Acylative kinetic resolution of racemic amines using N-phthaloyl-(S)-amino acyl chlorides

Article abstract of DOI:10.1016/j.tetasy.2010.05.013

A comparative study of the kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2,3-dihydro-3-methyl-4H-1,4-benzoxazine using N-phthaloyl-(S)-amino acyl chlorides as chiral acylating agents is described. Temperature and solvent effects on the stereochemical features have been examined. It has been found that N-phthaloyl-(S)-phenylalanyl and N-phthaloyl-(S)-2-phenylglycyl chlorides bearing aromatic substituents close to the stereogenic centre are more stereoselective acylating agents than N-phthaloyl-(S)-alanyl chloride. For the preparative kinetic resolution of racemic amines N-phthaloyl-(S)-phenylalanyl chloride proved to be the most appropriate chiral acylating agent.

Full text of DOI:10.1016/j.tetasy.2010.05.013

Tetrahedron: Asymmetry 21 (2010) 936–942
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Tetrahedron: Asymmetry
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Acylative kinetic resolution of racemic amines using N-phthaloyl-(S)-amino
acyl chlorides
*
Dmitry A. Gruzdev, Galina L. Levit , Victor P. Krasnov, Evgeny N. Chulakov, Liliya Sh. Sadretdinova,
Aleksandr N. Grishakov, 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:
A comparative study of the kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and
2,3-dihydro-3-methyl-4H-1,4-benzoxazine using N-phthaloyl-(S)-amino acyl chlorides as chiral acylating
agents is described. Temperature and solvent effects on the stereochemical features have been examined.
It has been found that N-phthaloyl-(S)-phenylalanyl and N-phthaloyl-(S)-2-phenylglycyl chlorides bear-
ing aromatic substituents close to the stereogenic centre are more stereoselective acylating agents than
N-phthaloyl-(S)-alanyl chloride. For the preparative kinetic resolution of racemic amines N-phthaloyl-(S)-
phenylalanyl chloride proved to be the most appropriate chiral acylating agent.
Received 9 April 2010
Accepted 10 May 2010
Available online 3 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
F
O
F
O
Preparation of chiral substances in enantiomerically pure form is
one ofthe main tasks of modernorganic synthesis. Kinetic resolution
is one of the oldest and most widely used approaches to obtain the
individual stereoisomers.1–3 In particular, acylative kinetic resolu-
tion has been applied for the synthesis of enantiopure amines. This
type of kinetic resolution includes both enzymatic4–7 and nonenzy-
matic processes in the presence of synthetic catalysts.8–10 Recently
the methods of kinetic resolution using enantiopure chiral acylating
agents have attracted considerable attention,11–15 most if not all of
the agents being chiral acyl-transfer agents. Our efforts have been
focused on the study of kinetic resolution processes of racemic
amines using low-molecular weight acylating agents, that is, chiral
acyl chlorides,16–20 which make it possible to obtain individual
enantiomers of heterocyclic amines in good-to-high yields. It should
be noted that the use of chiral acyl derivatives resulting in the forma-
tion of diastereoisomers provides an opportunity to enhance the
stereochemical purity of the acylation products by traditional
(non-stereospecific) methods. Derivatives of natural amino acids
are of considerable interest as chiral resolving agents since they
are easily accessible and inexpensive enantiomerically pure
compounds.
N
H
Me
N
Me
H
N
H
Me
O
1
2
(S)-3
Scheme 1. Racemic amines.
O
O
O
O
O
N
N
N
Cl
Cl
Cl
O
O
O
Me
6
4
5
Scheme 2. Chiral acylating agents.
interest as structural fragments of a number of biologically active
compounds.21–24 Moreover, amines 1 and 2 are close structural
analogues of 7,8-difluoro-2,3-dihydro-(3S)-methyl-4H-1,4-ben-
zoxazine (S)-3, the key intermediate in the synthesis of antibacte-
rial Levofloxacin.
To elucidate the effects of the structure of resolving agents and
the reaction conditions on the kinetic resolution efficiency we
studied the acylation of racemic amines 1 and 2 with N-phthaloyl
amino acyl chlorides 5 and 6 in comparison to acyl chloride 4.
Previously we reported the efficient kinetic resolution of
racemic 2-methyl-1,2,3,4-tetrahydroquinoline 1 and 2,3-dihydro-
3-methyl-4H-1,4-benzoxazine 2 (Scheme 1) using N-phthaloyl-
(S)-alanyl chloride 4 (Scheme 2) as a chiral acylating agent.20
Enantiomers of 2-methyl-1,2,3,4-tetrahydroquinoline are of
2. Results and discussion
Acyl chlorides 4–6 of >97% purity (according to 1H NMR spectra)
were prepared by the reaction of oxalyl chloride with the appropri-
* Corresponding author. Tel.: +7 343 362 3057; fax: +7 343 374 1189.
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.2010.05.013

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 21 (2010) 936–942
937
O
O
N
Cl
O
O
4-6
R
O
NH
1 equiv.
N
NH
Me
+
N
X
Me
(R)-1, 2
X
O
X
R
Me
2 equiv.
(S,S)-7: X = CH2, R = Me
(S,S )-8: X = O, R = Me
(S,S )-9: X = CH2, R = CH2Ph
(S,S )-10: X = O, R = CH2Ph
(S,S )-11: X = CH2, R = Ph
(S,S )-12: X = O, R = Ph
1: X = CH2
2: X = O
Scheme 3. Kinetic resolution of racemic amines 1 and 2 with chiral acylating agents 4–6.
ate N-phthaloyl amino acid in a hexanes/benzene solution in the
presence of catalytic amounts of DMF in 85–93% yields.20 Freshly
prepared acyl chlorides were used for further synthesis without
additional purification.
