Enantiomers of all-cis-5-(4-bromophenyl)-4-tert-butoxycarbonyl-2- methoxycarbonylpyrrolidine: Preparative HPLC separation and acylative kinetic resolution of the racemate

Article abstract of DOI:10.1016/j.tetasy.2012.10.020

The fundamental possibility of acylative kinetic resolution of racemic heterocyclic amines was demonstrated by the example of all-cis-5-(4-bromophenyl) -4-tert-butoxycarbonyl-2-methoxycarbonylpyrrolidine. Individual enantiomers (ee >99%) were obtained in

Full text of DOI:10.1016/j.tetasy.2012.10.020

Tetrahedron: Asymmetry 23 (2012) 1683–1688
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiomers of all-cis-5-(4-bromophenyl)-4-tert-butoxycarbonyl-2-methoxy-
carbonylpyrrolidine: preparative HPLC separation and acylative
kinetic resolution of the racemate
Evgeny N. Chulakov a, Dmitry A. Gruzdev a, Galina L. Levit a, , Konstantin V. Kudryavtsev b,c
,
⇑
Victor P. Krasnov a
a Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 22/20 S.Kovalevskoy/Akademicheskaya St., Ekaterinburg 620990, Russia
b Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia
c Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2012
Accepted 29 October 2012
The fundamental possibility of acylative kinetic resolution of racemic heterocyclic amines was demon-
strated by the example of all-cis-5-(4-bromophenyl)-4-tert-butoxycarbonyl-2-methoxycarbonylpyrroli-
dine. Individual enantiomers (ee >99%) were obtained in high yields via preparative chiral HPLC.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
propanoyl residue led to a potent (Ki 160 pM) angiotensin convert-
ing enzyme (ACE) inhibitor 2.1 The diastereoisomer of 2 with a
Enantiopure derivatives of 5-arylpyrrolidine-2,4-dicarboxylic
acid 1 represent a valuable compound class for different medicinal
chemistry projects. The parent molecular scaffold 1 comprises of a
conformationally rigid five-membered framework and three stere-
ogenic centres that dispose the substituents and functional groups
in a well-defined manner (Fig. 1). The secondary amine group and
two carboxylic functions of 1 provide an excellent possibility for
subsequent molecular diversity generation. Modification of the
(2S,4S,5R)-analogue of 1 (Ar = Ph) with (S)-3-mercapto-2-methyl-
(2R,4R,5S)-configuration of the pyrrolidine ring displayed very
weak ACE-inhibitory activity (Ki >1 M). (2S,4S,5R)-N-Benzoyl
l
2,4-diacid 3 was identified as a sub-micromolar (IC50 190 nM)
inhibitor of an RNA-dependent RNA polymerase activity of the
hepatitis C virus (HCV).2 The opposite (2R,4R,5S)-isomer of 3 was
two orders less effective. Subsequent optimization of compound
(2S,4S,5R)-3 led to the clinical development candidate of an
anti-HCV agent with the same absolute configuration of the pyrrol-
idine scaffold.3 Recently, non-basic racemic thrombin inhibitors
HOOC
COOH
Ar
N
H
1
COOtBu
Me
MeOOC
Ph
HOOC
S
MeOOC
N
Me
COOH
Me
N
N
Br
Cl
O
COOH
S
O
O
4
SH
2
CF3
3
Figure 1. Biologically active derivatives of 5-arylpyrrolidine-2,4-dicarboxylic acid 1.
⇑
Corresponding author. Fax: +7 343 3741189.
E-mail address: ca512@ios.uran.ru (G.L. Levit).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.020

1684
E. N. Chulakov et al. / Tetrahedron: Asymmetry 23 (2012) 1683–1688
that contain a 5-arylpyrrolidine-2,4-dicarboxylic acid fragment
were reported.4 Molecular modelling has differentiated binding
modes and energies of enantiomeric inhibitors and predicted some
favourable interactions of the (2R,4R,5S)-ligand 4 set with the en-
zyme active site.4
especially of interest, because our earlier attempts for acylative
KR of racemic secondary amines without a condensed aromatic
system, such as 2-methylpiperidine, were unsuccessful.9d
2. Results and discussion
Enantiomerically pure orthogonally protected diesters of 5-
arylpyrrolidine-2,4-dicarboxylic acid 1 can generally be efficiently
synthesized by the asymmetric 1,3-dipolar cycloaddition of acry-
lates to azomethine ylides.5 The resolution of racemic derivatives
of 1 via diastereoisomeric salt formation has been used in a few
cases.6 However, the preparation of enantiopure derivatives of 5-
arylpyrrolidine-2,4-dicarboxylic acid remains an important syn-
thetic challenge.
Herein we have studied approaches to individual enantiomers
of all-cis-pyrrolidine 57 (Scheme 1), which is a key precursor in
the synthesis of small-molecule thrombin inhibitors,4 based on
chiral HPLC and acylative kinetic resolution (KR) of the racemate.
