DMSO-d6 at 100 °C. All the 1H and 13C signals of compounds
(S,S)-8–11 were assigned on the basis of 2D 1H–13C HSQC and
HMBC experiments at 100 °C. 1H NMR spectra of N-phthaloyl-(S)-
amino acids and acyl chlorides 4 and 5 were recorded at ambient
temperature. Elemental analyses were performed on a Euro EA
3000 element analyzer (Eurovector, Italy).
4.3.2. O-Methyl-N-phthaloyl-(S)-tyrosyl chloride 5
Pale-yellow powder (0.327 g, 95%): mp 82.5–83.5 °C (lit.17 81–
82 °C). 1H NMR (400 MHz; CDCL3): d 3.49 (1H, dd, J 14.3 and
10.8, HB-3), 3.59 (1H, dd, J 14.3 and 5.3, HA-3), 3.71 (3H, s, OMe),
5.28 (1H, dd, J 10.8 and 5.3, H-2), 6.73 (2H, m, Ar), 7.05 (2H, m,
Ar), 7.74 (2H, m, Phth), 7.84 (2H, m, Phth).
4.4. General procedure for studying the kinetic resolution of
amines 1 and 2 with acyl chlorides 4 and 5
Analytical HPLC was performed on a Knauer Smartline-1100
instrument using a ReproSil 100 Si column (250 ꢁ 4.6 mm) for
amides 8–11, detection at 220 nm, 1 mL/min flow rate, n-hexane/
i-PrOH 80:1 as an eluting solvent; and a Chiralcel OD-H column
(250 ꢁ 4.6 mm) for amines 1 and 2, detection at 220 nm, 1 mL/
min flow rate, n-hexane/i-PrOH/MeOH 140:0.7:0.3 (s(R)-1 9.5–
9.6 min, s(S)-1 10.5–10.7 min) and 100:1.5:1.5 (s(R)-2 9.6–9.8 min,
s(S)-2 10.5–10.6 min) as eluting solvents.
A solution of acyl chloride 4 or 5 (0.15 mmol) in an appropriate
solvent (1.5 mL) was added to a solution of amine 1 or 2
(0.3 mmol) in the same solvent (1.5 mL) at +20 °C or ꢀ20 °C. The
reaction mixture was kept at a given temperature for 6 h, and then
washed consequently with 1 M HCl (3 mL), brine (3 ꢁ 3 mL), satu-
rated aqueous NaHCO3 (3 mL) and water (3 ꢁ 3 mL). The organic
layer was dried (MgSO4) and evaporated to dryness under reduced
pressure to give a mixture of diastereoisomeric amides 8–11, the
diastereoisomeric ratio of which was analysed by HPLC (ReproSil
100 Si) and 1H NMR. The combined acidic washings were alkalised
with Na2CO3 and then extracted with CHCl3 (3 ꢁ 2 mL). The com-
bined organic extracts were washed with water (2 ꢁ 3 mL), dried
and evaporated to dryness under reduced pressure to give unre-
acted amines 1 or 2, which were analysed by chiral HPLC (Chiralcel
OD-H). Each experiment was performed in 2–4 runs.
4.2. N-Phthaloyl-(S)-amino acids. General procedure
N-Carbethoxyphthalimide (6 mmol) was added to a stirred
solution of amino acid (6 mmol) and Na2CO3 (6 mmol) in water
(50 mL) at room temperature. The reaction mixture was stirred
for 2–3 h and then filtered off. The filtrate was acidified with 4 N
HCl up to pH 1–2. The precipitate was filtered off, recrystallised
from EtOH–H2O and dried in vacuum at 60 °C.
4.5. Diastereoisomeric amides 8–11. General procedure
4.2.1. N-Phthaloyl-3-(4-nitrophenyl)-(S)-alanine
The synthesis of mixtures of diastereoisomers 8–11 was carried
out as described in Section 4.4 starting from amine 1 or 2 (2 mmol)
in CH2Cl2 (10 mL) and acyl chloride 4 or 5 (1 mmol) in CH2Cl2
(10 mL). The reaction was carried out at +20 °C. Amides 8–11 were
isolated by flash column chromatography on silica gel using a ben-
zene–EtOAc mixture as eluent.