Acylation of 2 equiv of racemic amines 1 and 2 was carried out
with 1 equiv of acyl chlorides 4–6 in a variety of solvents at various
temperatures over 6 h (Scheme 3). The initial concentration of
racemic amine was 0.1 M. Diastereoisomeric amides 7–12 and
unreacted amines 1 and 2 were isolated from the reaction mixtures
and analyzed separately using HPLC to determine the de for amides
7–12 and the ee for amines 1–2 on a chiral stationary phase (Chi-
ralcel OD-H).
The ratio of diastereoisomers in amides 7–12 can be also deter-
mined using 1H NMR spectroscopy data. The most indicative sig-
nals which allow distinguishing the diastereoisomers are those of
the groups near the stereogenic centres both in the amine and in
the acyl moieties. The results obtained by 1H NMR spectroscopy
agreed with HPLC data. It should be noted that at ambient temper-
ature the signals of almost all the protons broadened considerably
both in DMSO-d6 and in CDCl3 solutions, whereas on heating the
sample solution in DMSO-d6 to 100 °C the signals became sharp.
The same phenomena were observed previously for other amides
containing the fragments of amines 1–3.16–18,20 The broadening
of the resonance signals is likely to be caused by the restricted
rotation about a partial double amide bond and by ring inversion.
Similar to the acylation of amines 1–2 with acyl chloride 4,20 ki-
netic resolution using compounds 5 and 6 resulted in the predom-
inant formation of (S,S)-amides 9–12, while unreacted amines
were enriched with the (R)-enantiomers (Scheme 3).
The major (S,S)-diastereoisomers of amides 9–12 were isolated
in enantiomerically pure form (de P97%) after kinetic resolution of
racemic amines 1 and 2 with acyl chlorides 5 and 6 in CH2Cl2 (or
CH3CN) at room temperature followed by crystallization of the
acylation products. Single crystal X-ray structure determinations
were performed for (S,S)-9–11 and unambiguously confirmed the
absolute configuration of the amine fragment taking into account
the known absolute configuration of N-phthaloyl amino acyl moi-
ety (Figs. 1–3).
Figure 1. X-ray structure of (S,S)-9.
unreacted substrates 1 and 2. Based on the data obtained we were
able to calculate the conversion (C, %) of the starting racemate
according to the equation: C = [eeamine/(eeamine + deamide)] ꢀ 100%
and the selectivity factor s = ln[(1 ꢁ C) ꢀ (1 ꢁ eeamine)]/ln[(1 ꢁ C) ꢀ
(1 + eeamine)].1 The results for the kinetic resolution of racemic
amines 1 and 2 acylated with acyl chlorides 4–6 at +20 °C in differ-
ent solvents are presented in Table 1.
The highest stereoselectivity in acylation of the racemic amine 1
with acyl chlorides 4 and 5 and the highest conversion of racemic
amine 1 were observed in CH2Cl2 and MeCN, selectivity factor
We managed to isolate the minor (R,S)-diastereoisomer from
the amide mixture by flash chromatography on silica gel only in
the case of amides 10. (R,S)-9 and (R,S)-11 were specially prepared
starting from (R)-118 in moderate yields (Scheme 4). Although
some data concerning the tendency of N-phthaloyl amino acids to-
wards racemization are available in the literature,25,26 we did not
observe that on using NEt3 as the base in the acylation of (R)-1 with
acyl chloride 5 and an excess of (R)-1 as a base in the case of acyl-
ation with compound 6 (Scheme 4).
We carried out 2–4 parallel experiments on the kinetic resolu-
tion of racemic amines 1 and 2 (Scheme 3) to determine the aver-
age values of de for the reaction products 7–12 and ee for
Figure 2. X-ray structure of (S,S)-10.

938
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 21 (2010) 936–942
chloride 6 was observed in less polar solvents, such as benzene and
toluene (Table 1, entries 10, 11 and 19), as compared with CH2Cl2
and MeCN (entries 12, 13 and 20).
The temperature effect on the stereochemical outcome of the
kinetic resolution with acyl chlorides 4–6 can be exemplified by
the acylation of racemic 1 in toluene and CH2Cl2 (Table 2).
It has been found that lowering the reaction temperature re-
sults in a marked increase in the selectivity of acylation of amine
1 with acyl chlorides 4 and 5. Thus, for example, in the case of acyl
chloride 5 in CH2Cl2 at +20 and ꢁ20 °C the selectivity factor s was
8.9 and 12, respectively (Table 2, entries 10 and 11). Conversion of
the starting racemate 1 tended to decrease with decrease in reac-
tion temperature only in toluene. In the case of kinetic resolution
with acyl chloride 6 the values of de and s almost did not vary with
temperature decrease in toluene (entries 12 and 13), but in CH2Cl2
we observed some increase in selectivity factor and de of (S,S)-
amide with decrease in reaction temperature (entries 14 and 15).
The results obtained point to the fact that acyl chlorides 5 and 6
bearing aromatic substituents close to the stereogenic centre are
more enantioselective in the acylation reactions than acyl chloride
4. Thus, acylation of racemic 1 with acyl chloride 5 in benzene at
+20 °C resulted in the formation of (S,S)-9 of de 61.9% at conversion
of the starting racemate C 42%, while acylation of amine 1 with acyl
chloride 4 under the same conditions resulted in (S,S)-7 of lower
diastereoisomeric excess (de(S,S)-7 47.1%) at C 40% (Table 1, entries
6 and 1, respectively). Acyl chloride 6 showed the highest selectiv-
ity among the studied resolving agents: selectivity factor s has at-
tained 22 when racemic amine 1 was acylated in toluene at +20 °C
(de(S,S)-11 89.1%) (Table 1, entry 11). However, in that case conver-
sion of the starting racemate C 18% was significantly lower than
that using acyl chlorides 4 and 5. Steric hindrances caused by phenyl
and phthalimide substituents located close to the stereogenic centre
in acyl chloride 6 are likely to complicate the acylation of heterocy-
clic amines 1 and 2 and at the same time they are responsible for the
highest stereoselectivity among the studied acyl chlorides. Proba-
bly, not only steric factors effect the enantiodiscrimination, but also
the aromatic interactions contribute to the process. Thus, in the
acylation of racemic amines 1 and 2 with acyl chlorides 5 and 6 bear-
ing aromatic fragments, values of the selectivity factor s were higher
as compared with acyl chloride 4.