Due to our experience in the acylative KR8 of racemic heterocy-
clic amines, such as 2-methyl-1,2,3,4-tetrahydroquinoline, 3-
methyl-2H-[1,4]benzoxazines and 2-methylindoline under the ac-
tion of 2-arylpropionyl9 and N-protected (S)-amino acyl chlo-
rides10 as chiral resolving agents (CRAs), we decided to use this
methodology to prepare the enantiomers of pyrrolidine 5. It was
For the acylative KR of racemic pyrrolidine 5 we used (S)-naprox-
en acyl chloride 6 and acyl chlorides 7–10 of N-protected (S)-amino
acids (N-tosyl-(S)-phenylalanine, N-methyl-N-tosyl-(S)-phenylala-
nine, N-phthaloyl-(S)-phenylalanine and N-phthaloyl-(S)-leucine)
as CRAs. The preparation of acyl chlorides 6,9a 10c and 1010e has al-
9
ready been described. Acyl chlorides 7 and 8 were prepared in good
yields by the reaction of the appropriate N-protected amino acids
with oxalyl chloride in benzene in the presence of catalytic amounts
of DMF followed by recrystallization from a hexane–CH2Cl2 mixture.
Acylation of racemic pyrrolidone 5 using acyl chlorides 6–10 at
an amine–acyl chloride molar ratio of 2:1 was carried out in tolu-
ene or dichloromethane at +20 °C for 6 h (Scheme 1). The initial
concentration of racemic pyrrolidone 5 was 0.1 M. After treatment
of the reaction mixtures, we determined the diastereoisomeric ex-
cess (de, %) of amides 11–15 (HPLC) and the enantiomeric excess
(ee, %) of the unreacted amine 5 (chiral HPLC) (see Table 1). Based
on these data, the conversion of racemic substrate 5 (C, %) and the
ButOOC
ButOOC
+
COOMe
COOMe
N
H
N
H
Br
Br
5
(-)-(2R,4R,5S)-
5
(+)-(2S,4S,5R)-
(2R,4R,5S)-selectivity
(2S,4S,5R)-selectivity
2
8-10
1
R Cl
6, 7
R Cl
(0.5 equiv.)
(0.5 equiv.)
ButOOC
ButOOC
ButOOC
ButOOC
+
+
COOMe
COOMe
COOMe
(+)-5
Me
COOMe
N
R1
N
R2
N
H
N
H
5
(-)-
13-15
11, 12
Br
Br
Br
Br
O
O
Me
N
O
O
H
N
R1
=
6, 11
7, 12
9, 14
PhthN
PhthN
10, 15
Tos
R2
=
8, 13
Tos
Bui
O
Bn
Bn
Bn
MeO
Scheme 1. Acylative kinetic resolution of all-cis-4-tert-butoxycarbonyl-2-methoxycarbonyl-5-(4-bromophenyl)pyrrolidine 5 with chiral acyl chlorides 6–10.
Table 1
Results of the kinetic resolution of racemic amine 5 via acylation with acyl chlorides 6–10 at +20 °Ca
Entry
Chiral resolving agent
Solvent
Amide, de %b (configuration)
Unreacted 5, ee %c (configuration)
Conversion, C %
Selectivity factor, s
1
2
3
4
5
6
7
8
6
6
7
7
8
8
8
9
9
9
10
10
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
Toluened
CH2Cl2
Toluene
Toluened
CH2Cl2
43.0 (20S,2R,4R,5S)
0
20.8 (2S,4S,5R)
0
32
nd
48
49
44
68
37
41
59
35
27
34
3.1
—
9.5 (20S,2R,4R,5S)
18.6 (20S,2R,4R,5S)
53.5 (20S,2S,4S,5R)
42.0 (20S,2S,4S,5R)
12.4 (2vS,2S,4S,5R)
55.0 (20S,2S,4S,5R)
55.4 (20S,2S,4S,5R)
38.2 (20S,2S,4S,5R)
52.0 (20S,2S,4S,5R)
33.8 (20S,2S,4S,5R)
8.7 (2S,4S,5R)
18.0 (2S,4S,5R)
42.6 (2R,4R,5S)
88.2 (2R,4R,5S)
7.2 (2R,4R,5S)
37.5 (2R,4R,5S)
81.0 (2R,4R,5S)
20.8 (2R,4R,5S)
19.6 (2R,4R,5S)
17.8 (2R,4R,5S)
1.3
1.7
5.0
6.5
1.4
4.8
8.3
2.7
3.9
2.4
9
10
11
12
Toluene
CH2Cl2
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).
Amine 5–acyl chloride–N,N-diethylaniline molar ratio of 1:0.75:0.75, ꢀ20 °C, 48 h.
d

E. N. Chulakov et al. / Tetrahedron: Asymmetry 23 (2012) 1683–1688
1685
selectivity factor (s) were calculated according to Kagan’s
equations:
C ¼ ½eeamine=ðeeamine þ deamideÞꢁ ꢂ 100%;
s ¼ ln½ð1 ꢀ CÞ ꢂ ð1 ꢀ eeamineÞꢁ= ln½ð1 ꢀ CÞ ꢂ ð1 þ eeamineÞꢁ:11
It has been found that acyl chlorides 6 and 7 preferentially re-
acted with (2R,4R,5S)-5, whereas acyl chlorides 8–10 reacted with
the (2S,4S,5R)-isomer (according to the chiral HPLC of unreacted
pyrrolidone 5). In the acylation of racemic pyrrolidone 5 with
(S)-naproxen acyl chloride 6, the selectivity factor and conversion
of the racemic substrate significantly depended on the solvent nat-
ure. Thus, acylation occurred with moderate selectivity (s 3.1) in
toluene (amide 11, 43.0% de), and the enantiomeric excess of
remaining (2S,4S,5R)-5 was 20.8% (Table 1, entry 1). However,
the acylation of racemic pyrrolidine 5 with acyl chloride 6 was
unselective in CH2Cl2. Acylation with N-tosyl-(S)-phenylalanyl
chloride 7 was inefficient both in toluene and dichloromethane, s
1.3–1.7, de of amide 13 was less 18.6% (Table 1, entries 3 and 4).