Colourless crystals (1.35 g, 66%): mp 207–208 °C (EtOH–H2O)
(lit.15a mp 204.7 °C;15b 209–211 °C). ½a 2D0
¼ ꢀ231:0 (c 1.3, EtOH)
ꢂ
{lit.,15b
½
a 2D0
ꢂ
¼ ꢀ233 ꢃ 2 (EtOH)}. Anal. Calcd for C17H12N2O6: C,
60.00; H, 3.55; N, 8.23. Found: C, 59.75; H, 3.41; N, 8.26. 1H NMR
(400 MHz; DMSO-d6): d 3.47 (1H, dd, J 14.2 and 11.4, HB-3), 3.63
(1H, dd, J 14.2 and 4.9, HA-3), 5.24 (1H, dd, J 11.4 and 4.9, H-2),
7.49 (2H, m, Ar), 7.86 (4H, m, Phth), 8.07 (2H, m, Ar), 13.49 (1H,
br s, COOH).
4.5.1. 2-Methyl-1-[3-(4-nitrophenyl)-N-phthaloyl-(S)-alanyl]-
1,2,3,4-tetrahydroquinoline 8 (diastereoisomeric mixture)
Pale-yellow solid (0.315 g, 67%): mp 140–146 °C. Anal. Calcd for
4.2.2. O-Methyl-N-phthaloyl-(S)-tyrosine
C27H23N3O5: C, 69.07; H, 4.94; N, 8.95. Found: C, 69.15; H, 4.88; N,
8.98. HPLC: s(R,S)-8 10.3 min and s(S,S)-8 12.2 min. 1H NMR
(500 MHz; DMSO-d6, 100 °C) [S,S/R,S ratio 76:24]: d 1.00 (0.76H,
d, J 6.4, Me-R,S), 1.03 (2.28H, d, J 6.6, Me-S,S), 1.11 (0.24H, m, HB-
3-R,S), 1.30 (0.76H dddd, J 13.1, 10.4, 6.9 and 5.1, HB-3-S,S), 2.19
(0.24H, m, HA-3-R,S), 2.24–2.36 (1.24H, m, HA-3-S,S, HA-4- and
HB-4-R,S), 2.48 (overlapped by DMSO, m, HB-4-S,S), 2.67 (0.72H,
Colourless crystals (1.46 g, 75%): mp 127–128 °C (EtOH–H2O)
(lit.16 128 °C). Anal. Calcd for C18H15NO5: C, 66.46; H, 4.65; N,
4.31. Found: C, 66.40; H, 4.48; N, 4.41. ½a D20
¼ ꢀ214:8 (c 1.0,
ꢂ
CH2Cl2) {lit.16
[a
]
D = ꢀ210.2 (c 1, CH2Cl2)}. 1H NMR (400 MHz;
DMSO-d6): d 3.28 (1H, dd, J 14.2 and 11.8, HB-3), 3.41 (1H, dd, J
14.2 and 4.8, HA-3), 3.63 (3H, s, OMe), 5.06 (1H, dd, J 11.8 and

188
G. L. Levit et al. / Tetrahedron: Asymmetry 22 (2011) 185–189
dt, J 15.1 and 5.1, HA-4-S,S), 2.81 (0.76H, dd, J 14.3 and 4.7, HB-30-
S,S). 3.27 (0.24H, dd, J 14.1 and 9.4, HB-30-R,S), 3.68 (0.24H, dd, J
14.1 and 5.4, HA-30-R,S), 3.85 (0.76H, dd, J 14.3 and 11.1, HA-30-
S,S), 4.58 (0.24H, m, H-2-R,S), 4.64 (0.76H, ddq, J 7.6, 6.9 and 6.6,
H-2-S,S), 5.60 (0.24H, dd, J 9.4 and 5.4, H-20-R,S), 5.80 (0.76H, dd,
J 11.1 and 4.7, H-20-S,S), 6.65 (0.24H, d, J 7.5, H-5-R,S), 6.75
(0.24H, td, J 7.5 and 1.2, H-6-R,S), 6.96–7.01 (1.76H, m, H-50-S,S
and H-7-R,S), 7.24 (0.24H, d, J 7.5, H-8-R,S), 7.25–7.30 (1.52H, m,
H-5- and H-6-S,S), 7.39 (0.76H, m, H-7-S,S), 7.43 (0.48H, d, J 8.6,
H-50-R,S), 7.53–7.56 (1.24H, m, H-8-S,S and H-400-R,S), 7.68
(0.48H, m, H-300-R,S), 7.83 (3.04H, s, H-300- and H-400-S,S), 7.92
(1.52H, d, J 8.8, H-60-S,S), 7.97 (0.48H, d, J 8.6, H-60-R,S).