Figure 3. X-ray structure of (S,S)-11.
O
O
5 (6), base
N
N
NH
Me
benzene, rt
O
R
Me
(R)-1
(R,S)-9: R = CH2Ph
(R,S)-11: R = Ph
Scheme 4. Synthesis of (R,S)-amides 9 and 11.
being 4.6, 8.0 and 8.9 (Table 1, entries 5, 8 and 9, respectively). In
benzene, toluene, p-xylene and Et2O, especially (entries 1–4, 6 and
7), the efficiency of the kinetic resolution was lower. Acylation of
racemic amine 2 with acyl chlorides 4 and 5 showed the same ten-
dencies (entries 14–18).
Unlike the kinetic resolution using acyl chlorides 4 and 5, the
highest selectivity in acylation of racemic amines 1 and 2 with acyl
Table 1
Results for the kinetic resolution of racemic amines 1 and 2 using acyl chlorides 4–6 (+20 °C, 6 h)
Entry
Racemic
amine
Resolving agent
Solvent
Diastereoisomeric
excess, de %
Enantiomeric excess,
Conversion, C %
Selectivity
factor, s
ee %b [(R)-amine]
a[(S,S)-amide]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
4 (R = Me)
4 (R = Me)
4 (R = Me)
4 (R = Me)
4 (R = Me)
5 (R = Bn)
5 (R = Bn)
5 (R = Bn)
5 (R = Bn)
6 (R = Ph)
6 (R = Ph)
6 (R = Ph)
6 (R = Ph)
4 (R = Me)
4 (R = Me)
5 (R = Bn)
5 (R = Bn)
5 (R = Bn)
6 (R = Ph)
6 (R = Ph)
Benzene
Toluene
p-Xylene
Et2O
CH2Cl2
Benzene
Toluene
CH2Cl2
MeCN
Benzene
Toluene
CH2Cl2
MeCN
Toluene
MeCN
47.1
38.3
36.1
6.9
30.9
22.0
15.6
3.9
37.2
44.9
33.3
56.9
56.1
15.8
20.3
25.6
6.7
20.3
33.1
37.5
48.0
48.7
26.3
20.6
40
36
30
36
41
42
40
46
47
15
18
24
8
32
40
43
45
45
24
20
3.7
2.8
2.5
1.2
4.6
6.5
4.1
8.9
8.0
21
53.1
61.9
48.8
67.1
64.8
89.5
89.1
80.0
80.5
42.6
49.3
50.6
59.2
59.8
83.7
81.5
9
10
11
12
13
14
15
16
17
18
19
20
22
12
9.8
3.0
4.0
4.3
6.2
6.3
15
Toluene
CH2Cl2
MeCN
Toluene
CH2Cl2
12
a
Determined by HPLC (see Section 4).
Determined by chiral HPLC (see Section 4).
b

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 21 (2010) 936–942
939
Table 2
Temperature effect on the kinetic resolution of (2RS)-methyl-1,2,3,4-tetrahydroquinoline 1 using acyl chlorides 4–6
Entry
Resolving agent
Solvent
Temperature (°C)
Diastereoisomeric
excess, de %a
[(S,S)-amide]
Enantiomeric
excess, ee %b
[(R)-amine]
Conversion, C %
Selectivity
factor, s
1
2
3
4
5
6
7
8
4 (R = Me)
4 (R = Me)
4 (R = Me)
4 (R = Me)
4 (R = Me)
4 (R = Me)
5 (R = Bn)
5 (R = Bn)
5 (R = Bn)
5 (R = Bn)
5 (R = Bn)
6 (R = Ph)
6 (R = Ph)
6 (R = Ph)
6 (R = Ph)
Toluene
Toluene
Toluene
Toluene
CH2Cl2
+20
0
38.3
49.0
51.3
68.4
53.1
63.3
48.8
58.4
68.9
67.1
74.4
89.1
91.9
80.0
89.6
22.0
23.7
17.8
7.2
36
33
26
10
41
40
40
39
32
46
45
18
12
24
15
2.8
3.7
3.7
5.8
4.6
6.6
4.1
5.4
7.6
8.9
12
ꢁ20
ꢁ40
+20
ꢁ20
+20
0
ꢁ20
+20
ꢁ20
+20
ꢁ20
+20
ꢁ20
37.2
41.5
33.3
36.7
33.3
56.9
60.4
20.3
12.5
25.6
16.2
CH2Cl2
Toluene
Toluene
Toluene
CH2Cl2
9
10
11
12
13
14
15
CH2Cl2
Toluene
Toluene
CH2Cl2
22
21
12
22
CH2Cl2
a
Determined by HPLC (see Section 4).
Determined by chiral HPLC (see Section 4).
b
From these experiments one can conclude that N-phthaloyl-(S)-
It has been found that N-phthaloyl-(S)-phenylalanyl
5 and
phenylalanyl chloride 5 is a better resolving agent for preparative
kinetic resolution than acyl chlorides 4 and 6 and the kinetic reso-
lution process should be carried out in CH2Cl2.
Acidic hydrolysis of individual (S,S)-amides 9–12 made it possi-
ble to obtain the (S)-enantiomers of amines 1 and 2 of high enan-
tiomeric excess in good yields, as described previously for (S,S)-7
and (S,S)-8.20 Thus, refluxing (S,S)-9 (de >99%) in a mixture of gla-
cial AcOH and concentrated HCl for 12 h resulted in enantiomeri-
cally pure (S)-1 (ee >99%) in 90% yield (Scheme 5). The overall
yield of (S)-1 from racemate was 23%.
N-phthaloyl-(S)-2-phenylglycyl chlorides bearing aromatic
6
substituents close to the chiral centre are more stereoselective
acylating agents as compared with N-phthaloyl-(S)-alanyl chloride
4. For the preparative kinetic resolution of racemic 1 and 2 acyl
chloride 5 proved to be the most appropriate chiral acylating agent.