In the case of N-methyl-N-tosyl-(S)-phenylalanyl 8 and N-
phthaloyl-(S)-phenylalanyl 9 chlorides, the acylation took place
most selectively in toluene: the de of amides 14 and 15 was
53.5% and 55.0%, respectively, (s 5.0 and 4.8); ee of unreacted
amine 5 was 42.6% and 37.5%, respectively (Table 1, entries 5
and 8). The KR with N-phthaloyl-(S)-leucyl chloride 10 (Table 1, en-
tries 11 and 12) proceeded with lower selectivity (s less 3.9) and
conversion as compared to N-phthaloyl-(S)-phenylalanyl chloride
9.
In order to obtain individual diastereoisomeric amides, we car-
ried out the acylation of racemic pyrrolidine 5 with equimolar
amounts of acyl chlorides 6–10 in the presence of N,N-diethylani-
line as an acceptor of HCl. Both diastereoisomers of amides 11, 14
and 15 were isolated from their mixtures by column flash-chroma-
tography on silica gel (benzene–EtOAc as an eluent) or recrystalli-
zation. However, we failed to separate the diastereoisomeric
mixtures of amides 12 and 13 either by recrystallization or by
chromatography.
Since the results of the KR of racemic pyrrolidine 5 with acyl
chlorides 6–10 as CRAs were not encouraging, we decided to iso-
late the enantioenriched unreacted amine 5 after acylation of the
racemate with 0.75 equiv of acyl chloride 8 or 9 in the presence
of 0.75 equiv of N,N-diethylaniline in toluene at +20 °C. As a re-
sult, the ee of unreacted amine 5 was 88.2 and 81.0% in the cases
of acyl chlorides 8 and 9, respectively (Table 1, entries 6 and 9).
However, the preparative chromatographic isolation of unreacted
amine 5 from the reaction mixture was laborious, and the yield
of enantioenriched pyrrolidine 5 was no more than 13% relative
to the starting racemate. Nevertheless, we have shown the
fundamental possibility of the KR of a heterocyclic non-aromatic
amine in the diastereoselective acylation with chiral acyl
chlorides.
Figure 2. X-ray structure of (+)-(2S,4S,5R)-5.
(Fig. 2). The X-ray structure of (ꢀ)-(2R,4R,5S)-5 has already been
published.12b
3. Conclusion
We have carried out a preparative HPLC resolution to obtain
enantiomerically pure (ee >99%) enantiomers of all-cis-5-(4-bro-
mo-phenyl)-4-tert-butoxycarbonyl-2-methoxycarbonylpyrroli-
dine, a key precursor in the synthesis of small-molecule thrombin
inhibitors. We have demonstrated the fundamental possibility of
the kinetic resolution of racemic heterocyclic amines without a
condensed aromatic system using chiral acyl chlorides as acylating
agents.
4. Experimental
4.1. General
All-cis-5-(4-bromophenyl)-4-tert-butoxycarbonyl-2-methoxy-
carbonylpyrrolidine 5,7 (S)-2-(6-methoxynaphth-2-yl)propionyl
chloride 6,9a N-phthaloyl-(S)-phenylalanyl chloride 9,10c N-phthal-
oyl-(S)-leucyl chloride 10,10e N-tosyl-(S)-phenylalanine13 and N-
methyl-N-tosyl-(S)-phenylalanine13 were synthesized according
to the literature. Other reagents are commercially available. The
solvents were dried according to standard methods14 and used as
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) or Bruker Avance 500 (500 MHz) spec-
trometer with TMS as an internal reference. The 1H NMR spectra of
amides (20S,2S,4S,5R)-14 and (20S,2S,4S,5R)-15 were recorded in
DMSO-d6 at 120 °C; the 1H NMR spectra of all of the other com-
pounds were recorded at ambient temperature. Elemental analysis
was performed using a Perkin Elmer 2400 II or EuroVector EA3000
analyser. Analytical HPLC of amine 5 and amide 11 was performed
on a Knauer Smartline-1100 instrument using a Chiralcel OD-H
Since the KR approach proved inefficient from a practical point
of view, we carried out a preparative HPLC separation of the enan-
tiomers of pyrrolidine
5
on
a
Chiralcel OD-H column
(20 ꢂ 250 mm, 5 m) using hexane–isopropanol 10:1 as an eluting
l
column (250 ꢂ 4.6 mm, 5
lm), detection at 230 nm, 1 mL/min flow
solvent. The enantiomers of all-cis-pyrrolidine 5 were obtained
from 300 mg of racemate: 114 mg of (+)-(2S,4S,5R)-5, ee >99.8%
(tR = 31 min) and 129 mg of (ꢀ)-(2R,4R,5S)-5, 99.2% ee
(tR = 47 min). Previously, (+)-5 and (ꢀ)-5 enantiomers were syn-
thesized by the asymmetric 1,3-dipolar cycloaddition with 6612a
and 95% ee,12b respectively. The assignment of the configuration
was made by comparing the specific rotation of the enantiomers
with the published data.12 In addition, the absolute configuration
of the stereogenic centres in (+)-(2S,4S,5R)-5 was established by
X-ray crystallography in experiments with anomalous scattering
rate, n-hexane–i-PrOH–MeOH 10:0.8:0.2 mixture as eluting sol-
vent. Analytical HPLC of amides 12–15 was performed on an Agi-
lent-1100 instrument using a Phenomenex Luna C18 column
(250 ꢂ 4.6 mm, 5
lm), detection at 230 nm, 0.8 mL/min flow rate,
MeCN–H2O 75:25 mixture 10:0.8:0.2 as eluting solvent.
