Acylative kinetic resolution of racemic heterocyclic amines using N-phthaloyl-(S)-amino acyl chlorides with alkyl side chains

Article abstract of DOI:10.1016/j.tetasy.2012.11.001

A comparative study of the acylative kinetic resolution of racemic 2-methyl-1,2,3,4 tetrahydroquinoline and 3,4-dihydro-3-methyl-2H-[1,4] benzoxazine using N-phthaloyl-(S)-amino acyl chlorides with alkyl side chains has been carried out. The influence of steric factors on the stereoselectivity of the acylation was demonstrated. The (S)-enantiomers of the heterocyclic amines (ee >99%) were obtained in good yields via a kinetic resolution protocol using N-phthaloyl-(S)-leucyl chloride.

Full text of DOI:10.1016/j.tetasy.2012.11.001

Tetrahedron: Asymmetry 23 (2012) 1640–1646
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Acylative kinetic resolution of racemic heterocyclic amines using
N-phthaloyl-(S)-amino acyl chlorides with alkyl side chains
⇑
Dmitry A. Gruzdev, Galina L. Levit , Victor P. Krasnov
Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 22/20 S. Kovalevskoy/Akademicheskaya St., Ekaterinburg 620990, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 September 2012
Accepted 6 November 2012
A comparative study of the acylative kinetic resolution of racemic 2-methyl-1,2,3,4 tetrahydroquinoline
and 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine using N-phthaloyl-(S)-amino acyl chlorides with alkyl
side chains has been carried out. The influence of steric factors on the stereoselectivity of the acylation
was demonstrated. The (S)-enantiomers of the heterocyclic amines (ee >99%) were obtained in good
yields via a kinetic resolution protocol using N-phthaloyl-(S)-leucyl chloride.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Enantiomerically pure heterocyclic amines have attracted con-
siderable attention as the structural fragments of biologically ac-
tive compounds, including alkaloids,1 antibacterials,2 modulators
of various types of receptors3 and chiral ligands.4
To obtain enantiomerically pure amines, acylative kinetic reso-
lution (KR) is frequently applied.5 Different approaches to the ki-
netic resolution of racemic amines including the use of acylating
enzymes,6 synthetic chiral acyl-transfer catalysts7 and chiral acyl-
ating agents8 are under active investigation.
N-Phthaloyl amino acyl chlorides derived from natural and
unnatural (S)-amino acids such as valine 2b, tert-leucine 2c, leu-
cine 2d and 3-cyclohexylalanine 2e were studied as the resolving
agents in comparison with the previously described N-phthaloyl-
(S)-alanyl10b 2a and N-phthaloyl-(S)-phenylalanyl 2f chlorides10c
(Scheme 1).
O
Over the last few years, we have studied the diastereoselective
acylation of racemic heterocyclic amines with 2-arylpropionyl9
and N-protected amino acyl chlorides.10 In particular, we studied
the KR of 2-methyl-1,2,3,4-tetrahydroquinoline 1a and 3,4-dihy-
dro-3-methyl-2H-[1,4]benzoxazine 1b (Fig. 1) using N-phthaloyl-
(S)-amino acyl chlorides.10b–d It has been established that the
presence of aromatic substituents in the amino acid side chain con-
tributes to an increase in stereoselectivity.10c We also used N-
phthaloyl-(S)-phenylalanyl chloride and its structural analogues to
N
H
Me
1a
N
H
Me
1b
Figure 1. Substrates for kinetic resolution.
O
O
i)
H2N
PhthN
O
OH
OH
demonstrate the influence of aromatic p–p interactions on the ste-
73-90%
reochemical results of the KR.10d N-Phthaloyl-(S)-leucyl chloride
was applied as a chiral acylating agent in the stereo- and regio-di-
rected synthesis of 6-substituted derivatives of 2-methyl-1,2,3,4-
tetrahydroquinoline.10e
R
R
2a: R = Me,
2b
2c
PhthN
ii)
85-99%
: R = CH(Me)2
: R = C(Me)3
Cl
Herein we report the effect of the structure of the resolving
agent on the stereochemical result of acylation of heterocyclic
amines 1a and 1b.
R
2d: R = CH2CH(Me)2
2e
: R = CH2cHex
2f: R = CH2Ph
2a-f
Reagents and conditions:
i) Phthalic anhydride (1 equiv.), NEt3 (0.1 equiv.), toluene, Δ;
ii) (COCl)2, DMF (cat.), C6H6/hexane, rt
⇑
Corresponding author.
E-mail address: ca512@ios.uran.ru (G.L. Levit).
Scheme 1. Synthesis of chiral resolving agents 2a–f.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.001

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 23 (2012) 1640–1646
NPhth
1641
R
(S)-2a-f (0.5 equiv.)
(RS)-1a,b
+
N
O
(R)-1a,b
solvent,
+20 or -20 oC, 6 h
X
Me
(S,S)-3-14
3: X = CH2, R = Me
9: X = O, R = Me
10: X = O, R = i-Pr
11: X = O, R = t-Bu
4
5
6
7
: X = CH2, R = i-Pr
: X = CH2, R = t-Bu
12
13
14
: X = CH2, R = CH2i-Pr
: X = CH2, R = CH2cHex
: X = O, R = CH2i-Pr
: X = O, R = CH2cHex
Figure 3. Structure of amide (S,S)-12 (thermal ellipsoids of 50% probability).
8: X = CH2, R = CH2Ph
: X = O, R = CH2Ph
Scheme 2. KR of racemic amines 1a and 1b using acyl chlorides 2a–f.
phy taking into account the absolute (S)-configuration of the N-
phthaloyl amino acyl fragment. Figures 2 and 3 show the struc-
tures of amides (S,S)-7 and (S,S)-12.
After the acylative KR was completed, the reaction mixtures
were treated appropriately to determine the diastereoisomeric ex-
cess (de, %) of the amides formed (using HPLC and 1H NMR spec-
troscopy) and the enantiomeric excess (ee, %) of the unreacted
amines (chiral HPLC). Based on the de and ee values, the conver-
sion of the racemic substrate (C, %) and the selectivity factor (s)
was calculated according to Kagan’s equations:
N-Phthaloyl-(S)-amino acids were obtained according to the lit-
erature11 by heating amino acids with phthalic anhydride in tolu-
ene in the presence of NEt3. Acyl chlorides 2a–f were prepared by
the reaction of the appropriate acids with oxalyl chloride in the
presence of catalytic amounts of DMF (Scheme 1). Freshly prepared
acyl chlorides of >98% purity (according to 1H NMR spectra) were
used without further purification.