4. Experimental
4.1. General
N-Phthaloyl-(S)-alanine, N-phthaloyl-(S)-phenylalanine and
N-phthaloyl-(S)-2-phenylglycine were obtained according to the
known procedure.27 (2RS)-2-Methyl-1,2,3,4-tetrahydroquinoline
1,28 (R)-118 and N-phthaloyl-(S)-alanyl chloride 420 were synthe-
sized as described previously. (3RS)-2,3-Dihydro-3-methyl-4H-
1,4-benzoxazine 2 was prepared by analogy with the procedure.29
The solvents were purified by standard methods. Melting points
were obtained using a SMP3 apparatus (Barloworld Scientific,
UK) and are uncorrected. Optical rotations were measured at a so-
dium D line with Perkin Elmer M 341 polarimeter. 1H and 13C NMR
spectra were recorded on a Bruker DRX-400 (400 and 100 MHz,
respectively) spectrometer with TMS as the internal reference. 1H
and 13C NMR spectra of amides 7–12 were recorded in DMSO-d6
at 100 °C, 1H NMR spectra of amines 1 and 2 and acid chlorides
4–6 were recorded in CDCl3 at ambient temperature. All the signals
in the 1H and 13C NMR spectra of (S,S)-9 and (R,S)-9 were assigned
on the basis of 2D 1H–1H COSY, 1H–13C HSQC and HMBC experi-
ments at 100 °C. Elemental analyses were performed on a Perkin
Elmer 2400 II instrument.
HPLC analyses of amides 7–10 and 12 were performed on
Merck-Hitachi chromatograph with L-4000A Intelligent Pump,
L-4000A UV Detector and D-2500A Chromato-Integrator using
ReproSil 100 Si column (250 ꢀ 4.6 mm) for amides 8, 9, 12 and
Finepak Sil column (250 ꢀ 4.6 mm) for amides 7 and 10; detection
at 220 nm, flow rate of 1 mL/min and hexanes/isopropanol as an
eluting solvent. HPLC analyses of amide 11 were performed on Agi-
lent 1100 chromatograph using Phenomenex Luna C18(2) column
(250 ꢀ 4.6 mm), detection at 230 nm, flow rate of 0.8 mL/min and
MeCN/water as an eluting solvent. HPLC analyses of amines 1 and 2
were performed on Knauer Smartline-1100 chromatograph using
Chiralcel OD-H column (250 ꢀ 4.6 mm), detection at 220 nm, flow
rate of 1 mL/min and hexanes/isopropanol 140:1 for 1 (s(R)-1 11.2
and s(S)-1 11.9 min) and 40:1 for 2 (s(R)-1 15.1 and s(S)-2 15.7 min)
as eluting solvents.
NH
Me
2 equiv.
(RS)-1
1. 5 (1 equiv.), CH2Cl2
2. Recrystallization
O
N
O
N
O
Me Ph
(S,S )-9 de >99%
1. HCl/AcOH, Δ
2. Na2CO3
NH
Me
(S)-1 ee >99%
Scheme 5. Preparation of (S)-1 via kinetic resolution of racemate.
The preparation of (S)-1 in enantiomerically pure form (ee >99%
according to chiral HPLC) as a result of kinetic resolution of its
racemate followed by acidic hydrolysis of (S,S)-9 showed no race-
mization of the resolving acylating agent and/or amine during
the chemical transformations.
3. Conclusion
In conclusion, the comparative study of the efficiency of kinetic
resolution of racemic amines 1 and 2 with N-phthaloyl-(S)-amino
acyl chlorides 4–6 as chiral acylating agents has been carried out.

940
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 21 (2010) 936–942
Crystallographic data for (S,S)-amides 9–11 have been deposited
(10 mL) at room temperature. After 6 h under stirring at room tem-
perature the reaction mixture was washed with 1 N HCl (5 mL),
water (3 ꢀ 5 mL), 5% NaHCO3 (5 mL) and water (2 ꢀ 5 mL). Organic
layer was separated, dried over MgSO4 and evaporated under re-
duced pressure. The residue was recrystallized from a ethyl ace-
tate/hexanes mixture to give (S,S)-amides 9 and 10.
with the Cambridge Crystallographic Data Centre (CCDC Nos.
770449–770451). Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.2. N-Phthaloyl-(S)-amino acid chlorides 4–6. General
procedure20
4.4.1. (2S)-2-Methyl-N-[N0-phthaloyl-(20S)-phenylalanyl]-1,2,3,4-
tetrahydroquinoline (S,S)-9
Oxalyl chloride (3.5 mL, 40 mmol) was added dropwise to a stir-
red solution of N-phthaloyl-(S)-amino acid (20 mmol) and DMF
(0.01 mL) in a benzene/hexanes 1:1 mixture (100 mL) at room
temperature. The reaction mixture was stirred at room tempera-
ture for 8 h, evaporated to dryness under reduced pressure. The
residue was treated with dry hexanes (20 mL) and the formed pre-
cipitate (in case of 4 and 5) was filtered off and dried in vacuo.