3.44 (0.22H, dd, J 14.1 and 5.5, HA-30-R,S), 3.64 (2.34H, s, OMe-
S,S), 3.65 s (0.66H, s, OMe-R,S), 3.66 (0.78H, dd, J 14.1 and 10.2,
HA-30-S,S), 4.06 (0.78H, dd, J 11.0 and 3.2, HB-2-S,S), 4.10 (0.44H,
d, J 2.1, H-2-R,S), 4.18 (0.78H, dd, J 11.0 and 1.7, HA-2-S,S), 4.51
(0.22H, m, H-3-R,S), 4.76 (0.78H, qdd, J 6.8, 3.2 and 1.7, H-3-S,S),
5.55 (0.22H, dd, J 9.6 and 5.5, H-20-R,S), 5.71 (0.78H, dd, J 10.2
and 5.6, H-20-S,S), 6.60 (0.22H, dd, J 8.1 and 1.5, H-8-R,S), 6.67–
6.75 (2.22H, m, H-60-S,S, H-60-R,S and H-7-R,S), 6.83 (0.22H, ddd, J
8.1, 7.3 and 1.5, H-6-R,S), 6.90 (0.78H, dd, J 8.2 and 1.5, H-8-S,S),
6.93 (1.56H, d, J 8.8, H-50-S,S), 6.97 (0.78H, ddd, J 8.1, 7.3 and 1.5,
H-6-S,S), 7.05 (0.44H, d, J 8.6, H-50-R,S), 7.12 (0.78H, ddd, J 8.2,
7.3 and 1.5, H-7-S,S), 7.43 (0.22H, dd, J 8.1 and 1.5, H-5-R,S), 7.68
(0.44H, m, H-400-R,S), 7.72 (0.78H, dd, J 8.1 and 1.5, H-5-S,S), 7.74
(0.44H, m, H-300-R,S), 7.82 (3.12H, s, H-300- and H-400-S,S).
4.5.2. 2,3-Dihydro-3-methyl-4-[3-(4-nitrophenyl)-N-phthaloyl-
(S)-alanyl]-4H-1,4-benzoxazine 9 (diastereoisomeric mixture)
Pale-yellow foam (0.330 g, 70%). Anal. Calcd for C26H21N3O6: C,
66.24; H, 4.49; N, 8.91. Found: C, 66.33; H, 4.62; N, 8.68. HPLC
s(R,S)-9 9.3 min and s(S,S)-9 12.8 min. 1H NMR (400 MHz; DMSO-d6,
100 °C) [S,S/R,S ratio 68:32]: d 0.86 (0.96H, d, J 6.7, Me-R,S), 1.09
(2.04H, d, J 6.7, Me-S,S), 3.36 (0.32H, dd, J 14.1 and 9.2, HB-30-
R,S), 3.43 (0.68H, dd, J 14.2 and 6.1, HB-30-S,S), 3.65 (0.32H, dd, J
14.1 and 5.3, HA-30-R,S), 3.85 (0.68H, dd, J 14.2 and 9.7, HA-30-S,S),
4.04 (0.68H, dd, J 11.0 and 3.3, HB-2-S,S), 4.08–4.18 (1.32H, m,
HA-2-S,S, HA-2- and HB-2-R,S), 4.56 (0.32H, m, H-3-R,S), 4.75
(0.68H, m, H-3-S,S), 5.73 (0.32H, dd, J 9.2 and 5.3, H-20-R,S), 5.81
(0.68H, dd, J 9.7 and 6.1, H-20-S,S), 6.57 (0.32H, d, J 7.9, H-8-R,S),
6.72 (0.32H, t, J 7.8, H-6-R,S), 6.79–6.86 (1H, m, H-7-R,S and H-8-
S,S), 6.95 (0.68H, ddd, J 8.2, 7.3 and 1.5, H-6-S,S), 7.10 (0.68H,
ddd, J 8.2, 7.3 and 1.6, H-7-S,S), 7.35 (1.36H, d, J 8.6, H-50-S,S),