Acylation of amines 1a and 1b using acyl chlorides 2b–e with an
amine-acyl chloride molar ratio of 2:1 was carried out in toluene,
dichloromethane or acetonitrile at +20 or ꢀ20 °C for 6 h
(Scheme 2). The initial concentration of the racemic amine was
0.1 M. Similar to the acylation of amines 1a,b with N-phthaloyl-
(S)-amino acyl chlorides 2a and 2f,10b–d the reaction with acyl chlo-
rides 2b–e under the same conditions resulted in the predominant
formation of (S,S)-amides 4–7, 10–13; unreacted amines 1a or 1b
were enriched with the (R)-enantiomers (according to chiral
HPLC).
The major (S,S)-diastereoisomers of amides 4, 6, 7 and 12 were
isolated from the diastereoisomeric mixtures by recrystallisation;
(S,S)-amides 5, 10, 11 and 13 and the minor (R,S)-diastereoisomers
of amides 4, 5 and 10–13 were isolated by flash column chroma-
tography on silica gel. In order to obtain the diastereoisomers of
amides 5 and 11 we carried out the acylation of amines 1a and
1b with acyl chloride 2c bearing the bulky tert-butyl substituent
in toluene at +50 °C, since the reaction at +20 °C afforded amides
in low yields.
C ¼ ½eeamine=ðeeamine þ deamideÞꢁ ꢂ 100%;
s ¼ ln½ð1 ꢀ CÞ ꢂ ð1 ꢀ eeamineÞꢁ=ln½ð1 ꢀ CÞ ꢂ ð1 þ eeamineÞꢁ
5a
The results of the KR of racemic amines 1a and 1b with acyl
chlorides 2a–f in different solvents at +20 °C are presented in Ta-
ble 1. As can be seen from Table 1, acylation of racemic amines
1a and 1b with N-phthaloyl-(S)-amino acyl chlorides 2a–f pro-
ceeded more stereoselectively in dichloromethane or acetonitrile
than in toluene. N-Phthaloyl-(S)-leucyl chloride 2d and N-phthal-
oyl-3-cyclohexyl-(S)-alanyl chloride 2e (Table 1, entries 9–14,
25–30) were more selective reagents as compared to alanine 2a,
valine 2b or tert-leucine 2c derivatives. For example, in the acyla-
tion of racemic amines 1a and 1b with acyl chloride 2e the selec-
tivity factors s were 13 and 11, respectively.
The stereochemical results of the KR of racemic amines 1a and
1b in dichloromethane at ꢀ20 °C are presented in Table 2. As can
be seen, lowering the reaction temperature led in all the cases to
an increase in de of (S,S)-amides formed and selectivity factors,
although conversions decreased slightly. Thus, for the KR of amine
1a with acyl chloride 2e in CH2Cl2, the de of amide (S,S)-7 was
75.2% (C 45%, s 13) at +20 °C (Table 1, entry 13) and 83.7% (C
43%, s 21) at ꢀ20 °C (Table 2, entry 4).
The configurations of amides (S,S)-4, (S,S)-7, (R,S)-10, (S,S)-11
and (S,S)-12 were confirmed unambiguously by X-ray crystallogra-
A comparison of the results of the KR of racemic amines 1a and
1b with acyl chlorides 2a–e indicated that the stereoselectivity
was unaffected by the volume of the R substituent attached di-
rectly to the asymmetric carbon atom. Thus, the KR of amines
1a,b with acyl chlorides 2a (R = Me), 2b (R = i-Pr) and 2c (R = t-
Bu) occurred with almost the same selectivity. For example, the
selectivity factors s in the KR of racemic amine 1a carried out in
CH2Cl2 at +20 °C were 4.6, 5.1 and 5.7, respectively. At the same
time, the conversion of amine 1a when acylated with agent 2c (C
17%) was significantly lower compared with the acylation with
acyl chlorides 2a (C 41%) or 2b (C 46%). It should be noted that
the KR of amines 1a,b using N-phthaloyl-(S)-phenylglycyl chloride
also proceeded with low conversion.10c
Increasing the volume of the substituent close to the reaction
centre of acyl chlorides 2b (R = i-Pr) and 2c (R = t-Bu) seemed to
cause steric hindrances in the interaction of the reacting mole-
cules. In the case of acylating agents 2d (R = CH2i-Pr) and 2e
(R = CH2cHex), the branched alkyl chain separated from the
Figure 2. Structure of amide (S,S)-7 (thermal ellipsoids of 50% probability).

1642
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 23 (2012) 1640–1646
Table 1
Results of the kinetic resolution of racemic amines 1a and 1b via acylation with acyl chlorides 2a–f at +20 °Ca
Entry
Racemic amine
Resolving agent
Solvent
(S,S)-Amide, deb (%)
Unreacted (R)-amine, eec (%)
Conversion, C (%)
Selectivity factor, s
1
2
1a
1a
2a (R = Me)
2a (R = Me)
Toluene
CH2Cl2
38.3
53.1
22.0
37.2
36
41
2.810c
4.610c
3
4
5
1a
1a
1a
2b (R = i-Pr)
2b (R = i-Pr)
2b (R = i-Pr)
Toluene
CH2Cl2
MeCN
37.9
52.8
55.8
22.2
46.0
53.1
37
46
49
2.7
5.1
5.9
6
7
8
1a
1a
1a
2c (R = t-Bu)
2c (R = t-Bu)
2c (R = t-Bu)
Toluene
CH2Cl2
MeCN
55.9
66.7
70.5
4.0
13.9
18.4
7
17
21
3.7
5.7
6.9
9
10
11
1a
1a
1a
2d (R = CH2i-Pr)
2d (R = CH2i-Pr)
2d (R = CH2i-Pr)
Toluene
CH2Cl2
MeCN
64.1
76.0
76.0
43.0
60.4
59.6
40
44
44
6.9
13
13
12
13
14
1a
1a
1a
2e (R = CH2cHex)
2e (R = CH2cHex)
2e (R = CH2cHex)
Toluene
CH2Cl2
MeCN
60.5
75.2
67.9
36.9
60.5
59.4
38
45
47
5.8
13
9.4
15
16
17
1a
1a
1a
2f (R = CH2Ph)
2f (R = CH2Ph)
2f (R = CH2Ph)
Toluene
CH2Cl2
MeCN
48.8
67.1
64.8
33.3
56.9
56.1
40
46
47
4.110c
8.910c
8.010c
18
19
1b
1b
2a (R = Me)
2a (R = Me)
Toluene
CH2Cl2
42.6
49.3
20.3
33.1
32
40
3.010c
4.010c
20
21
22
1b
1b
1b
2b (R = i-Pr)
2b (R = i-Pr)
2b (R = i-Pr)
Toluene
CH2Cl2
MeCN
49.1
55.6
63.9
16.0
32.4
39.9
25
37
38
3.4
4.7
6.7
23
24
1b
1b
2c (R = t-Bu)
2c (R = t-Bu)
CH2Cl2
MeCN
56.6
72.3
6.6
9.1
10
11
3.8
6.8
25
26
27
1b
1b
1b
2d (R = CH2i-Pr)
2d (R = CH2i-Pr)
2d (R = CH2i-Pr)
Toluene
CH2Cl2
MeCN
63.6
69.5
68.5
45.6
59.1
58.7
42
46
46
6.9
9.9
9.5
28
29
30
1b
1b
1b
2e (R = CH2cHex)
2e (R = CH2cHex)
2e (R = CH2cHex)
Toluene
CH2Cl2
MeCN
56.3
71.1
67.7
40.6
59.3
57.4
42
46
46
5.3
11
9.1
31
32
33
1b
1b
1b
2f (R = CH2Ph)
2f (R = CH2Ph)
2f (R = CH2Ph)
Toluene
CH2Cl2
MeCN
50.6
59.2
59.8
37.5
48.0
48.7
43
45
45
4.310c
6.210c
6.310c
a
b
c
Average values for 2–4 parallel runs are presented.
