A practical, two-stage preparation of benzyl (3R)-3-amino-2-oxo-1- pyrrolidinecarboxylate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanediote (2:1)

Article abstract of DOI:10.1016/S0957-4166(03)00546-9

A convenient, efficient and cost-effective two-stage synthesis of benzyl (3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate (2S,3S)-2,3-bis[(4-methylbenzoyl) oxy]butanediote (2:1) via a crystallisation-induced dynamic resolution process is reported.

Full text of DOI:10.1016/S0957-4166(03)00546-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3627–3631
A practical, two-stage preparation of benzyl
(3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate
(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanediote (2:1)
Roger Barrett, Darren M. Caine, Kevin S. Cardwell,* Jason W. B. Cooke, Ron M. Lawrence,
,
Peter Scott and Asa Sjolin
Chemical Development, GlaxoSmithKline Research & Development, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire SG1 2NY, UK
Received 22 April 2003; accepted 13 June 2003
Abstract—A convenient, efficient and cost-effective two-stage synthesis of benzyl (3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate
(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanediote (2:1) via a crystallisation-induced dynamic resolution process is reported.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
(R)-2 (Scheme 1).5 Herein we report the development of
a cost-effective synthesis of this protected 3-aminopyrro-
lidinone as its (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-
butanedioc acid (di-p-toluoyltartarate) salt.
Pyrrolidine-trans-lactams have emerged recently as
attractive templates around which selective serine
protease inhibitors can be developed.1–3 A recent example
is the potent, human neutrophil elastase inhibitor 1,4
which is of interest as a potential therapy for respiratory
diseases such as cystic fibrosis and chronic bronchitis. A
key intermediate in the preparation of these compounds
is benzyl (3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate
Previous work has described the preparation of (R)-2
from the expensive unnatural amino acid (R)-methionine
3.6 Our strategy for preparing (R)-2 is based around
introducing the 3-amino substituent towards the end of
the synthesis, relying on a final dynamic resolution step
Scheme 1.
* Corresponding author. Tel.: +44(0)1438 768160; fax: +44(0)1438 764414; e-mail: kevin.cardwell@gsk.com
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00546-9

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R. Barrett et al. / Tetrahedron: Asymmetry 14 (2003) 3627–3631
Scheme 2. Reagents and conditions: (i) (1) Br2, 100°C, (2) Aq. NH3, CH2Cl2; (ii) (1) (COCl)2, CH2Cl2, (2) PhMe, 60°C, (3) benzyl
alcohol.
to impart the requisite homochirality. The route
described relies on the intramolecular cyclisation of a
CBZ-protected amide and avoids amino acid starting
materials.6–8 Apart from using inexpensive, readily
available starting materials, a key feature of this
approach is that the labile stereogenic centre is estab-
lished at a late stage in the synthesis.
2. Results and discussion
Bromine was added to 4-chlorobutanoyl chloride at ca.
100°C (Scheme 2). At this temperature, in the absence
of solvent, the reaction was addition rate controlled.9
The crude reaction mixture was cooled and added
directly to a mixture of aqueous ammonia and
dichloromethane to provide amide 4. Under these con-
ditions, displacement of the 4-chloro or 2-bromo sub-
stituents by ammonia was not observed and so the
product was isolated in an excellent yield (100%). The
required CBZ protecting group was introduced at this
point. Introducing this group post cyclisation to 3-
bromo-2-oxopyrrolidine10 proved difficult, so acidic
conditions11 were used to introduce the CBZ group
early to avoid premature cyclisation that can occur
under basic conditions. Thus treatment of 4 with oxalyl
chloride, followed by warming of solution to ca. 60°C
in toluene, generated the putative acyl isocyanate 6,
which on addition of benzyl alcohol provided diimide 5.
One approach to improving throughput and efficiency
is to minimise the number of isolated intermediates.
Hence, we established that 5 could be prepared directly
from 4-chlorobutanoyl chloride, without needing to
isolate 4, in 68% yield overall. Isolation at this point
was attractive, as this proved to be the last crystalline
intermediate before the final product.
Scheme 3. Reagents and conditions: (i) NaN3, DMF; (ii)
Na2CO3, DMF; (iii) Aq. Na2CO3, NaN3, cat. BnBu3NBr,
EtOAc.
alternative reaction sequence. Treatment of 5 with base
i
t
(e.g. K2CO3, Pr2NEt, BuNH2) in DMF induced rapid
cyclisation to provide a mixture of halolactams 8 and 9.
Both 8 and 9 react with azide, but the displacement of
chloride from 8 was unacceptably slow.12 Remarkably,
we were able to circumvent this issue by introducing a
phase transfer catalyst (benzyltributylammonium bro-
mide). Under these conditions, using a mixture of
Na2CO3 and NaN3 in EtOAc/water, 8 was not observed
during the cyclisation step and introduction of the azide
to produce 10 proceeded smoothly.
A Staudinger reduction13 of 10 readily provided 2,
though careful control of the hydrolysis conditions was
required. The critical parameters were water content
and temperature, as under the slightly basic conditions
of this reaction, formation of the insoluble dimer 11
was facile (Scheme 4).14 The final step was a crystallisa-
tion-induced dynamic resolution.15,16 Key to the
efficiency of this process is a large difference in solubil-
ity between the diastereomeric salt pairs. We screened
the salts formed between 2 and a wide range of chiral
acids, selected on the basis of their low cost and bulk
availability. Rather than measure solubility directly, we
With the pivotal intermediate 5 in hand, we turned our
attention to the later stages. Treatment of 5 with
sodium azide led cleanly to chloroazide 7, which, on
addition of Na2CO3, cyclised readily to the desired
azidolactam 10 (Scheme 3). However, to avoid a poten-
tial thermal runaway on scale-up [the process is
exothermic and 7 decomposes thermally with a rela-
tively low onset temperature (46°C)], we investigated an