Preparative HPLC of pyrrolidine 5 was performed at ambient
temperature using a chromatograph system consisting of Chiralcel
OD-H column (20 ꢂ 250 mm, 5
lm) (Daicel Corporation, Japan),
Gilson-305 pump (France), injector with the 2.0 mL loop,
L-4000A UV Detector (Hitachi, Japan), detection at 230 nm,

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E. N. Chulakov et al. / Tetrahedron: Asymmetry 23 (2012) 1683–1688
6.0 mL/min flow rate, n-hexane–iPrOH 10:1 mixture as eluting sol-
vent. Retention times for (2S,4S,5R)-5 and (2R,4R,5S)-5 were 31 and
47 min, respectively.
Crystallographic data for (2S,4S,5R)-5 have been deposited with
the Cambridge Crystallographic Data Centre (CCDC No. 905540).
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].
with 5% NaHCO3 (2 ꢂ 3 mL) and water (2 ꢂ 3 mL). The organic layer
was dried over MgSO4 and evaporated under reduced pressure. Dia-
stereoisomers of amide 11 and inseparable diastereoisomeric mix-
tures of amides 12 and 13 were obtained after flash-column
chromatography on silica gel (benzene–EtOAc as eluent). Amides
(20S,2R,4R,5S)-14 and (20S,2R,4R,5S)-15 were isolated after crystalli-
zation of the reaction products from EtOH; amides (20S,2S,4S,5R)-14
and (20S,2S,4S,5R)-15 were isolated from the mother liquor after
evaporation of theresidueand recrystallizationfrom hexane–EtOAc.
4.2. (2S,4S,5R)-5-(4-Bromophenyl)-4-tert-butoxycarbonyl-2-
methoxycarbonylpyrrolidine (2S,4S,5R)-5
4.5.1. (2R,4R,5S)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-1-
[(20S)-20-(600-methoxynaphth-200-yl)propionyl]-2-methoxy-
carbonylpyrrolidine [(20S,2R,4R,5S)-11]
Colourless powder (114 mg, 38%): mp 85 °C. 99.8% ee (HPLC,
Chiralcel OD-H, tR 8.0 min). ½a D20
ꢁ
¼ þ31:0 (c 1.0, C6H6); +30.3 (c
Colourless powder (fast eluting isomer, 0.140 g, 31%): mp
0.75, CH2Cl2) {lit.12a
½
aꢁD
¼ þ18 (c 0.76, CH2Cl2), 66% ee}. 1H NMR
202 °C. ½a 2D0
¼ ꢀ132 (c 1.0, C6H6). De >99.9% (HPLC, Chiralcel OD-
ꢁ
(400 MHz, DMSO-d6): d 1.00 (s, 9H, COOtBu); 2.15 (ddd, 1H, J
12.5, 8.4 and 7.9 Hz, H-3B); 2.26 (m, 1H, H-3A); 3.21 (m, 1H, H-
4); 3.69 (s, 3H, COOMe); 3.86 (dd, 1H, J 8.4 and 8.4 Hz, H-2); 4.43
(d, 1H, J 8.5 Hz, H-5); 7.30 (m, 2H, Ar); 7.50 (m, 2H, Ar). Anal. Calcd
for C17H22BrNO4 (384, 26): C, 53.14; H, 5.77; N, 3.65. Found: C,
53.42; H, 6.02; N, 3.59.
H, tR 17.2 min). 1H NMR (400 MHz, DMSO-d6): d 1.02 (d, 3H, J
6.9 Hz, Me-naproxen); 1.09 (s, 9H, COOtBu); 2.15 (1H, m, H-3A);
2.27 (1H, m, H-3B); 3.44 (1H, ddd, J 12.6, 8.9 and 6.5 Hz, H-4);
3.50 (1H, q, J 6.9 Hz, CH-naproxen); 3.76 (3H, s, COOMe); 3.87
(3H, s, OMe); 4.32 (1H, dd, J 11.1 and 6.8 Hz, H-2); 5.10 (1H, d, J
8.9 Hz, H-5); 7.17 (1H, dd, J 8.9 and 2.5 Hz, H-300); 7.31 (1H, d, J
2.5 Hz, H-100); 7.38 (1H, dd, J 8.6 and 1.6 Hz, H-700); 7.67 (5H, m,
H-500 and C6H4); 7.80 (1H, d, J 8.6 Hz, H-800); 7.83 (1H, d, J 8.9 Hz,
H-400). Anal. Calcd for C31H34BrNO6 (596.51): C, 62.42; H, 5.75; N,
2.35. Found: C, 62.59; H, 5.81; N, 2.35.
4.3. (2R,4R,5S)-5-(4-Bromophenyl)-4-tert-butoxycarbonyl-2-
methoxycarbonylpyrrolidine (2R,4R,5S)-5
Colourless powder (129, 43%): mp 85 °C. 99.2% (HPLC, Chiralcel
OD-H, tR 10.4 min). ½a D20
ꢁ
¼ ꢀ33:0 (c 1.0, C6H6). {lit.12b
½
a 2D0
ꢁ
¼ ꢀ23:2
4.5.2. (2S,4S,5R)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-1-
[(20S)-20-(600-methoxynaphth-200-yl)propionyl]-2-methoxy-
carbonyl-pyrrolidine (20S,2S,4S,5R)-11
(c 0.5, CH2Cl2), 95% ee.}. 1H NMR spectrum was identical to the
spectrum of (2S,4S,5R)-5.