Determined by HPLC (Reprosil 100Si, see Section 4).
Determined by chiral HPLC (Chiralcel OD-H, see Section 4).
Table 2
Results of the kinetic resolution of racemic amines 1a and 1b using acyl chlorides 2a, b, d–f in CH2Cl2 at ꢀ20 °Ca
Entry
Racemic amine
Resolving agent
(S,S)-Amide, deb (%)
Unreacted (R)-amine, eec (%)
Conversion, C (%)
Selectivity factor, s
1
2
3
4
5
1a
1a
1a
1a
1a
2a (R = Me)
2b (R = i-Pr)
2d (R = CH2i-Pr)
2e (R = CH2cHex)
2f (R = CH2Ph)
63.3
72.1
80.2
83.7
74.4
41.5
27.2
64.7
62.3
60.4
40
27
44
43
45
6.610c
8.0
1910e
21
1210c
6
7
1b
1b
2d (R = CH2i-Pr)
2e (R = CH2cHex)
77.6
74.8
56.5
49.8
42
40
14
11
a
b
c
Average values for 2–4 parallel runs are presented.
Determined by HPLC (Reprosil 100Si, see Section 4).
Determined by chiral HPLC (Chiralcel OD-H, see Section 4).
asymmetric carbon by an additional methylene group causes less
steric hindrance for the reaction and at the same time enhances
the stereochemical differentiation.
in compound 2f causes less steric hindrance than the bulkier, con-
formationally labile, cyclohexyl fragment of reagent 2e.
Thus, we established that the KR of heterocyclic amines via
acylation with N-phthaloyl-(S)-amino acyl chlorides bearing
branched alkyl side chains can proceed with higher stereoselectiv-
ity than the KR using amino acyl chlorides with aromatic substitu-
ents in the backbone. This allowed us to conclude that both steric
factors and aromatic interactions make an equally important con-
tribution to the stereoselectivity of the acylation.
N-Phthaloyl-(S)-leucyl chloride 2d, the most efficient of the
resolving agents studied, was used to obtain enantiopure amines
(S)-1a and (S)-1b from racemates (Scheme 3). KR in dichlorometh-
N-Phthaloyl-3-cyclohexyl-(S)-alanyl chloride 2e (R = CH2cHex)
turned out to be a more stereoselective acylating agent than N-
phthaloyl-(S)-phenylalanyl chloride 2f (R = CH2Ph): for the KR of
amine 1a in CH2Cl2 at +20 °C, s values of 13 and 8.9, respectively
(Table 1, entries 13 and 16). When the KR was carried out at
ꢀ20 °C, the difference in selectivity was more significant (s 21
and 12, respectively) (Table 2, entries 4 and 5). In the acylation
of amine 1b the same regularities were observed (Table 2, entries
6 and 7). This is probably because the planar phenyl substituent

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 23 (2012) 1640–1646
Me Me
1643
NPhth
O
i), ii)
iii)
NH
NH
X
N
X
Me
X
Me
Me
de >99%
ee >99%
(S)-1a,b
1a,b
1a
: X = CH2
1b: X = O
(S,S)-6: X = CH2, 55%
(S,S)-12: X = O, 54%
Reagents and conditions: i) 2d (0.5 equiv.), CH2Cl2, -20 oC, 6 h;
ii) recrystallisation; iii) HCl, AcOH, 90 oC, 15 h
Scheme 3. Preparation of enantiopure amines (S)-1a,b from racemates via KR protocol using acyl chloride 2d.
ane at ꢀ20 °C followed by recrystallisation of the acylation prod-
ucts led to the diastereoisomerically pure amides (S,S)-6 and
(S,S)-12 (de >99%, according to HPLC) in 55% and 54% yields,
respectively. Acidic hydrolysis of (S,S)-amides readily afforded
enantiopure amines (S)-1a and (S)-1b (ee >99%, according to chiral
HPLC) in 25% and 23% total yields relative to the starting
racemates.
side chains separated from stereogenic centre by a methylene
group were found to be more selective acylating agents in the ki-
netic resolution of the racemic amines studied. Enantio pure (S)-
2-methyl-1,2,3,4-tetrahydroquinoline
and
(S)-3,4-dihydro-3-
methyl-2H-[1,4]benzoxazine were obtained in good yields via ki-
netic resolution of racemates using N-phthaloyl-(S)-leucyl chloride.
It should be noted that the problem of racemisation of the chiral
acylating agent in the course of KR is very important. It is known
that acyl chlorides and other derivatives of N-phthaloyl amino
acids are prone to racemisation,12 especially in the presence of var-
ious highly basic and highly nucleophilic tertiary amines, which
take place through ketene formation.13 Acyl ammonium salts of
N-phthaloyl amino acids and DMAP are also prone to racemisation
in the presence of DCC.14
In our case, we carried out the acylation of amines 1a and 1b with
N-phthaloyl amino acyl chlorides without the use of auxiliary bases.
Obtaining the enantiopure amines (S)-1a or (S)-1b as a result of the
KR of racemates under the action of N-phthaloyl-(S)-leucyl chloride
2d indicates the absence of racemization both at the acylation step
and at the stage of subsequent acidic hydrolysis of amides. Previ-
ously we have shown that the loss of enantiomeric activity does
not occur during the synthesis of amines (S)-1a or (S)-1b via KR with
N-phthaloyl-(S)-alanyl chloride 2a10b and N-phthaloyl-(S)-phenyl-
alanyl chloride 2f10c followed by acidic hydrolysis.