Colourless crystals (0.225 g, 53%): mp 186 °C. ½a D20
¼ þ364 (c
ꢂ
1.0, CHCl3). De = >99.9% (HPLC: ReproSil 100 Si, hexanes/isopropa-
nol 80:1;
s
11.5 min). 1H NMR (DMSO-d6, 100 °C): d 1.04 (d,
J = 6.5 Hz, 3H, CH3), 1.30 (dddd, J = 13.2, 10.6, 7.0 and 5.1 Hz, 1H,
C3HB-quin.), 2.36 (dddd, J = 13.2, 7.8, 5.4 and 4.9 Hz, 1H, C3HA-quin.),
2.49 (ddd, J = 15.1, 10.6 and 5.4 Hz, 1H, C4HB-quin.), 2.64 (dd, J = 14.2
and 4.2 Hz, 1H, C3HB-Phe), 2.68 (dt, J = 15.1 and 5.0 Hz, 1H, C4HA-
quin.), 3.71 (dd, J = 14.2 and 11.6 Hz, 1H, C3HA-Phe), 4.66 (ddq,
J = 7.8, 7.0 and 6.5 Hz, 1H, C2H-quin.), 5.77 (dd, J = 11.6 and 4.2 Hz,
1H, C2H-Phe), 6.70 (dd, J = 7.8 and 1.8 Hz, 2H, Ho), 7.08–6.99 (m,
3H, Hm + Hp), 7.28 (ddd, J = 7.5, 7.0 and 1.9 Hz, 1H, C6H-quin.),
7.32 (dd, J = 7.5 and 2.0 Hz, 1H, C5H-quin.), 7.40 (ddd, J = 7.8, 7.0
and 2.0 Hz, 1H, C7H-quin.), 7.54 (dd, J = 7.8 and 1.0 Hz, 1H, C8H-
quin.), 7.81 (m, 4H, Phth). 13C NMR (DMSO-d6, 100 °C): d 19.39
(CH3-quin.), 24.82 (C4-quin.), 31.35 (C3-Phe), 31.56 (C3-quin.),
4.2.1. N-Phthaloyl-(S)-alanyl chloride 420
Colourless crystals (4.4 g, 93%): mp 55 °C. 1H NMR (CDCl3): d
1.79 (d, J = 7.3 Hz, 3H, CH3), 5.17 (q, J = 7.3 Hz, 1H, C2H), 7.79 m
and 7.92 m (4H, Phth). Anal. Calcd for C11H8ClNO3: C, 56.00; H,
3.39; N, 5.89. Found: C, 55.70; H, 3.29; N, 5.94.
4.2.2. N-Phthaloyl-(S)-phenylalanyl chloride 5
Colourless crystals (5.46 g, 87%): mp 86 °C (lit.30 mp 83–84 °C).
1H NMR (CDCl3): d 3.55 (dd, J = 14.3 and 10.9 Hz, 1H, C3HB), 3.65
(dd, J = 14.3 and 5.2, 1H, C3HA), 5.33 (dd, J = 10.9 and 5.2 Hz, 1H,
C2H), 7.13–7.23 (m, 5H, Ph), 7.74 m and 7.83 m (4H, Phth). Anal.
Calcd for C17H12ClNO3: C, 65.08; H, 3.86; N, 4.46. Found: C,
65.10; H, 3.61; N, 4.42.
48.80 (C -quin.), 54.64 (C -Phe), 122.44 (C , C ), 124.68 (C -quin.),
2
2
3
6
8
0
0
125.84 (Cp), 125.86 (C6-quin.), 126.22 (C7-quin.), 127.42 (Co), 127.45
(C5-quin.), 127.61 (Cm), 130.63 (C2a0, C 0), 134.00 (C , C ), 135.48
6a
4
5
0
0
(C4a-quin.), 136.02 (C8a-quin.), 136.56 (Ci), 166.87 (CONH), 167.42
2
0
7
0
(C , C ). Anal. Calcd for C27H24N2O3: C, 76.39; H, 5.70; N, 6.60.
Found: C, 76.20; H, 5.77; N, 6.66.
4.2.3. N-Phthaloyl-(S)-2-phenylglycyl chloride 6
4.4.2. (3S)-2,3-Dihydro-3-methyl-N-[N0-phthaloyl-(20S)-
phenylalanyl]-4H-1,4-benzoxazine (S,S)-10
Yellow oil (5.10 g, 85%). 1H NMR (CDCl3): d 6.19 (s, 1H, C2H),
7.38–7.43 (m, 3H, Ph), 7.57 (m, 2H, Ph), 7.77 m and 7.90 m (4H,
Phth). Anal. Calcd for C16H10ClNO3: C, 64.12; H, 3.36; N, 4.67.
Found: C, 64.43; H, 3.30; N, 4.66.
Colourless crystals (0.111 g, 26%): mp 168 °C. ½a D20
¼ þ341 (c
ꢂ
1.0, CHCl3). De = 99.4% (HPLC: FinepakSil, hexanes/isopropanol
80:1;
s d 1.07 (d,
11.9 min). 1H NMR (DMSO-d6, 100 °C):
J = 6.8 Hz, 3H, CH3), 3.23 (dd, J = 14.0 and 5.6 Hz, 1H, C3HB-Phe),
3.73 (dd, J = 14.0 and 10.4 Hz, 1H, C3HA-Phe), 4.06 (dd, J = 11.0
and 3.2 Hz, 1H, C2HB-benz.), 4.18 (dd, J = 11.0 and 1.8 Hz, 1H,
C2HA-benz.), 4.76 (qdd, J = 6.8, 3.2 and 1.8 Hz, 1H, C3H-benz.),
5.76 (dd, J = 10.4 and 5.6 Hz, 1H, C2H-Phe), 6.90 (dd, J = 8.1 and
1.5 Hz, 1H, C8H-benz.), 6.97 (ddd, J = 8.1, 7.3 and 1.5, 1H, C6H-
benz.), 7.03 (d, J = 7.8 Hz, 2H, Ho), 7.03–7.16 (m, 4H, Hm, Hp,
C7H-benz.), 7.72 (dd, J = 8.1 and 1.5 Hz, 1H, C5H-benz.), 7.82 (s,
4H, Phth). 13C NMR (DMSO-d6, 100 °C): d 14.52, 32.85, 45.27,
53.95, 69.41, 116.19, 119.79, 122.54, 122.86, 124.21, 125.75,
126.05, 127.70, 127.92, 130.56, 134.09, 136.31, 146.02, 166.52,
167.18. Anal. Calcd for C26H22N2O4: C, 73.23; H, 5.20; N, 6.57.
Found: C, 72.84; H, 5.23; N, 6.50.