R. Barrett et al. / Tetrahedron: Asymmetry 14 (2003) 3627–3631
3629
Scheme 4. Reagents and conditions: (i) PPh3, THF; (ii) EtOAc, THF, water; (iii) (+)-di-p-toluoyltartaric acid 12, cat. 3,5-
dichlorosalicylaldehyde, EtOAc, water, 60°C.
looked initially for a marked difference in melting point
between the pairs. A large difference in melting point
infers a large difference in solubility with the higher
melting salt being least soluble.17 For each acid, the
melting point of the solid formed from a 1:1 mixture
(and 1:2 for bifunctional acids) of the acid and the
individual enantiomers of 218 was determined (Table 1);
a range of solvents was used in the screen to improve
the probability that crystalline salts would be obtained.
(+)-Di-p-toluoyltartaric acid 12, with a melting point
difference of 44°C between the pair of salts was selected
for further work.
with a markedly improved resolution rate. Fortunately,
it was found that a similar rate enhancement could be
achieved by raising the reaction temperature from 20 to
60°C, so the process was further developed without
including the additional base. From this work, a simple
process from 7 to 13 was readily identified that pro-
duced 13 in 67% yield [(R)-2 of 98% ee].20
In summary, a convenient, efficient, two-stage process
for the preparation of 13, a key intermediate in the
synthesis of pyrrolidine-trans-lactams, has been devel-
oped from inexpensive starting materials.
The dynamic resolution process was developed using 12
and a catalytic quantity of 3,5-dichlorosalicylaldehyde.
EtOAc was chosen as the solvent to avoid isolation of
10 and, attractively, deliver a single organic solvent for
the entire stage. Initially, a designed experiment was
performed to identify factors (water, tributylamine and
12) that were critical for high diastereomeric purity of
the bulk reaction mixture.19 From this study, additional
water and to a lesser extent excess 12 were identified as
the factors that had a significant positive effect. In
3. Experimental
3.1. General procedure
Melting points were measured using an Electrothermal
A1 8102 Digital Melting Point Apparatus in open
capillary tubes and are uncorrected. Differential scan-
ning calorimetry (DSC) screening tests were carried out
on a Mettler 12E calorimeter in a high-pressure gold
plated pan with a 5°C/min ramp rate. NMR spectra
contrast,
tributylamine
had
little
effect
on
diastereomeric purity, but caused some degradation,
1
were recorded on a Bruker DPX250 spectrometer; H
NMR spectra at 250 MHz (chemical shifts are
expressed in ppm relative to internal TMS, coupling
constants in Hz) and 13C at 100 MHz. Infrared spectra
were recorded in Nujol mull on a Nicolet 20SXC FTIR
spectrophotometer. Mass spectra were obtained on a
Micromass Q-TOF hybrid quadrupole time of flight
mass spectrometer using +ve ion electrospray and ery-
thromycin as lock mass. Elemental analyses were per-
formed by Butterworth Laboratories Limited. HPLC
was carried out using the following method: a gradient
from 100% A to 95% B over 8 min (A=water:TFA
1000:0.5. B=acetonitrile:TFA 1000:0.5); column 50
mm×2.0 mm Luna C18(2), 3 mm; flow rate 1.0 mL/min;
temperature 40°C; UV detection at 220 nm. Chiral
Table 1. Melting points of the diastereomeric salts
Chiral acid
Mp (°C)
(S)-2
(R)-2
(−)-Camphorsulphonic acida
(+)-Dibenzoyltartaric acida
(+)-Di-p-toluoyltartaric acid 12a
(−)-Malic acid
154
168
184
171
132
108
193
162
175
140
167
113
144
168
(−)-Mandelic acida
(−)-Pyrrolidone-5-carboxylic acid
(−)-Tartaric acida
a Both enantiomers available at low cost.