Herein we required additional experimental confirmation of the
absence of epimerisation of the acyl moiety in the amides formed.
To do this, we carried out the acylation of enantiopure amine (S)-
1b (1 equiv, 97% ee) with N-phthaloyl-(S)-tert-leucine 2c (0.5 equiv)
in CH2Cl2 at +20 °C. Analysis of the reaction mixture by HPLC on sil-
ica gel showed the presence of only one of the amides, (S,S)-11
which was isolated in diastereoisomerically pure form (97% de) in
75% yield relative to the starting acyl chloride.
4. Experimental
4.1. General
(RS)-2-Methyl-1,2,3,4-tetrahydroquinoline 1a,15 (RS)-3,4-dihy-
dro-3-methyl-2H-[1,4]benzoxazine 1b,16 N-phthaloyl-(S)-alanyl
chloride 2a,10b N-phthaloyl-(S)-leucyl chloride 2d10e and N-phthal-
oyl-(S)-phenylalanyl chloride 2f10c were synthesised according to
the literature. Other reagents were commercially available. Amides
3, 6, 8, 9 and 14 were obtained as previously described.10b,10c,10e
The solvents were dried according to standard methods17 and used
freshly prepared. Flash column chromatography was performed
using Silica gel 60 (230–400 mesh) (Alfa Aesar, UK). Melting points
were obtained on a SMP3 apparatus (Barloworld Scientific, UK) and
are uncorrected. Optical rotations were measured on a Perkin El-
mer M341 polarimeter. The 1H NMR spectra were recorded on a
Bruker DRX-400 (400 MHz) spectrometer with TMS as an internal
reference. The 1H NMR spectra of amides were recorded in DMSO
at 100 °C; the 1H NMR spectra of all other compounds were re-
corded in CDCl3 at ambient temperature. Elemental analysis was
performed using Perkin Elmer 2400 II or EuroVector EA3000 ana-
lysers. Analytical HPLC was performed on a Knauer Smartline-
1100 instrument using a ReproSil 100 Si column (250 ꢂ 4.6 mm,
5 lm) for amides 3–14, detection at 220 nm, 1 mL/min flow rate,
n-hexane–i-PrOH mixtures as eluting solvents; and a Chiralcel
OD-H column (250 ꢂ 4.6 mm) for amines 1a and 1b, detection at
220 nm, 1 mL/min flow rate, n-hexane–i-PrOH–MeOH mixtures
as eluting solvents. The HRMS spectra were registered on 1200
Infinity (Agilent Technologies) instrument using 6540 Accurate-
Mass Q-TOF (Agilent Technologies) detector operating in positive
ion mode with ESI probe installed at N2 flow rate 10 L/min, nebu-
lizer pressure 40 psi. The probe voltage was set to 3.5 kV.
Crystallographic data for (S,S)-4, (S,S)-7, (R,S)-10, (S,S)-11 and
(S,S)-12 have been deposited with the Cambridge Crystallographic
Data Centre (CCDC Nos. 894452–894456). 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].
3. Conclusion
We have shown that the diastereoselectivity of the acylation of
racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 3,4-dihydro-3-
methyl-2H-[1,4]benzoxazine with N-phthaloyl-(S)-amino acyl
chlorides significantly depends on steric factors and not just aro-
matic interactions. It has been found that the steric hindrance
caused by the bulky substituents attached to the stereogenic centre
of the acylating agent hinders the reaction without increasing the
stereoselectivity. At the same time, N-phthaloyl-(S)-leucyl and N-
phthaloyl-3-cyclohexyl-(S)-alanyl chlorides with branched alkyl

1644
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 23 (2012) 1640–1646
4.2. N-Phthaloyl-(S)-amino acyl chlorides 2b, c, e. General
procedure
4.3.2. (2R)-2-Methyl-1-[N-phthaloyl-(S)-valyl]-1,2,3,4-tetra-
hydroquinoline (R,S)-4
Colourless crystals (80 mg, 21% after flash column chromatogra-
phy of the mother liquor after recrystallization, fast eluting isomer):
Oxalyl chloride (1.15 mL, 13.2 mmol) and DMF (5 lL) were
added to a suspension of N-phthaloyl-(S)-amino acid (6 mmol) in
a hexane–C6H6 1:1 mixture (30 mL). The reaction mixture was stir-
red at ambient temperature for 5–7 h and then evaporated under
reduced pressure. The residue was treated with hexane (40 mL)
and the precipitate formed was filtered off and dried in vacuo over
P2O5.
mp 99–101 °C. ½a 2D0
ꢁ
¼ ꢀ241 (c 0.7, CHCl3). De >99.0% (ReproSil 100
Si, hexane–i-PrOH 80:1,
s
6.67 min). 1H NMR (400 MHz, DMSO-d6,
100 °C): d 0.77 (3H, d, J 6.9 Hz, Me); 0.98 (3H, d, J 6.5 Hz, Me);
1.06 (3H, d, J 6.7 Hz, Me); 1.08–1.16 (1H, m, H-3B); 2.11ꢀ2.30
(3H, m, C4H2 and H-3A); 2.70 (1H, m, H-30); 4.56 (1H, dqd, J 6.8,
6.7, 6.5 Hz, H-2); 4.95 (1H, d, J 7.2 Hz, H-20); 6.65 (1H, d, J 7.4 Hz,
H-5); 6.79 (1H, ddd, J 7.5, 7.4, 0.9 Hz, H-6); 7.03 (1H, m, H-7);
7.19 (1H, d, J 8.0 Hz, H-8); 7.60–7.65 (2H, m, Phth); 7.70–7.75
(2H, m, Phth). Anal. calcd for C23H24N2O3 (376.46): C, 73.38; H,
6.43; N, 7.44; found: C, 73.20; H, 6.44; N, 7.56.
4.2.1. N-Phthaloyl-(S)-valyl chloride 2b
Colourless solid (1.36 g, 85%): mp 122–123 °C (hexane) (lit.
120–121 °C18a; 121–122 °C18b). ½a 2D5
ꢁ
¼ ꢀ100 (c 1.0, C6H6) {lit.18b
½
a D
ꢁ
¼ ꢀ101 (c 1.5, C6H6)}. 1H NMR (400 MHz, CDCl3): d 0.92 (3H,
d, J 6.8 Hz, Me-3B); 1.17 (3H, d, J 6.8 Hz, Me-3A); 2.76 (1H, dsept,
J 8.4, 6.8 Hz, H-3); 4.75 (1H, d, J 8.4 Hz, H-2); 7.81 (2H, m, Phth);
7.94 (2H, m, Phth). Anal. calcd for C13H12ClNO3 (265.70): C,
58.77; H, 4.55; N, 5.27; Cl, 13.34; found: C, 59.05; H, 4.38; N,
5.25; Cl, 13.06.