7.43 (0.32H, d, J 7.9, H-5-R,S), 7.48 (0.64H, d, J 8.6, H-50-R,S), 7.67
(0.64H, m, H-400-R,S), 7.72–7.77 (1.32H, m, H-5-S,S and H-300-R,S),
7.83 (2.72H, s, H-300- and H-400-S,S), 7.97–8.00 (2H, m H-60-S,S and
H-60-R,S).
4.6. (S,S)-Amides 8–11. General procedure
A solution of acyl chloride 4 or 5 (0.5 mmol) in CH2Cl2 (5 mL)
was added to a stirred solution of amine (S)-1 or (S)-2 (1.0 mmol)
in CH2Cl2 (5 mL) at +20 °C. The reaction mixture was stirred at
+20 °C for 6 h and then washed with 1 M HCl (5 mL), brine
(3 ꢁ 5 mL), saturated aqueous NaHCO3 (5 mL), and water
(3 ꢁ 5 mL). The organic layer was dried (MgSO4) and evaporated
to dryness under reduced pressure. The residue was purified by
flash column chromatography (eluent benzene/EtOAc 96:4) and
then treated with hexane.
4.6.1. (2S)-2-Methyl-1-[3-(4-nitrophenyl)-N-phthaloyl-(S)-
alanyl]-1,2,3,4-tetrahydroquinoline (S,S)-8
Colourless powder (0.291 g, 62%): mp 141–143 °C. ½a D20
¼ þ383
ꢂ
(c 1.0, CHCl3). Anal. Calcd for C27H23N3O5: C, 69.07; H, 4.94; N, 8.95.
Found: C, 68.82; H, 4.83; N, 8.87. HPLC: de 99.7% (s
12.22 min). 1H
NMR (400 MHz; DMSO-d6, 100 °C): d 1.04 (3H, d, J = 6.6, Me), 1.30
(1H, dddd, J 13.1, 10.4, 6.9 and 5.1, HB-3), 2.33 (1H, ddt, J 13.1, 7.6
and 5.2, HA-3), 2.48 (overlapped by DMSO, m, HB-4), 2.67 (1H, dt, J
15.1 and 5.1, HA-4), 2.82 (1H, dd, J 14.3 and 4.7, HB-30), 3.85 (1H, dd,
J 14.3 and 11.1, HA-30), 4.65 (1H, ddq, J 7.6, 6.8 and 6.6, H-2), 5.80
(1H, dd, J 11.1 and 4.7, H-20), 7.00 (2H, d, J 8.8, H-50), 7.25–7.30 (2H,
m, H-5 and H-6), 7.38 (1H, m, H-7), 7.55 (1H, d, J 7.6, H-8), 7.83 (4H,
s, H-300 and H-400), 7.92 (2H, d, J 8.8, H-60). 13C NMR (125 MHz;
DMSO-d6; 100 °C): d 19.35 (Me), 24.79 (C4), 31.45 and 31.59 (C3,
C30), 48.98 (C2), 53.96 (C20), 122.62 (C300), 122.72 (C60), 124.64
(C8), 125.96 (C6), 126.32 (C7), 127.55 (C5), 128.79 (C50), 130.61
(C200a), 134.18 (C400), 135.43 (C4a), 135.83 (C8a), 144.47 (C40),
146.13 (C70), 166.41 (C10), 167.46 (C200).