4.3. General procedure for kinetic resolution of racemic amines
1 and 2 with N-phthaloyl-(S)-alanyl chloride 4 was described
previously20
4.3.1. (2S)-2-Methyl-N-[N0-phthaloyl-(20S)-alanyl]-1,2,3,4-
tetrahydroquinoline (S,S)-720
Colourless crystals: mp 230–231 °C. ½a D20
¼ þ461 (c 1.45, ben-
ꢂ
zene). De = >99.9% (HPLC: FinepakSil, hexanes/isopropanol 80:1;
s
21.3 min). Elemental analysis and 1H NMR (DMSO-d6, 100 °C)
data are in good agreement with those published.20 13C NMR
(DMSO-d6, 100 °C): d 12.78, 19.32, 24.63, 31.43, 48.57, 48.66,
122.35, 124.49, 125.56, 126.13, 127.22, 131.07, 133.86, 134.97,
136.07, 168.76, 169.61.
4.5. General procedure for kinetic resolution of racemic amines
1 and 2 with N-phthaloyl-(S)-2-phenylglycyl chloride 6
4.3.2. (3S)-2,3-Dihydro-3-methyl-N-[N0-phthaloyl-(20S)-alanyl]-
4H-1,4-benzoxazine (S,S)-820
Colourless crystals: mp 204–206 °C. ½a D20
ꢂ
¼ þ331 (c 1.3, ben-
A solution of 6 (0.30 g, 1 mmol) in toluene (10 mL) was added to
a stirred solution of racemic amine 1 or 2 (2 mmol) in toluene
(10 mL) at room temperature. After 6 h under stirring at room tem-
perature the reaction mixture was washed with 1 N HCl (5 mL),
water (3 ꢀ 5 mL), 5% NaHCO3 (5 mL) and water (2 ꢀ 5 mL). Organic
layer was separated, dried over MgSO4 and evaporated under re-
duced pressure. The residue was recrystallized from a ethyl ace-
tate/hexanes mixture to give (S,S)-amides 11 and 12.
zene). De = 100% (HPLC: ReproSil 100 Si, hexanes/isopropanol
80:1;
s
13.9 min). Elemental analysis and 1H NMR (DMSO-d6,
100 °C) data are in good agreement with those published.20 13C
NMR (DMSO-d6, 100 °C): d 13.91, 14.64, 45.31, 48.41, 69.36,
116.02, 119.78, 122.44, 122.92, 124.18, 125.46, 130.98, 133.93,
145.84, 167.20, 167.92.
4.4. General procedure for kinetic resolution of racemic amines
1 and 2 with N-phthaloyl-(S)-phenylalanyl chloride 5
4.5.1. (2S)-2-Methyl-N-[N0-phthaloyl-(20S)-2-phenylglycyl]-
1,2,3,4-tetrahydroquinoline (S,S)-11
A solution of 5 (0.32 g, 1 mmol) in CH2Cl2 (10 mL) was added to
a stirred solution of racemic amine 1 or 2 (2 mmol) in CH2Cl2
Colourless crystals (0.123 g, 30%): mp 194–195 °C. ½a D20
¼ þ562
ꢂ
(c 1.0, CHCl3). De = 100% (HPLC: Phenomenex Luna C 18(2), MeCN/

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 21 (2010) 936–942
941
H2O 70:30;
s
13.6 min). 1H NMR (DMSO-d6, 100 °C): d 0.94 (d,
isomer. Colourless crystals (8 mg, 16%): mp 80–83 °C. ½a D20
ꢂ
¼ ꢁ337
J = 6.4 Hz, 3H, CH3), 1.26 (dddd, J = 13.0, 9.8, 6.7 and 5.5 Hz, 1H,
C3HB-quin.), 2.16 (ddd, J = 15.0, 9.8 and 5.5 Hz, 1H, C4HB-quin.),
2.30 (ddt, J = 13.0, 7.4 and 5.5 Hz, 1H, C3HA-quin.), 2.42 (dt, J = 15.0
and 5.5 Hz, 1H, C4HA-quin.), 4.64 (m, 1H, C2H-quin.), 6.60 (s, 1H,
C2H-Phg), 6.94 (d, J = 7.5 Hz, 1H, C5H-quin.), 7.02 (ddd, J = 7.5, 7.3
and 1.2 Hz, 1H, C6H-quin.), 7.11–7.22 (m, 6H, Ph, C7H-quin.), 7.49
(d, J = 7.9 Hz, 1H, C8H-quin.), 7.82 (m, 4H, Phth). 13C NMR (DMSO-
d6): d 19.98, 24.24, 31.19, 48.93, 56.53, 122.45, 124.77, 125.26,
125.68, 126.83, 126.93, 127.32, 129.25, 130.85, 131.87, 133.96,
134.68, 135.49, 166.04, 166.62. Anal. Calcd for C26H22N2O3: C,
76.08; H, 5.40; N, 6.82. Found: C, 75.76; H, 5.30; N, 6.73.
(c 0.22, CHCl3). De = 95% (HPLC: FinepakSil, hexanes/isopropanol
80:1;
s
9.2 min). 1H NMR (DMSO-d6, 100 °C): d 0.88 (d, J = 6.8 Hz,
3H, CH3), 3.29 (dd, J = 14.1 and 9.3 Hz, 1H, C3HB-Phe), 3.52 (dd,
J = 14.1 and 5.6 Hz, 1H, C3HA-Phe), 4.08 (dd, J = 10.9 and 2.1 Hz, 1H,
C2HB-benz.), 4.11 (dd, J = 10.9 and 3.1 Hz, 1H, C2HA-benz.), 4.54
(qdd, J = 6.8, 3.1 and 2.1 Hz, 1H, C3H-benz.), 5.60 (dd, J = 9.3 and
5.6 Hz, 1H, C2H-Phe), 6.60 (dd, J = 8.1 and 1.5 Hz, 1H, C8H-benz.),
6.72 (ddd, J = 8.0, 7.4 and 1.5 Hz, 1H, C6H-benz.), 6.83 (ddd, J = 8.1,
7.4 and 1.6, 1H, C7H-benz.), 7.08–7.16 (m, 5H, Ph), 7.43 (dd, J = 8.0
and 1.6 Hz, 1H, C5H-benz.), 7.66 (m, 2H, Phth), 7.73 (m, 2H, Phth).