4.3.3. (2S)-2-Methyl-1-[N-phthaloyl-(S)-tert-leucyl]-1,2,3,4-tet-
rahydroquinoline (S,S)-5
Colourless powder (117 mg, 30% after flash column chromatog-
raphy, slow eluting isomer): mp 59–60 °C. ½a D20
¼ þ252 (c 0.9,
ꢁ
CHCl3). De 99.2% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
7.72 min). 1H NMR (400 MHz, DMSO-d6, 100 °C): d 0.99 (3H, d, J
6.5 Hz, Me-2); 1.00 (9H, s, t-Bu); 1.31 (1H, dddd, J 13.2, 9.1, 6.0,
5.8 Hz, H-3B); 2.10 (1H, m, H-3A); 2.39 (1H, ddd, J 15.3, 9.1,
6.2 Hz, H-4B); 2.62 (1H, ddd, J 15.3, 5.8, 5.8 Hz, H-4A); 4.51 (1H,
dqd, J 6.6, 6.5, 6.2 Hz, H-2); 5.06 (1H, s, H-20); 7.14 (3H, m, H-5,
H-6 and H-7); 7.35 (1H, m, H-8); 7.88 (4H, m, Phth). HRMS for
4.2.2. N-Phthaloyl-(S)-tert-leucyl chloride 2c
Colourless solid (1.66 g, 99%): mp 90.6 °C (hexane).
½
a 2D5
ꢁ
¼ ꢀ86:0 (c 1.2, C6H6). 1H NMR (400 MHz, CDCl3): d 1.15 (9H,
s, t-Bu); 4.78 (1H, s, H-2); 7.81 (2H, m, Phth); 7.95 (2H, m, Phth).
Anal. calcd for C14H14ClNO3 (279.72): C, 60.12; H, 5.04; N, 5.01;
Cl, 12.67; found: C, 60.22; H, 5.01; N, 5.12; Cl, 12.72.
C
24H27N2O3 (M+H+), calcd 391.2016, found 391.2019.
4.2.3. N-Phthaloyl-3-cyclohexyl-(S)-alanyl chloride 2e
4.3.4. (2R)-2-Methyl-1-[N-phthaloyl-(S)-tert-leucyl]-1,2,3,4-tet-
rahydroquinoline (R,S)-5
Colourless solid (1.78 g, 93%): mp 84 °C (hexane). ½a D20
¼ ꢀ73:9
ꢁ
(c 1.2, C6H6). 1H NMR (400 MHz, CDCl3): d 0.96 (2H, m, cHex);
1.16 (4H, m, cHex); 1.67 (4H, m, cHex); 1.86 (1H, m, cHex); 2.11
(1H, ddd, J 14.5, 9.8, 4.4 Hz, H-3B); 2.31 (1H, ddd, J 14.5, 10.9,
4.0 Hz, H-3A); 5.16 (1H, dd, J 10.9, 4.4 Hz, H-2); 7.80 (2H, m, Phth);
7.93 (2H, m, Phth). Anal. calcd for C17H18ClNO3 (319.79): C, 63.85;
H, 5.67; N, 4.38; Cl, 11.09; found: C, 63.96; H, 5.74; N, 4.38; Cl,
11.11.
Colourless powder (78 mg, 20% after flash column chromatogra-
phy, fast eluting isomer): mp 116–121 °C. ½a D20
¼ ꢀ219 (c 0.5,
ꢁ
CHCl3). De 98.8% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
4.95 min). 1H NMR (400 MHz, DMSO-d6, 100 °C): d 0.95 (3H, d, J
6.4 Hz, Me-2); 1.03 (1H, m, H-3B); 1.11 (9H, s, t-Bu); 2.08 (1H, m,
H-3A); 2.21 (2H, m, C4H2); 4.51 (1H, m, H-2); 4.95 (1H, s, H-20);
6.58 (1H, d, J 7.5 Hz, H-5); 6.79 (1H, ddd, J 7.6, 7.5, 0.9 Hz, H-6);
7.04 (1H, ddd, J 7.9, 7.6, 0.5 Hz, H-7); 7.18 (1H, d, J 7.9 Hz, H-8);
7.60–7.64 (2H, m, Phth); 7.71–7.75 (2H, m, Phth). HRMS for
4.3. Diastereoisomeric amides 4, 5, 7, 10–13. General procedure
C
24H27N2O3 (M+H+), calcd 391.2016, found 391.2014.
A solution of the appropriate acyl chloride (1 mmol) in CH2Cl2
(10 mL) was added to a solution of amine 1a or 1b (2 mmol) in
CH2Cl2 (10 mL) at +20 °C (in the case of acyl chloride 2c, the reac-
tions were carried out in toluene at +50 °C). The reaction mixture
was kept in a thermostat at a given temperature for 6 h, then suc-
cessively washed with 1 M HCl (2 ꢂ 5 mL), saturated aqueous NaCl
(3 ꢂ 15 mL), 5% NaHCO3 (10 mL) and water (2 ꢂ 15 mL). The or-
ganic layer was separated, dried over MgSO4 and evaporated under
reduced pressure. The diastereoisomers of amides 4, 5, 7 and 10–
13 were isolated by recrystallisation or flash column chromatogra-
phy on silica gel (eluent benzene–ethyl acetate).
4.3.5. (2S)-2-Methyl-1-[N-phthaloyl-3-cyclohexyl-(S)-alanyl]-
1,2,3,4-tetrahydroquinoline (S,S)-7
Colourless crystals (162 mg, 38%): mp 184–184.5 °C (hexane–
EtOAc). ½a 2D0
ꢁ
¼ þ416 (c 1.0, CHCl3). De 99.2% (ReproSil 100 Si, hex-
ane–i-PrOH 160:1,
s
14.60 min). 1H NMR (DMSO-d6, 100 °C,
400 MHz): d 0.18–0.25 (1H, m, cHex); 0.62–0.70 (1H, m, cHex);
0.87–0.96 (2H, m, cHex); 0.96–1.05 (2H, m, cHex); 1.01 (3H, d, J
6.5 Hz, Me-2); 1.21–1.45 (6H, m, 5H-cHex and H-3B); 2.36 (1H,
ddd, J 13.0, 8.1, 5.0, 4.9 Hz, H-3A); 2.42–2.51 (3H, overlapped by
0
DMSO, m, C3 H2 and H-4B); 2.69 (1H, ddd, J 14.8, 4.7, 4.7 Hz, H-
4A); 4.58 (1H, m, H-2); 5.56 (1H, dd, J 11.9, 3.4 Hz, H-20); 7.25
(1H, ddd, J 7.5, 7.4, 0.8 Hz, H-6); 7.30–7.35 (2H, m, H-5, H-7);
7.47 (1H, d, J 7.8 Hz, H-8); 7.86 (4H, m, Phth). Anal. calcd for
4.3.1. (2S)-2-Methyl-1-[N-phthaloyl-(S)-valyl]-1,2,3,4-tetra-
hydroquinoline (S,S)-4
Colourless crystals (118 mg, 31%): mp 185–186 °C (hexane–
C27H30N2O3 (430.55): C, 75.32; H, 7.02; N, 6.51; found: C, 75.43;
H, 7.16; N, 6.54.