4.5.3. 2-Methyl-1-[O-methyl-N-phthaloyl-(S)-tyrosyl]-1,2,3,4-
tetrahydroquinoline 10 (diastereoisomeric mixture)
Colourless foam (0.336 g, 74%). Anal. Calcd for C28H26N2O4: C,
73.99; H, 5.77; N, 6.16. Found: C, 74.03; H, 6.04; N, 6.09. HPLC
s(R,S)-10 10.0 min, s(S,S)-10 11.7 min. 1H NMR (400 MHz; DMSO-d6,
100 °C) [S,S/R,S ratio 85:15]: d 0.98 (0.45H, d, J 6.7, Me-R,S), 1.03
(2.55H, d, J 6.7, Me-S,S), 1.14 (0.15H, m, HB-3-R,S), 1.29 (0.85H,
dddd, J 13.0, 10.5, 7.1 and 5.0, HB-3-S,S), 2.17–2.39 (1.3H, m, HA-
3-S,S, HA-3-R,S, HA-4- and HB-4-R,S), 2.49 (overlapped by DMSO,
m, HB-4-S,S), 2.56 (0.85H, dd, J 14.1 and 4.2, HB-30-S,S), 2.68
(0.85H, dt, J 15.1 and 5.0, HA-4-S,S), 3.12 (0.15H, dd, 14.3 and 9.5,
HB-30-R,S), 3.48 (0.15H, dd, J 14.3 and 5.4, HA-30-R,S), 3.60 (2.55H,
s, OMe-S,S), 3.63 (0.45H, s, OMe-R,S), 3.64 (0.85H, dd, J 14.1 and
11.6, HA-30-R, S), 4.57 (0.15H, m, H-2-R,S), 4.65 (0.85H, ddq, J 7.7,
7.1 and 6.7, H-2-S,S), 5.42 (0.15H, dd, J 9.5 and 5.4, H-20-R,S), 5.72
(0.85H, dd, J 11.6 and 4.2, H-20-S,S), 6.59 (1.7H, d, J 9.1, H-50-S,S),
6.62 (1.7H, d, J 9.1, H-60-S,S), 6.64–6.70 (0.45H, m, H-5 and
H-60-R,S), 6.78 (0.15H, td, J 7.5 and 1.5, H-6-R,S), 6.96–7.02
(0.45H, m, H-7- and H-50-R,S), 7.18 (0.15H, d, J 7.9, H-8-R,S),
7.26–7.33 (1.7H, m, H-6- and H-5-S,S), 7.39 (0.85H, ddd, J 7.8, 7.0
and 1.6, H-7-S,S), 7.52–7.57 (1.15H, m, H-400-R,S and H-8-S,S),
7.68 (0.3H, m, H-300-R,S), 7.82 (3.4H, s, H-300- and H-400-S,S).
4.6.2. (3S)-2,3-Dihydro-3-methyl-4-[3-(4-nitrophenyl)-N-
phthaloyl-(S)-alanyl]-4H-1,4-benzoxazine (S,S)-9
Colourless powder (0.259 g, 55%): mp 106–108 °C. ½a D20
¼ þ339
ꢂ
(c 1.0, CHCl3). Anal. Calcd for C26H21N3O6: C, 66.24; H, 4.49; N, 8.91.
Found: C, 66.26; H, 4.76; N, 8.63. HPLC: de P99.9% (s 12.98 min).