Anal. Calcd for C26H22N2O4: C, 73.23; H, 5.20; N, 6.57. Found: C,
73.18; H, 5.28; N, 6.37.
4.5.2. (3S)-2,3-Dihydro-3-methyl-N-[N0-phthaloyl-(20S)-2-
phenylglycyl]-4H-1,4-benzoxazine (S,S)-12
4.6.3. (2R)-2-Methyl-N-[N0-phthaloyl-(20S)-2-phenylglycyl]-
1,2,3,4-tetrahydroquinoline (R,S)-11
Colourless crystals (0.177 g, 43%): mp 178 °C. ½a D20
¼ þ228 (c
ꢂ
1.0, CHCl3). De = 97% (HPLC: ReproSil 100 Si, hexanes/isopropanol
A solutionof 6 (136 mg, 0.45 mmol) in CH2Cl2 (4.5 mL)was added
to a solution of (R)-1, ee 91% (134 mg, 0.9 mmol) in CH2Cl2 (4.5 mL).
The reaction mixture was kept at +20 °C for 6 h, then washed with
1 N HCl (3 mL), brine (3 ꢀ 3 mL), 5% NaHCO3 (3 mL) and water
(2 ꢀ 3 mL). Organic layer was separated, dried over MgSO4 and
evaporated under reduced pressure. The residue was crystallized
from hexanes/ethyl acetate to give (R,S)-11 (110 mg, 59%). Colour-
80:1;
s d 0.72 (d,
11.5 min). 1H NMR (DMSO-d6, 100 °C):
J = 6.7 Hz, 3H, CH3), 4.13 and 4.14 (ABX system, JAB = 11.1 Hz,
JBX = 2.3 Hz, JAX = 1.8 Hz, 2H, C2H2-benz.), 4.60 (qm, J = 6.7 Hz, 1H,
C3H-benz.), 6.60 (s, 1H, C2H-Phg), 6.77 (dd, J = 8.1 and 1.5 Hz, 1H,
C8H-benz.), 6.87 (ddd, J = 8.2, 7.2 and 1.5 Hz, 1H, C6H-benz.), 7.00
(ddd, J = 8.1, 7.2 and 1.5, 1H, C7H-benz.), 7.27–7.31 (m, 3H, Hm
and Hp), 7.48 (dd, J = 7.7 and 1.8 Hz, 2H, Ho), 7.71 (dd, J = 8.2 and
1.5 Hz, 1H, C5H-benz.), 7.83 (m, 4H, Phth). 13C NMR (DMSO-d6): d
13.76, 45.85, 56.32, 69.29, 115.76, 119.49, 122.47, 122.53, 124.54,
125.29, 127.46, 127.78, 129.72, 130.80, 132.31, 134.05, 145.72,
165.33, 166.50. Anal. Calcd for C25H20N2O4: C, 72.80; H, 4.89; N,
6.79. Found: C, 72.75; H, 5.02; N, 6.51.
less crystals: mp 235–237 °C (decomp.). ½a D20
¼ ꢁ22:8 (c 0.19,
ꢂ
CHCl3). De = 98% (HPLC: Phenomenex Luna C 18(2), MeCN/H2O
70:30;
s d 1.05 (d,
10.7 min). 1H NMR (DMSO-d6, 100 °C):
J = 6.5 Hz, 3H, CH3), 1.26 (m, 1H, C3HB-quin.), 2.16 (m, 2H, C4HB-
quin), 2.30 (m, 1H, C3HA-quin.), 2.42 (m, 1H, C4HA-quin.), 4.64 (m,
1H, C2H-quin.), 6.31 (s, 1H, C2H-Phg), 6.84 (m, 1H, C5H-quin.), 7.02
(m, 1H, C6H-quin.), 7.29–7.42 (m, 6H, Ph and C7H-quin.), 7.49 (m,
1H, C8H-quin.), 7.73 (m, 2H, Phth), 7.79 (m, 2H, Phth). Anal. Calcd
for C26H22N2O3: C, 76.08; H, 5.40; N, 6.82. Found: C, 75.68; H, 5.53;
N, 6.88.
4.6. (R,S)-Amides 9–11
4.6.1. (2R)-2-Methyl-N-[N0-phthaloyl-(20S)-phenylalanyl]-
1,2,3,4-tetrahydroquinoline (R,S)-9
A solution of 5 (244 mg, 0.78 mmol) in CH2Cl2 (3 mL) was added
to a solution of (R)-1 (ee 98%; 115 mg, 0.78 mmol) and NEt3
4.7. General procedure for studying the kinetic resolution
(109
l
L, 0.78 mmol) in CH2Cl2 (4.8 mL). The reaction mixture was
To a solution of amine 1 or 2 (0.3 mmol) in an appropriate sol-
vent (1.5 mL) was added a solution of acyl chloride 4 (5 or 6)
(0.15 mmol) in the same solvent (1.5 mL) at specified temperature.
The reaction mixture was kept at the appropriate temperature for
6 h, then washed with 1 N HCl (3 mL), brine (3 ꢀ 3 mL), 5% NaHCO3
(3 mL) and water (2 ꢀ 3 mL). In case of MeCN, 1 N HCl (3 mL) was
added to the reaction mixture, then amides were extracted with
benzene (3 ꢀ 3 mL). Organic layer was separated, dried over
MgSO4 and evaporated under reduced pressure to give a mixture
of diastereoisomeric amides 7–12 which was analyzed by HPLC.