EtOAc). ½a 2D0
ꢁ
¼ þ406 (c 1.0, CHCl3). De >99.8% (ReproSil 100 Si, hex-
ane–i-PrOH 80:1,
s
10.30 min). 1H NMR (400 MHz, DMSO-d6,
100 °C): d 0.79 (3H, d, J 7.4 Hz, Me-30); 0.81 (3H, d, J 7.4 Hz, Me-
30); 1.02 (3H, d, J 6.3 Hz, Me-2); 1.35 (1H, dddd, J 13.2, 9.2, 6.1,
5.9 Hz, H-3B); 2.23 (1H, m, H-3A); 2.44–2.51 (1H, overlapped by
DMSO, m, H-4B); 2.66 (1H, ddd, J = 15.4, 6.0, 5.9 Hz, H-4A); 2.82–
2.95 (overlapped by water signal, 1H, m, H-30); 4.69 (1H, m, H-
2); 5.11 (1H, d, J 9.3 Hz, H-20); 7.14–7.26 (3H, m, H-5, H-6 and H-
7); 7.62 (1H, d, J 7.8 Hz, H-8); 7.83–7.89 (4H, m, Phth). Anal. calcd
for C23H24N2O3 (376.46): C, 73.38; H, 6.43; N, 7.44; found: C, 73.35;
H, 6.46; N, 7.15.
4.3.6. (3S)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-valyl]-2H-
[1,4]benzoxazine (S,S)-10
Colourless powder (217 mg, 48% after flash column chromatog-
raphy, slow eluting isomer): mp 161 °C. ½a D20
ꢁ
¼ þ163 (c 1.0, CHCl3).
De 99.4% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
10.58 min). 1H
NMR (400 MHz, DMSO-d6, 100 °C): d 0.90 (3H, d, J 6.6 Hz, Me);
0.96 (3H, d, J 6.7 Hz, Me); 1.17 (3H, d, J 6.7 Hz, Me-3); 3.11 (1H,
dsept, J 10.0, 6.7 Hz, H-30); 4.05 (1H, dd, J 11.0, 3.1 Hz, H-2B);
4.19 (1H, dd, J 11.0, 1.8 Hz, H-2A); 4.82 (1H, qdd, J 6.7, 3.1,

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 23 (2012) 1640–1646
1645
1.8 Hz, H-3); 5.03 (1H, d, J 10.1 Hz, H-20); 6.87 (1H, dd, J 8.1, 1.4 Hz,
H-8); 6.90 (1H, ddd, J 8.4, 7.4, 1.4 Hz, H-6); 7.06 (1H, ddd, J 8.0, 7.4,
1.8 Hz, H-7); 7.83–7.88 (5H, m, Phth and H-5). Anal. calcd for
mer). ½a 2D0
ꢁ
¼ ꢀ216 (c 0.2, CHCl3). De 95.0% (ReproSil 100 Si,
4.93 min). 1H NMR (400 MHz, DMSO-d6,
hexane–i-PrOH 80:1,
s
100 °C): d 0.886 (3H, d, J 6.8 Hz, Me); 0.892 (3H, d, J 6.6 Hz, Me);
0.95 (3H, d, J 6.6 Hz, Me); 1.54 (1H, m, H-40); 1.95 (1H, ddd, J
14.1, 9.0, 5.1 Hz, H-30B); 2.04 (1H, ddd, J 14.1, 8.6, 5.2 Hz, H-30A);
4.09 (1H, dd, J 11.0, 1.9 Hz, H-2B); 4.13 (1H, dd, J 11.0, 3.0 Hz, H-
2A); 4.52 (1H, m, H-3); 5.32 (1H, dd, J 9.0, 5.2 Hz, H-20); 6.60
(1H, dd, J 8.1, 1.4 Hz, H-8); 6.75 (1H, ddd, J 8.1, 7.3, 1.5 Hz, H-7);
6.84 (1H, ddd, J 8.0, 7.3, 1.4 Hz, H-6); 7.43 (1H, dd, J 8.0, 1.5 Hz,
H-5); 7.74–7.80 (4H, m, Phth). Anal. calcd for C23H24N2O4
(392.46): C, 70.39; H, 6.16; N, 7.14; found: C, 69.97; H, 6.26; N,
6.80.
C22H22N2O4 (378.43): C, 69.83; H, 5.86; N, 7.40; found: C, 69.90;
H, 5.84; N, 7.37.
4.3.7. (3R)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-valyl]-2H-
[1,4]benzoxazine (R,S)-10
Colourless powder (38 mg, 8.4% after flash column chromatog-
raphy, fast eluting isomer): mp 182–183 °C. ½a D20
ꢁ
¼ ꢀ256 (c 1.0,
CHCl3). De 99.0% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
5.77 min). 1H NMR (400 MHz, DMSO-d6, 100 °C): d 0.84 (3H, d, J
6.8 Hz, Me); 0.85 (3H, d, J 6.7 Hz, Me); 1.07 (3H, d, J 6.7 Hz, Me-
3); 2.74 (1H, dsept, J 7.4, 6.8 Hz, H-30); 4.07 (1H, dd, J 10.9,
1.7 Hz, H-2B); 4.12 (1H, dd, J 10.9, 3.0 Hz, H-2A); 4.60 (1H, m, H-
3); 5.07 (1H, d, J 7.4 Hz, H-20); 6.55 (1H, dd, J 8.1, 0.9 Hz, H-8);
6.73 (1H, ddd, J 8.0, 7.7, 1.4 Hz, H-6); 6.81 (1H, ddd, J 8.1, 7.7,
1.5 Hz, H-7); 7.40 (1H, dd, J 8.0, 1.2 Hz, H-5); 7.74–7.80 (4H, m,
Phth). Anal. calcd for C22H22N2O4 (378.43): C, 69.83; H, 5.86; N,
7.40; found: C, 70.06; H, 5.89; N, 7.41.