Colourless powder (slow eluting isomer, 0.185 g, 41%): mp
4.4. Acyl chlorides 7 and 8: general procedure
170 °C. ½a 2D0
¼ þ35:4 (c 1.0, C6H6). De >99.9% (HPLC, Chiralcel OD-
ꢁ
H, tR 13.3 min). 1H NMR (400 MHz, DMSO-d6): d 1.13 (9H, s, COOt-
Bu); 1.33 (3H, d, J 6.8 Hz, Me-naproxen); 2.07 (1H, m, H-3B); 2.29
(1H, m, H-3A); 3.63 (1H, ddd, J 13.0, 8.8 and 6.4 Hz, H-4); 3.67 (3H,
s, COOMe); 3.83 (3H, s, OMe); 3.87 (1H, q, J 6.8 Hz, CH-naproxen);
4.35 (1H, dd, J 11.5 and 6.7 Hz, H-2); 5.59 (1H, d, J 8.8 Hz, H-5);
6.69 (1H, m, H-500); 6.85 (1H, dd, J 8.6 and 1.6 Hz, H-700); 7.06
(1H, dd, J 8.9 and 2.5 Hz, H-300); 7.14 (1H, d, J 2.5 Hz, H-100); 7.18
(2H, m, C6H4); 7.35 (2H, m, C6H4); 7.38 (1H, d, J 8.9 Hz, H-400);
7.43 (1H, d, J 8.6 Hz, H-800). Anal. Calcd for C31H34BrNO6 (596.51):
C, 62.42; H, 5.75; N, 2.35.Found: C, 62.47; H, 5.77; N, 2.33.
Oxalyl chloride (0.18 mL, 2.1 mmol) and DMF (3 ll) were added
to a suspension of N-tosyl-(S)-phenylalanine or N-methyl-N-tosyl-
(S)-phenylalanine (1 mmol) in benzene (7 mL). The reaction mix-
ture was stirred at ambient temperature for 5–7 h and then evap-
orated under reduced pressure. The residue was recrystallized
from a hexane–CH2Cl2 mixture.
4.4.1. N-Tosyl-(S)-phenylalanyl chloride 7
Pale pink powder (0.306 g, 90.6%): mp 134–135 °C (hexane–
CH2Cl2) (lit.15 mp 132.5–133.5 °C). ½a 2D0
ꢁ
¼ þ14:9 (c 2.0, C6H6). 1H
NMR (400 MHz, CDCl3): d 2.42 s (3H, Tos); 3.17 (2H, d, J 6.0 Hz,
C3H2); 4.52 (1H, dt, J 9.7 and 6.0 Hz, C2H); 4.97 (1H, d, J 9.7 Hz,
NH); 7.09 (2H, m, Ph); 7.24 (2H, m, Tos); 7.27 (3H, m, Ph); 7.60
(2H, m, Tos). Anal. Calcd for C16H16ClNO3S (337.82): C, 56.89; H,
4.77; N, 4.15; Cl, 10.49; S, 9.49. Found: C, 56.84; H, 4.68; N, 4.12;
Cl, 10.51; S, 9.69.
4.5.3. (2S⁄,4S⁄,5R⁄)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-
1-[(20S)-N-tosylphenylalanyl]-2-methoxycarbonyl-pyrrolidine
12 (diastereoisomeric mixture)
Colourless powder (0.329 g, 60%): mp 93–102 °C. Dr 52:48
[HPLC, Phenomenex Luna C18, tR 14.5 min (major (20S,2R,4R,5S)-
12), tR 16.4 min (minor (20S,2S,4S,5R)-12)]. 1H NMR (400 MHz,
DMSO-d6, 120 °C): d 1.11 (4.7H, s, COOtBu (20S,2R,4R,5S)); 1.14
(4.3H, s, COOtBu (20S,2S,4S,5R)); 2.10–2.42 (6H, m, 2ꢂH-3, H-30B
and Me-Tos); 2.65–2.80 (1H, m, H-30A, overlapped by water sig-
nal); 2.90 (0.52H, m, H-4 (20S,2R,4R,5S)); 3.30 (0.48H, m, H-
4(20S,2R,4R,5S)); 3.7 (3H, br s, COOMe); 3.82 (0.48H, m, H-2
(20S,2S,4S,5R)); 3.88 (0.52H, m, H-2 (20S,2R,4R,5S)); 4.15 (0.48H,
dd, J 10.8 and 7.1 Hz, H-20 (20S,2S,4S,5R)); 4.30–5.05 (1.04H, m, H-
20 (20S,2R,4R,5S) and H-5 (20S,2R,4R,5S)); 5.24 (0.48H, d, J 8.7, H-5
(20S,2S,4S,5R)); 6.30-7.75 (14H, m, Ph, C6H4-Tos, C6H6-Br and NH).