1H NMR (400 MHz; DMSO-d6, 100 °C): d 1.09 (3H, d, J 6.9, Me), 3.42
(1H, dd, J 14.2 and 6.1, HB-30), 3.85 (1H, dd, J 14.2 and 9.7, HA-30),
4.04 (1H, dd, J 11.0 and 3.3, HB-2), 4.17 (1H, dd, J 11.0 and 1.7,
HA-2), 4.75 (1H, qdd, J 6.9, 3.3 and 1.7, H-3), 5.81 (1H, dd, J 9.7
and 6.1, H-20), 6.85 (1H, dd, J 8.2 and 1.5, H-8), 6.96 (1H, ddd, J
8.2, 7.3 and 1.5, H-6), 7.10 (1H, ddd, J 8.2, 7.3 and 1.6, H-7), 7.35
(2H, d, J 8.5, H-50), 7.75 (1H, dd, J 8.2 and 1.6, H-5), 7.83 (4H, s,
H-300 and H-400), 7.98 (2H, d, J 8.5, H-60). 13C NMR (125 MHz;
DMSO-d6, 100 °C): d 14.64 (Me), 33.14 (C30), 45.30 (C3), 53.28
(C20), 69.36 (C2), 116.16 (C8), 11 9.85 (C6), 122.69 (C300), 122.76
(C4a), 124.19 (C5), 125.81 (C7), 129.37 (C50), 130.53 (C200a),
134.23 (C400), 144.32 (C40), 146.01 (C8a), 146.23 (C70), 166.03
(C10), 164.18 (C200).
4.5.4. 2,3-Dihydro-3-methyl-4-[O-methyl-N-phthaloyl-(S)-
tyrosyl]-4H-1,4-benzoxazine 11 (diastereoisomeric mixture)
Colourless solid (0.324 g, 71%): mp 74–79 °C. Anal. Calcd for
C
27H24N2O5: C, 71.04; H, 5.30; N, 6.14. Found: C, 71.06; H, 5.48;
N, 6.15. HPLC s(R,S)-11 9.0 min, s(S,S)-11 12.2 min. 1H NMR
(400 MHz; DMSO-d6, 100 °C) [S,S/R,S ratio 78:22]: d 0.87 (0.66H,
d, J 6.8, Me-R,S), 1.08 (2.34H, d, J 6.8, Me-S,S), 3.16 (0.78H, dd, J
14.1 and 5.6, HB-30-S,S), 3.22 (0.22H, dd, J 14.1 and 9.6, HB-30-R,S),

G. L. Levit et al. / Tetrahedron: Asymmetry 22 (2011) 185–189
189
4.6.3. (2S)-2-Methyl-1-[O-methyl-N-phthaloyl-(S)-tyrosyl]-
References
1,2,3,4-tetrahydroquinoline (S,S)-10
Colourless powder (0.318 g, 70%): mp 122 °C. ½a D20
¼ þ369 (c
ꢂ
1. (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330; (b) Vedejs, E.;
Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974–4001; (c) Faber, K. Chem. Eur. J.
2001, 7, 5004–5010; (d) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth.
Catal. 2001, 343, 5–26; (e) Fogassy, E.; Nógrádi, M.; Kozma, D.; Egri, G.; Pálovics,
E.; Kiss, V. Org. Biomol. Chem. 2006, 4, 3011–3030; (f) Breuer, M.; Ditrich, K.;
Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.; Zelinski, T. Angew. Chem., Int.
Ed. 2004, 43, 788–824.
2. For examples of the kinetic resolution of amines using enzymes, see: (a)
Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry 1999, 10, 107–117;
(b) Nechab, M.; Azzi, N.; Vanthuyne, N. J. Org. Chem. 2007, 72, 6918–6923; (c)
Ditrich, K. Synthesis 2008, 14, 2283–2287.
3. For examples of the kinetic resolution of amines using chiral acyl transfer
catalysts, see: (a) Arai, S.; Bellemin-Lapponnaz, S.; Fu, G. Angew. Chem., Int. Ed.
2001, 40, 234–236; (b) Fu, G.; Arp, F. J. Am. Chem. Soc. 2006, 128, 14264–14265;
(c) Wurz, R. P. Chem. Rev. 2007, 107, 5570–5595; (d) Arnold, K.; Davies, B.;
Hérault, D.; Whiting, A. Angew. Chem., Int. Ed. 2008, 47, 2673–2676; (e) De, C.
K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060–17061; (f)
Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem. Soc. 2010, 132, 2870–2871.