4.3.12. (3S)-3,4-Dihydro-3-methyl-1-[N-phthaloyl-3-cyclohexyl-
(S)-alanyl]-2H-[1,4]benzoxazine (S,S)-13
Colourless crystals (61 mg, 14% after flash column chromatogra-
phy, slow eluting isomer): mp 170–172 °C. ½a D20
¼ þ344 (c 1.0,
ꢁ
CHCl3). De 99.7% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
7.60 min). 1H NMR (400 MHz, DMSO-d6, 100 °C): d 0.57–0.67 (1H,
m, cHex); 0.79–0.89 (1H, m, cHex); 1.01–1.08 (3H, m, cHex); 1.12
(3H, d, J 6.8 Hz, Me-3); 1.18–1.29 (1H, m, cHex); 1.47–1.55 (6H,
m, 6H-cHex and H-30B); 2.54 (1H, ddd, J 14.1, 11.3, 4.4 Hz, H-
30A); 4.10 (1H, dd, J 11.0, 3.2 Hz, H-2B); 4.21 (1H, dd, J 11.0,
1.7 Hz, H-2A); 4.75 (1H, qdd, J 6.8, 3.2, 1.7 Hz, H-3); 5.59 (1H, dd,
J 11.3, 4.3 Hz, H-20); 6.93 (1H, dd, J 7.9, 1.4 Hz, H-8); 6.96 (1H,
ddd, J 8.0, 7.4, 1.4 Hz, H-6); 7.13 (1H, ddd, J 8.0, 7.5, 1.4 Hz, H-7);
7.60 (1H, dd, J 8.0, 1.4 Hz, H-5); 7.84–7.89 (4H, m, Phth). Anal. calcd
for C26H28N2O4 (432.52): C, 72.20; H, 6.52; N, 6.48; found: C, 72.10;
H, 6.55; N, 6.42.
4.3.8. (3S)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-tert-leucyl]-
2H-[1,4]benzoxazine (S,S)-11
Colourless powder (59 mg, 15% after flash column chromatogra-
phy, slow eluting isomer): mp 130.5 °C. ½a D20
ꢁ
¼ þ77:8 (c 1.0, CHCl3).
De 99.6% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
7.32 min). 1H
NMR (400 MHz, DMSO-d6, 100 °C): d 1.11 (9H, s, t-Bu); 1.15 (3H,
d, J 6.7 Hz, Me-3); 3.80 (1H, dd, J 10.9, 2.8 Hz, H-2B); 4.10 (1H,
dd, J 10.9, 1.5 Hz, H-2A); 4.37 (1H, m, H-3); 5.10 (1H, s, H-20);
6.83 (1H, dd, J 8.1, 1.1 Hz, H-8); 6.89 (1H, m, H-6); 7.04 (1H, m,
H-7); 7.84 (1H, dd, J 8.3, 0.9 Hz, H-5); 7.86–7.90 (4H, m, Phth).
Anal. calcd for C23H24N2O4 (392.46): C, 70.39; H, 6.16; N, 7.14;
found: C, 70.38; H, 6.37; N, 7.09.
4.3.13. (3R)-3,4-Dihydro-3-methyl-1-[N-phthaloyl-3-cyclohexyl-
(S)-alanyl]-2H-[1,4]benzoxazine (R,S)-13
Colourless foam (27 mg, 6.2% after flash column chromatogra-
phy, fast eluting isomer). ½a D20
ꢁ
¼ ꢀ183 (c 0.4, CHCl3). De 96.0%
4.3.9. (3R)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-tert-leucyl]-
2H-[1,4]benzoxazine (R,S)-11
(ReproSil 100 Si, hexane–i-PrOH 80:1, s
4.70 min). 1H NMR
(400 MHz, DMSO-d6, 100 °C): d 0.89 (3H, d, J 6.8 Hz, Me-3);
0.93–1.04 (2H, m, cHex); 1.11–1.18 (3H, m, cHex); 1.20–1.31
(1H, m, cHex); 1.52–1.68 (4H, m, cHex); 1.89 (1H, m, cHex);
1.92 (1H, ddd, J 14.2, 9.0, 5.2 Hz, H-30B); 2.08 (1H, ddd, J 14.2,
8.4, 5.2 Hz, H-30A); 4.09 (1H, dd, J 10.9, 1.8 Hz, H-2B); 4.13 (1H,
dd, J 10.9, 2.7 Hz, H-2A); 4.52 (1H, qdd, J 6.8, 2.7, 1.8 Hz, H-3);
5.34 (1H, dd, J 9.0, 5.2 Hz, H-20); 6.60 (1H, dd, J 8.1, 1.5 Hz, H-
8); 6.74 (1H, ddd, J 8.1, 7.4, 1.5 Hz, H-6); 6.84 (1H, ddd, J 8.1,
7.4, 1.5 Hz, H-7); 7.43 (1H, dd, J 8.1, 1.5 Hz, H-5); 7.74–7.80 (4H,
m, Phth). HRMS for C26H29N2O4 (M+H+), calcd 433.2122, found
433.2117.
Colourless powder (17 mg, 4.4% after flash column chromatog-
raphy, fast eluting isomer): mp 149–151 °C. ½a D20
¼ ꢀ266 (c 1.0,
ꢁ
CHCl3). De >99.0% (ReproSil 100 Si, hexane–i-PrOH 80:1,
s
4.22 min). 1H NMR (DMSO-d6, 100 °C, 400 MHz): d 0.77 (3H, d, J
6.8 Hz, Me-3); 1.13 (9H, s, t-Bu); 4.02 (1H, dd, J 10.8, 1.5 Hz, H-
2B); 4.10 (1H, dd, J 10.8, 3.2 Hz, H-2A); 4.55 (1H, br s, H-3); 5.04
(1H, s, H-20); 6.47 (1H, d, J 7.5 Hz, H-8); 6.73 (1H, ddd, J 7.6, 7.6,
1.4 Hz, H-6); 6.79 (1H, ddd, J 7.6, 7.6, 1.1 Hz, H-7); 7.35 (1H, d, J
7.6 Hz, H-5); 7.72-7.79 (4H, m, Phth). HRMS for C23H25N2O4
(M+H+), calcd 393.1809, found 393.1805.
4.3.10. (3S)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-leucyl]-
2H-[1,4]benzoxazine (S,S)-12
4.4. Kinetic resolution of racemic amines 1a and 1b. General
procedure
Colourless crystals (211 mg, 54%): mp 183 °C (hexane–EtOAc).