Anal. Calcd for C33H37BrN2O7S (685.63): C, 57.81; H, 5.44; N,
4.09; S, 4.68. Found: C, 57.86; H, 5.47; N, 4.13; S, 4.71.
4.4.2. N-Methyl-N-tosyl-(S)-phenylalanyl chloride 8
Colourless powder (0.257 g, 73%): mp 86–87 °C (hexane–
CH2Cl2). ½a 2D0
ꢁ
¼ þ45:3 (c 1.1, C6H6). 1H NMR (400 MHz, CDCl3): d
2.40 (3H, s, Tos); 2.86 (3H, s, NMe), 2.90 (1H, dd, J 14.4 and
9.4 Hz, H-3B); 3.43 (1H, dd, J 14.4 and 5.8 Hz, H-3A); 5.25 (1H,
dd, J 9.4 and 5.8 Hz, H-2); 7.18 (4H, m, 2H-Tos and 2H-Ph); 7.30
(3H, m, Ph); 7.42 (2H, m, Tos). Anal. Calcd for C17H18ClNO3S
(351.85): C, 58.03; H, 5.16; N, 3.98; Cl, 10.08; S, 9.11. Found: C,
57.91; H, 5.09; N, 3.91; Cl, 10.15; S, 9.14.
4.5. Diastereoisomeric amides 11–15: general procedure
4.5.4. (2S⁄,4S⁄,5R⁄)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-
1-[(20S)-N-methyl-N-tosylphenylalanyl]-2-methoxy-carbonyl
pyrrolidine 13 (diastereoisomeric mixture)
Colourless powder (0.324 g, 58%): mp 91–105 °C. Dr 55:45
[HPLC, Phenomenex Luna C18, tR 22.0 min (major (20S,2R,4R,5S)-
13), tR 29.2 min (minor (20S,2S,4S,5R)-13)]. 1H NMR (400 MHz,
A solution of the appropriate acyl chloride (0.8 mmol) in CH2Cl2
(3 mL) and a solution of N,N-diethylaniline (119.4 mg, 0.8 mmol)
in CH2Cl2 (2 mL) were added to a solution of pyrrolidine 5
(307.4 mg, 0.8 mmol) in CH2Cl2 (3 mL) at +20 °C. The reaction mix-
ture was then stirred at +20 °C for 6 h, and then successively washed

E. N. Chulakov et al. / Tetrahedron: Asymmetry 23 (2012) 1683–1688
1687
DMSO-d6, 120 °C): d 1.11 (4.0H, s, COOtBu (20S,2R,4R,5S)); 1.14
(5.0H, s, COOtBu (20S,2S,4S,5R)); 2.15–2.40 (5H, m, 2 ꢂ H-3 and
Me-Tos); 2.47 (0.55H, m, H-30B (20S,2S,4S,5R), overlapped by DMSO
signal); 2.55–2.75 (m, 1H, H-30A (20S,2S,4S,5R) and H-30B
(20S,2R,4R,5S)); 2.85 (1.35H, s, NMe (20S,2R,4R,5S)); 2.88 (1.65H, s,
NMe (20S,2S,4S,5R)); 3.10 (0.9H, m, H-30A (20S,2R,4R,5S) and H-4
(20S,2R,4R,5S)); 3.50 (0.55H, m, H-4 (20S,2S,4S,5R)); 3.71 (3H, s,
COOMe); 4.33 (0.55H, dd, J 10.8 and 7.0 Hz, H-20 (20S,2S,4S,5R));
4.48 (0.55H, m, H-2 (20S,2S,4S,5R)); 4.67 (0.45H, m, H-2
(20S,2R,4R,5S)); 4.70–5.40 (0.9H, m, H-20 (20S,2R,4R,5S) and H-5
(20S,2R,4R,5S)); 6.35–7.48 (13H, m, Ph, C6H4-Tos, C6H6–Br). Anal.
calcd for C34H39BrN2O7S (699.55): C, 58.37; H, 5.62; N, 4.00; S,
4.58. Found: C, 58.62; H, 5.80; N, 4.01; S, 4.48.
(2H, m, H-30B and 2 ꢂ H-3); 3.56 (1H, ddd, J 11.7, 8.9 and 6.8 Hz,
H-4); 3.69 (3H, s, COOMe); 4.41 (1H, dd, J 10.1 and 7.2 Hz, H-2);
4.72 (1H, dd, J 10.3 and 4.4 Hz, H-20); 5.50 (1H, d, J 8.9 Hz, H-5);
7.56 (4H, m, C6H4); 7.83 (4H, m, Phth). Anal. Calcd for
C31H35BrN2O7 (627.52): C, 59.33; H, 5.62; N, 4.46. Found: C,
59.54; H, 5.64; N, 4.47.
4.6. Kinetic resolution of racemic amine 5: general procedure
A solution of the appropriate acyl chloride (0.05 mmol) in the
chosen solvent (0.5 mL) was added to a solution of amine 5
(38.4 mg, 0.1 mmol) in the same solvent (0.5 mL) at +20 °C. The
reaction mixture was kept at +20 °C for 6 h, and then washed with
5% NaHCO3 (2 ꢂ 3 mL) and water (2 ꢂ 3 mL). The organic layer was
dried over MgSO4 and evaporated under reduced pressure to give a
mixture of diastereoisomeric amides 11–15 and unreacted amine
5, which were analysed by HPLC. Each experiment was performed
in 2–4 runs.