4. For examples of the kinetic resolution of amines using chiral acylating agents,
see: (a) Yokomatsu, T.; Arakawa, A.; Shibuya, S. J. Org. Chem. 1994, 59, 3506–
3508; (b) Kondo, K.; Kurosaki, T.; Murakami, Y. Synlett 1998, 725–726; (c) Zhao,
M.; Wang, Ch.; Peng, S.; Winterfeldt, E. Tetrahedron: Asymmetry 1999, 10, 3899–
3905; (d) Tanaka, T.; Fang, X.; Azuma, T.; Uchida, S.; Ishida, T.; In, Y.; Iwata, C.;
Maezaki, N. J. Chin. Chem. Soc. 2000, 47, 865–868; (e) Atkinson, R.; Al-Sehemi,
A.; Fawcett, J. J. Chem. Soc., Perkin Trans. 1 2002, 257–274; (f) Mioskowski, C.;
Arseniyadis, S.; Valleix, A.; Wagner, A. Angew. Chem., Int. Ed. 2004, 43, 3314–
3317; (g) Karnik, A.; Kamath, S. Tetrahedron: Asymmetry 2008, 19, 45–48.
5. (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543–559; (b) Sikorski, J. A. J. Med.
Chem. 2006, 49, 1–22.
1.0, CHCl3). Anal. Calcd for C28H26N2O4: C, 73.99; H, 5.77; N, 6.16.
Found: C, 74.12; H, 6.03; N, 5.92. HPLC: de 99.7% (s 11.68 min).
1H NMR (400 MHz; DMSO-d6, 100 °C): d 1.03 (3H, d, J 6.7, Me),
1.29 (1H, dddd, J 13.0, 10.5, 7.1 and 5.0, HB-3), 2.35 (1H, ddt, J
13.0, 7.7 and 5.0, HA-3), 2.48 (overlapped by DMSO, m, HB-4),
2.56 (1H, dd, J 14.1 and 4.2, HB-30), 2.68 (1H, dt, J 15.1 and 5.0,
HA-4), 3.60 (3H, s, OMe), 3.64 (1H, dd, J 14.1 and 11.6, HA-30),
4.65 (1H, ddq, J 7.7, 7.1 and 6.7, H-2), 5.71 (1H, dd, J 11.6 and
4.2, H-20), 6.59 (2H, d, J 9.1, H50), 6.62 (2H, d, J 9.1, H60), 7.26–
7.33 (2H, m, H-5 and H-6), 7.40 (1H, ddd, J 7.8, 7.0 and 1.5, H-7),
7.53 (1H, d, J 7.8, H-8), 7.82 (4H, s, H-300 and H-400). 13C NMR
(125 MHz; DMSO-d6, 100 °C): d 19.47 (Me), 24.90 (C4), 30.47
(C30), 31.64 (C3), 48.84 (C2), 54.50 (OMe), 54.94 (C20), 113.49
(C60), 122.50 (C300), 124.71 (C8), 125.89 (C6), 126.27 (C7), 127.48
(C5), 128.47 (C50), 128.48 (C40), 130.67 (C200a), 134.08 (C400),
135.58 (C4a), 136.07 (C8a), 157.60 (C70), 166.98 (C10), 167.52 (C200).
4.6.4. (3S)-2,3-Dihydro-3-methyl-4-[O-methyl-N-phthaloyl-(S)-
tyrosyl]-4H-1,4-benzoxazine (S,S)-11
Colourless powder (0.310 g, 68%): mp 79–80 °C. ½a D20
¼ þ305 (c
ꢂ
1.0, CHCl3). Anal. Calcd for C27H24N2O5: C, 71.04; H, 5.30; N, 6.14.
6. (a) Brown, K. S., Jr.; Djerassi, C. J. Am. Chem. Soc. 1964, 86, 2451–2463; (b) Zhou,
Y.-G.; Yang, P.-Y.; Han, X.-W. J. Org. Chem. 2005, 70, 1679–1683.