½
a 2D0
PrOH 80:1,
ꢁ
¼ þ370 (c 1.0, CHCl3). De 99.8% (ReproSil 100 Si, hexane–i-
A solution of the appropriate acyl chloride (0.15 mmol) in the
chosen solvent (1.5 mL) was added to a solution of amine
s
7.80 min). 1H NMR (DMSO-d6, 100 °C, 400 MHz): d
0.66 (3H, d, J 6.4 Hz, Me); 0.77 (3H, d, J 6.5 Hz, Me); 1.13 (3H, d, J
6.8 Hz, Me-3); 1.40 (1H, ddd, J 13.5, 9.3, 4.0 Hz, H-30B); 1.44–1.54
(1H, m, H-40); 2.58 (1H, ddd, J 13.5, 11.4, 3.9 Hz, H-30A); 4.10 (1H,
dd, J 11.1, 3.4 Hz, H-2B); 4.20 (1H, dd, J 11.1, 1.8 Hz, H-2A); 4.75
(1H, qdd, J 6.8, 3.4, 1.8 Hz, H-3); 5.57 (1H, dd, J 11.4, 4.0 Hz, H-20);
6.93 (1H, dd, J 8.0, 1.4 Hz, H-8); 6.96 (1H, ddd, J 8.0, 7.4, 1.4 Hz,
H-6); 7.13 (1H, ddd, J = 8.0, 7.4, 1.5 Hz, H-7); 7.60 (1H, dd, J 8.0,
1.5 Hz, H-5); 7.83–7.89 (4H, m, Phth). Anal. calcd for C23H24N2O4
(392.46): C, 70.39; H, 6.16; N, 7.14; found: C, 70.19; H, 6.27; N, 7.11.
(0.30 mmol) in the same solvent (1.5 mL) at a specified tempera-
ture. The reaction mixture was kept at the appropriate tempera-
ture for 6 h, then washed with 1 M HCl (2 ꢂ 3 mL), saturated
aqueous NaCl (3 ꢂ 3 mL), 5% NaHCO3 (3 mL) and water
(2 ꢂ 3 mL) [in the case of acetonitrile solution, 1 M HCl (3 mL)
was added to the reaction mixture and amides were extracted with
benzene]. The organic layer was separated, dried over MgSO4 and
evaporated under reduced pressure to give a mixture of diastereo-
isomeric amides 3–14, which was analysed by HPLC and 1H NMR
spectroscopy. Acidic washing solutions were collected and alka-
lised with Na2CO3 up to pH 8–9, and extracted with CHCl3
(2 ꢂ 3 mL). The organic layer was separated, dried over MgSO4
and evaporated under reduced pressure to give an enantiomeric
mixture of unreacted amine 1a or 1b.
4.3.11. (3R)-3,4-Dihydro-3-methyl-4-[N-phthaloyl-(S)-leucyl]-
2H-[1,4]benzoxazine (R,S)-12
Amorphous solid (16 mg, 4.0% after flash column chromatogra-
phy of the mother liquor after recrystallisation, fast eluting iso-

1646
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 23 (2012) 1640–1646
Grega, K. C.; Lee, C. S.; Dolak, L. A.; Seest, E. P.; Watt, W.; Adams, W. J.; Friis, J.
M.; Ford, C. W.; Zurenko, G. E. Bioorg. Med. Chem. Lett. 2003, 13, 4235–4239; (d)
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4.5. Enantiopure amines (S)-1a and (S)-1b. General procedure
A solution of acyl chloride 2d (4.20 g, 15 mmol) was added to a
solution of racemic amine 1a or 1b (30 mmol) in CH2Cl2 (150 mL)
at ꢀ20 °C. The reaction mixture was kept at ꢀ20 °C for 6 h, then
washed with 1 M HCl (2 ꢂ 100 mL), saturated aqueous NaCl
(3 ꢂ 100 mL), 5% NaHCO3 (2 ꢂ 100 mL) and water (2 ꢂ 100 mL).
The organic layer was separated, dried over MgSO4 and evaporated
under reduced pressure. The residue was recrystallised from hex-
ane–ethyl acetate to give amide (S,S)-6 (de >99%, 3.22 g, 55% yield)
or (S,S)-12 (de >99%, 3.18 g, 54% yield). (S,S)-Amide 6 or 12 was dis-
solved in AcOH (30 mL) after which concentrated HCl (30 ml) was
added to the solution, and the resulting mixture was heated at
90 °C for 15 h. The reaction mixture was evaporated under reduced
pressure to half-volume, and then poured into water (200 mL). The
aqueous solution was washed with CHCl3 (2 ꢂ 25 mL), then
alkalised with Na2CO3 up to pH 8–9 and extracted with CHCl3
(3 ꢂ 40 mL). The organic layer was washed with water
(2 ꢂ 30 mL), dried over MgSO4 and evaporated under reduced
pressure.
4. Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 2076–2082.
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4.5.1. (2S)-2-Methyl-1,2,3,4-tetrahydroquinoline (S)-1a
Colourless oil (1.10 g, 25% relative to rac-1a). ½a D20
¼ ꢀ85 (c 1.5,
ꢁ
C6H6) [lit.19 (R)-1a: +85 (c 2, C6H6)]. Ee >99% (Chiralcel OD-H, n-
hexane–i-PrOH–MeOH 100:0.8:0.2,
s
10.02 min). 1H NMR (CDCl3)
data are in good agreement with the literature.10c
4.5.2. (3S)-3,4-Dihydro-3-methyl-2H-[1,4]benzoxazine (S)-1b
Yellowish oil (1.07 g, 23% relative to rac-1b). ½a D20
¼ þ23:0 (c
ꢁ
1.0, CHCl3) [lit.10b +19.8 (c 1, CHCl3)]. Ee >99% (Chiralcel OD-H, n-
hexane–i-PrOH–MeOH 100:1.5:1.5,
s
11.97 min). 1H NMR (CDCl3)
data are in good agreement with the literature.9a,10b
Acknowledgments
The authors thank Liliya Sh. Sadretdinova for performing HPLC
analyses, Dr. Pavel A. Slepukhin for performing X-ray crystallogra-
phy analyses and Dr. Mikhail I. Kodess for registration of NMR
spectra. The work was financially supported by the Russian Foun-
dation for Basic Research (grants Nos. 10-03-00084, 12-03-31615
and 12-03-33029), the Ural Branch of RAS (grant 12-P-3-1030),
and the State Program for Supporting of Leading Scientific Schools
of the Russian Federation (grant NSh-5505.2012.3).
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