Acidic washing solutions were collected and then alkalized with
Na2CO3 up to pH 8–9, extracted with CHCl3 (3 ꢀ 2 mL). Organic
layers were separated, dried over MgSO4 and evaporated under re-
duced pressure to give unreacted amines 1–2 which were analyzed
by chiral HPLC.
kept at +20 °C for 6 h, then washed with 1 N HCl (3 mL), brine
(3 ꢀ 3 mL), 5% NaHCO3 (3 mL) and water (2 ꢀ 3 mL). Organic layer
was separated, dried over MgSO4 and evaporated under reduced
pressure. The residue was purified by flash silica gel chromatogra-
phy (eluent: hexanes/ethyl acetate) to give (R,S)-9 (125 mg, 38%) as
an amorphous solid. ½a D20
ꢂ
¼ ꢁ360 (c 0.8, CHCl3). De = 96% (HPLC:
ReproSil 100 Si, hexanes/isopropanol 80:1;
s
8.4 min). 1H NMR
(DMSO-d6, 100 °C): d 0.99 (d, J = 6.4 Hz, 3H, CH3), 1.13 (m, 1H,
C3HB-quin.), 2.16–2.35 (m, 3H, C4H2- and C3HA-quin.), 3.18 (dd,
J = 13.9 and 9.7 Hz, 1H, C3HB-Phe), 3.55 (dd, J = 13.9 and 5.4 Hz,
1H, C3HA-Phe), 4.58 (m, 1H, C2H-quin.), 5.49 (dd, J = 9.7 and
5.4 Hz, 1H, C2H-Phe), 6.68 (d, J = 7.4 Hz, 1H, C5H-quin.), 6.77 (dd,
J = 7.4 and 7.5 Hz, 1.0, 1H, C6H-quin.), 6.99 (dd, J = 7.5 and 7.6 Hz,
1H, C7H-quin.), 7.03–7.10 (m, 5H, Ph-Phe), 7.19 (d, J = 7.6 Hz, 1H,
C8H-quin.), 7.54 (m, 2H, Phth), 7.67 (m, 2H, Phth), 13C NMR
(DMSO-d6, 100 °C): d 19.30 (CH3-quin.), 24.15 (C4-quin.), 31.19
(C3-quin.), 35.07 (C3-Phe), 48.79 (C2-quin.), 52.18 (C2-Phe),
4.8. (2S)-2-Methyl-1,2,3,4-tetrahydroquinoline (S)-1
3
6
0
8
6
p
0
121.93 (C , C ), 124.13 (C -quin.), 124.52 (C -quin.), 125.62 (C ),
To a solution of (S,S)-9 (4.00 g, 9.42 mmol) in AcOH (40 mL) was
added concentrated HCl (40 mL). The reaction mixture was heated
at 110–115 °C for 12 h, then evaporated under reduced pressure.
Water (250 mL) was added to the residue, the precipitate formed
was filtered off. The filtrate was alkalized with Na2CO3 up to pH
8–9, extracted with benzene (3 ꢀ 50 mL). Organic layers were sep-
arated, dried over MgSO4 and evaporated under reduced pressure
126.22 (C5-quin.), 126.36 (C7-quin), 127.37 (Cm), 128.62 (Co),
130.10 (C2a0, C 0), 133.62 (C , C ), 133.68 (C4a-quin.), 135.82
6a
4
0
5
0
(C8a-quin.), 137.12 (C ), 165.32 (C , C ), 166.72 (CONH). Anal.
Calcd for C27H24N2O3: C, 76.39; H, 5.70; N, 6.60. Found: C, 75.95;
H, 5.47; N, 6.50.
i
2
7
0
0
4.6.2. (3R)-2,3-Dihydro-3-methyl-N-[N0-phthaloyl-(20S)-
phenylalanyl]-4H-1,4-benzoxazine (R,S)-10
to give (S)-1 (1.25 g, 90%) as a yellowish oil. ½a D20
¼ ꢁ85 (c 1.5, ben-
ꢂ
zene). {Lit.31: (R)-1 [
a]D = +85 (c 2, benzene)}. Ee >99.0%. (HPLC:
This diastereoisomer was obtained by flash silica gel chromatog-
Chiralcel OD-H, hexanes/isopropanol 100:1; s 11.64 min). Elemen-
raphy (eluent: benzene/ethyl acetate) of
a
diastereoisomeric
tal analysis and 1H NMR (CDCl3) data are in good agreement with
those published.20
mixture (S,S)-9/(R,S)-9 74:26 (195 mg) as a fast-eluting diastereo-

942
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 21 (2010) 936–942
15. Karnik, A.; Kamath, S. Tetrahedron: Asymmetry 2008, 19, 45–48.
Acknowledgements
16. 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.
17. Krasnov, V. P.; Levit, G. L.; Andreeva, I. N.; Grishakov, A. N.; Charushin, V. N.;
Chupakhin, O. N. Mendeleev Commun. 2002, 12, 27–28.
18. 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.
19. Krasnov, V. P.; Levit, G. L.; Korolyova, M. A.; Bukrina, I. M.; Sadretdinova, L. S.;
Andreeva, I. N.; Charushin, V. N.; Chupakhin, O. N. Russ. Chem. Bull. 2004, 53,
1253–1256.
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 Dr. Pavel Slepukhin for taking X-ray crys-
tallography analyses.
20. Krasnov, V. P.; Levit, G. L.; Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N.
Tetrahedron: Asymmetry. 2004, 15, 859–862.
21. Kmecz, I.; Simándi, B.; Bálint, J.; Székeli, E.; Fogassy, E.; Kemény, S. Chirality
2001, 13, 568–570.
22. Kumar, M. B.; Potter, D. W.; Hormann, R. E.; Edwards, A.; Tice, C. M.; Smith, H.
C.; Dipietro, M. A.; Polley, M.; Lawless, M.; Wolohan, P. R. N.; Kethidi, D. R.;
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23. Sikorski, J. A. J. Med. Chem. 2006, 49, 1–22.
24. Srinisawa, A.; Mahadevan, K. M.; Hulikal, V. Synth. Commun. 2009, 48, 93–101.
25. Liberek, B. Tetrahedron Lett. 1963, 4, 1103–1108.
26. Camps, P.; Perez, F.; Soldevilla, N.; Borrego, M. A. Tetrahedron: Asymmetry 1999,
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