4.5.5. (2R,4R,5S)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-1-
[(20S)-N-phthaloylphenylalanyl]-2-methoxycarbonyl-pyrroli
dine (20S,2R,4R,5S)-14
Colourless powder (0.185 g, 35%): mp 287 °C (decomp.) (EtOH).
½
a 2D0
ꢁ
¼ ꢀ223 (c 1.0, C6H6). De >99.9% (HPLC, Phenomenex Luna C18,
tR 15.0 min). 1H NMR (400 MHz, DMSO-d6): d 1.17 (9H, s, COOtBu);
1.84 (1H, m, H-3B); 2.25 (1H, m, H-3A); 3.06 (1H, dd, J 13.9 and
11.2 Hz, H-30B); 3.23 (1H, dd, J 13.9 and 4.4 Hz, H-30A); 3.47 (1H,
m, H-4); 3.76 (3H, s, COOMe); 4.35 (1H, dd, J 11.8 and 6.7 Hz, H-
2); 5.06 (1H, d, J 7.8 Hz, H-5); 5.38 (1H, dd, J 10.7 and 4.4 Hz, H-
20); 6.88 (2H, m, Ph); 6.98 (2H, m, C6H4); 7.07 (3H, m, Ph); 7.15
(2H, m, C6H4); 7.42 (2H, m, Phth); 7.63 (2H, m, Phth). Anal. Calcd
for C34H33BrN2O7 (661.54): C, 61.73; H, 5.03; N, 4.23. Found: C,
61.54; H, 4.82; N, 4.08.
4.7. Enantioenriched pyrrolidine (2R,4R,5S)-5: general
procedure
A solution of acyl chloride 8 (127.7 mg, 0.363 mmol) in toluene
(2 mL) and a solution of PhNEt2 (54.2 mg, 0.363 mmol) in toluene
(0.8 mL) were added to
a solution of amine 5 (186.1 mg,
0.484 mmol) in toluene (2 mL) at ꢀ20 °C. The reaction mixture
was then kept at ꢀ20 °C for 48 h, and then washed with 5% NaHCO3
(2 ꢂ 3 mL) and water (2 ꢂ 3 mL). The organic layer was dried over
MgSO4 and evaporated under reduced pressure. Flash-column chro-
matography (benzene–EtOAc as eluent) of the acylation product
gave 24.9 mg (13.4%) of unreacted amine (2R,4R,5S)-5 of 88.2% ee.
4.5.6. (2S,4S,5R)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-1-
[(20S)-N-phthaloylphenylalanyl]-2-methoxycarbonyl-pyrroli
dine (20S,2S,4S,5R)-14
Colourless powder (0.213 g, 40%): mp 186–188 °C (hexane–
Acknowledgments
EtOAc). ½a 2D0
¼ þ52:4 (c 1.0, C6H6). 94.5% de (HPLC, Phenomenex
ꢁ
Luna C18, tR 21.0 min). 1H NMR (400 MHz, DMSO-d6, 120 °C): d
1.12 (9H, s, COOtBu); 2.29 (1H, m, H-3B); 2.40 (1H, m, H-3A); 2.8
(1H, m, H-30B, overlapped by water signal); 3.48 (1H, dd, J 14.3
and 10.0 Hz, H-30A); 3.47 (1H, m, H-4); 3.65 (3H, s, COOMe); 4.45
(1H, dd, J 9.5 and 7.7 Hz, H-2); 4.97 (1H, dd, J 10.1 and 5.0 Hz, H-
20); 5.52 (1H, d, J 8.9 Hz, H-5); 6.70 (2H, m, Ph); 7.04 (3H, m, Ph);
7.52 (4H, m, C6H4); 7.79 (4H, m, Phth). Anal. Calcd for
The authors thank Liliya Sh. Sadretdinova for performing HPLC
analyses, Dr. Pavel A. Slepukhin for performing X-ray crystallogra-
phy analysis and Dr. Mikhail I. Kodess for registration of NMR spec-
tra. The work was financially supported by the Russian Foundation
for Basic Research (grants No. 10-03-00084, 11-03-00630-a, 11-03-
91375-ST_a and 12-03-31615), 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).
C
34H33BrN2O7 (661.54): C, 61.73; H, 5.03; N, 4.23. Found: C,
61.79; H, 4.89; N, 4.03.
References
4.5.7. (2R,4R,5S)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-1-
[(20S)-N-phthaloylleucyl]-2-methoxycarbonyl-pyrrolidine
(20S,2R,4R,5S)-15
1. Murphy, M. M.; Schullek, J. R.; Gordon, E. M.; Gallop, M. A. J. Am. Chem. Soc.
1995, 117, 7029–7030.
2. Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-Goerke, J.; Baker,
A.; Earnshaw, D. L.; Hofmann, G. A.; Keenan, R. M.; Dhanak, D. Bioorg. Med.
Chem. Lett. 2005, 15, 1553–1556.
Colourless powder (0.201 g, 40%): mp 242 °C (decomp.) (EtOH).
½
a 2D0
ꢁ
¼ ꢀ54:5 (c 0.5, C6H6). De >99.9% (HPLC, Phenomenex Luna
3. Sofia, M. J.; Chang, W.; Furman, P. A.; Mosley, R. T.; Ross, B. S. J. Med. Chem.
2012, 55, 2481–2531.