7. (a) Charushin, V. N.; Krasnov, V. P.; Levit, G. L.; Korolyova, M. A.; Kodess, M. I.;
Chupakhin, O. N.; Kim, M. H.; Lee, H. S.; Park, Y. J.; Kim, K.-C. Tetrahedron:
Asymmetry 1999, 10, 2691–2702; (b) Krasnov, V. P.; Levit, G. L.; Andreeva, I. N.;
Grishakov, A. N.; Charushin, V. N.; Chupakhin, O. N. Mendeleev Commun. 2002,
12, 27–28.
8. Krasnov, V. P.; Levit, G. L.; Bukrina, I. M.; Andreeva, I. N.; Sadretdinova, L. Sh.;
Korolyova, M. A.; Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N. Tetrahedron:
Asymmetry 2003, 14, 1985–1988.
9. Krasnov, V. P.; Levit, G. L.; Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N.
Tetrahedron: Asymmetry 2004, 15, 859–862.
10. Gruzdev, D. A.; Levit, G. L.; Krasnov, V. P.; Chulakov, E. N.; Sadretdinova, L. Sh.;
Grishakov, A. N.; Ezhikova, M. A.; Kodess, M. I.; Charushin, V. N. Tetrahedron:
Asymmetry 2010, 21, 936–942.
Found: C, 71.13; H, 5.43; N, 6.14. HPLC: de P99.9%
(s
12.13 min). 1H NMR (400 MHz; DMSO-d6, 100 °C): d 1.08 (3H, d, J
6.7, Me), 3.16 (1H, dd, J 14.1 and 5.6, HB-30), 3.64 (3H, s, OMe),
3.66 (1H, dd, J 14.1 and 10.2, HA-30), 4.06 (1H, dd, J 11.0 and 3.3,
HB-2), 4.18 (1H, dd, J 11.0 and 1.7, HA-2), 4.76 (1H, qdd, J 6.7, 3.2
and 1.7, H-3), 5.71 (1H, dd, J 10.2 and 5.6, H-20), 6.70 (2H, d, J
8.8, H-60), 6.90 (1H, dd, J 8.2 and 1.5, H-8), 6.93 (2H, d, J 8.8, H-
50), 6.98 (1H, ddd, J 8.1, 7.3 and 1.5, H-6), 7.12 (1H, ddd, J 8.2, 7.3
and 1.5, H-7), 7.72 (1H, dd, J 8.1 and 1.5, H-5), 7.82 (4H, s, H-300
and H-400). 13C NMR (125 MHz; DMSO-d6, 100 °C): d 14.54 (Me),
32.02 (C30), 45.30 (C3), 54.23 (C20), 54.56 (OMe), 69.44 (C2),
113.55 (C60), 116.21 (C8), 119.81 (C6), 122.56 (C300), 122.88 (C4a),
124.25 (C5), 125.77 (C7), 128.20 (C40), 128.96 (C50), 130.61
(C200a), 134.10 (C400), 146.05 (C8a), 157.77 (C70), 166.66 (C10),
167.27 (C200).
11. For reviews on aromatic interactions, see: (a) Hunter, C. A.; Sanders, J. K. M. J.
Am. Chem. Soc. 1990, 112, 5525–5534; (b) Hunter, C. A. Chem. Soc. Rev. 1994, 23,
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669.
12. (a) Smithrud, D. B.; Diederich, F. J. Am. Chem. Soc. 1990, 112, 339–343; (b)
Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42,
1210–1250.
Acknowledgements
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The work was financially supported by the Russian Foundation
for Basic Research (Grant 10-03-00084), the State Program for Sup-
porting of Leading Scientific Schools of the Russian Federation
(Grant NSh 65261.2010.3), the State Contract No. 02.522.12.2011
and by the Ural Division of RAS (Grants 09-P-3-2001 and 09-I-3-
2004). The authors thank the Ural Division of RAS for financial sup-
port for D.A.G. and E.N.C.
16. Effenberger, F.; Steegmüller, D.; Null, V.; Ziegler, T. Chem. Ber. 1988, 121, 125–
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´, K.; Thaller, V.; Filipovic´, L. Helv. Chim. Acta 1951, 34, 744–747.