C18, tR 15.2 min). 1H NMR (500 MHz, DMSO-d6): d 0.80 (3H, d, J
6.6 Hz, Me-40); 0.87 (3H, d, J 6.4 Hz, Me-40); 1.17 (9H, s, COOtBu);
1.23 (1H, m, H-30B); 1.75 (2H, m, H-30A and H-40); 1.84 (1H, m,
H-3B); 2.22 (1H, m, H-3A); 3.51 (1H, m, H-4); 3.74 (3H, s, COOMe);
4.29 (1H, dd, J 12.1 and 6.7 Hz, H-2); 5.10 (2H, m, H-20 and H-5);
6.94 (2H, m, C6H4); 7.20 (2H, m, C6H4); 7.53 (2H, m, Phth); 7.70
(2H, m, Phth). Anal. Calcd for C31H35BrN2O7 (627.52): C, 59.33; H,
5.62; N, 4.46. Found: C, 59.31; H, 5.57; N, 4.43.
4. Kudryavtsev, K. V.; Shulga, D. A.; Chupakhin, V. I.; Churakov, A. V.; Datsuk, N.
G.; Zabolotnev, D. V.; Zefirov, N. S. Russ. Chem. Bull. 2011, 60, 685–693.
5. For some relevant reviews, see: (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem.
Rev. 2006, 106, 4484–4517; (b) Najera, C.; Sansano, J. M. Top. Heterocycl. Chem.
2008, 12, 117–145; (c) Najera, C.; Sansano, J. M. Monatsh. Chem. 2011, 142, 659–
680.
6. Slater, M. J.; Amphlett, E. M.; Andrews, D. M.; Bravi, G.; Burton, G.; Cheasty, A.
G.; Corfield, J. A.; Ellis, M. R.; Fenwick, R. H.; Fernandes, S.; Guidetti, R.; Haigh,
D.; Hartley, C. D.; Howes, P. D.; Jackson, D. L.; Jarvest, R. L.; Lovegrove, V. L. H.;
Medhurst, K. J.; Parry, N. R.; Price, H.; Shah, P.; Singh, O. M. P.; Stocker, R.;
Thommes, P.; Wilkinson, C.; Wonacott, A. J. Med. Chem. 2007, 50, 897–900.
7. (a) Kudryavtsev, K. V. Russ. J. Org. Chem. 2010, 46, 372–379; (b) Kudryavtsev, K.
V.; Shulga, D. A.; Chupakhin, V. I.; Churakov, A. V.; Datsuk, N. G.; Zabolotnev, D.
V.; Zefirof, N. S. Russ. Chem. Bull. 2011, 60, 685–693.
4.5.8. (2S,4S,5R)-5-(4-Bromophenyl)-4-tert-butoxy-carbonyl-1-
[(20S)-N-phthaloylleucyl]-2-methoxycarbonyl-pyrrolidine
(20S,2S,4S,5R)-15
8. Krasnov, V. P.; Gruzdev, D. A.; Levit, G. L. Eur. J. Org. Chem. 2012, 1471–1493.
9. (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; (c) Chulakov, E. N.; Gruzdev, D. A.; Levit, G. L.; Sadretdinova, L. Sh.;
Colourless powder (0.215 g, 43%): mp 187–188 °C (hexane–
EtOAc). ½a 2D0
¼ þ58:5 (c 1.0, C6H6). 97.1% de (HPLC, Phenomenex
ꢁ
Luna C18, tR 20.8 min). 1H NMR (400 MHz, DMSO-d6, 120 °C): d
0.42 (3H, d, J 5.9 Hz, Me-40); 0.58 (3H, d, J 6.2 Hz, Me-40); 1.15
(9H, s, COOtBu); 1.17–1.32 (2H, m, H-30B and H-40); 2.19–2.42

1688
E. N. Chulakov et al. / Tetrahedron: Asymmetry 23 (2012) 1683–1688
Krasnov, V. P.; Charushin, V. N. Russ. Chem. Bull. 2011, 60, 948–954; (d)
Chulakov, E. N.; Levit, G. L.; Tumashov, A. A.; Kodess, M. I.; Krasnov, V. P. Chem.
Heterocycl. Compd. 2012, 48, 724–732.
I.; Charushin, V. N. Tetrahedron: Asymmetry 2011, 22, 185–189; (e) Gruzdev, D.
A.; Levit, G. L.; Kodess, M. I.; Krasnov, V. P. Chem. Heterocycl. Compd. 2012, 48,
748–757.
10. (a) 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; (b) Krasnov, V. P.; Levit, G. L.;
Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N. Tetrahedron: Asymmetry 2004,
15, 859–862; (c) 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; (d) Levit, G. L.; Gruzdev, D. A.;
Krasnov, V. P.; Chulakov, E. N.; Sadretdinova, L. Sh.; Ezhikova, M. A.; Kodess, M.
11. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330.
12. (a) Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett. 2005, 7, 4672–4679; (b)
Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175.
13. Fischer, E.; Lipschitz, W. Ber. Dtsch. Chem. Ges. 1915, 48, 360–378.
14. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 6th ed.;
Butterworth Heinemann: USA, 2009. p 760.
15. Hashimoto, S.; Kase, S.; Suzuki, A.; Yanagiya, Y.; Ikegami, S. Synth. Commun.
1991, 21, 833–839.