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R. Barrett et al. / Tetrahedron: Asymmetry 14 (2003) 3627–3631
HPLC was carried out using the following method:
isocratic with heptane/ethanol mixtures, column Chiral-
celADorOD-H250×4.6 mm, 5 mm; flowrate1.0mL/min;
temperature ambient–50°C; UV detection at 215 nm.
Reagents and solvents were obtained from commercial
suppliers and used without further purification.
3.1.3. Benzyl 2-azido-4-chlorobutanoylcarbamate, 7.
Sodium azide (0.70 g, 10.8 mmol) was added to a mixture
of 5 (3.0 g, 9.0 mmol), sodium bicarbonate (1.5 g, 17.9
mmol) and benzyltributylammonium bromide (0.12 g, 0.3
mmol) in ethyl acetate (30 mL) and water (30 mL)
vigorously stirred at 20°C. After 5 h, the organic phase
was separated, dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash column chromatog-
raphy using a gradient of ethyl acetate and isooctane
(1:10–3:7) as eluant gave 7 (1.3 g, 47%) as a colourless
oil. IR: v=1713, 1770, 2113, 3276 cm−1. 1H NMR
(CDCl3): l=2.12–2.22 (m, 1H), 2.34–2.43 (m, 1H),
3.65–3.75 (m, 2H), 4.59–4.67 (m, 1H), 5.22 (s, 2H),
7.34–7.42 (m, 5H), 8.16 (br s, 1H). 13C NMR (CDCl3):
l=34.3, 40.4, 60.5, 68.5, 127.1, 127.5, 128.9, 134.5, 150.4.
HRMS: m/z calcd for C12H13ClN4O3 (M+H+): 297.0754.
Found: 297.0752. DSC: exotherm range 46–168°C, 132
kJ with rapid gas evolution; 168–257°C, 56 kJ.
3.1.1. 2-Bromo-4-chlorobutanamide, 4. Bromine (191 g,
1.20 mol) was added to 4-chlorobutanoyl chloride (100
g, 0.70 mol) stirred at 95–110°C over 3 h. After a further
15 min, the solution was cooled to <30°C, diluted with
CH2Cl2 (400 mL) and added to a rapidly stirred mixture
of aqueous ammonia (0.88 specific gravity, 60 g, 3.5 mol),
water (180 mL) and CH2Cl2 (600 mL) maintained at
20–30°C. The phases were separated, the aqueous phase
extracted with CH2Cl2 (250 mL) and the combined
organic phases washed with saturated brine (370 mL,
containing 3 g of sodium metabisulphite). CH2Cl2 (240
mL) was added, the solution concentrated and dried in
vacuoat45°C togive 4asapalebrownsolid (114 g, 100%).
3.1.4. Benzyl 3-chloro-2-oxopyrrolidine-1-carboxylate, 8.
A solution of 5 (5.0 g, 14.9 mmol) and diisopropylethyl-
amine (3.0 mL, 17.2 mmol) in DMF (20 mL) was stirred
at 20°C. After 15 h, the aqueous sulphuric acid (2 M, 100
mL) was added. The mixture was extracted with CH2Cl2
(2×50 mL), the combined organic phases washed with
water (3×50 mL), dried over MgSO4, filtered and concen-
trated in vacuo to give a mixture of 8 and 9 (6:1, 3.98
g) as an orange oil. A sample (3.5 g) was purified by flash
column chromatography using ethyl acetate and isooc-
tane(1:9–2:3)aseluanttogive8(1.2g, 34%)asacolourless
Whilst this material was sufficiently pure to use in
subsequent process investigation, a sample was recrys-
tallised from tert-butylmethylether:isooctane to provided
4 as a white solid; mp 88–89°C. IR: w=1664, 3184, 3344
cm−1. 1H NMR (D6-DMSO): l=2.25–2.33 (m, 2H),
3.64–3.77 (m, 2H), 4.47–4.53 (m, 1H), 7.35 (br s, 1H), 7.82
(br s, 1H). 13C NMR (D6-DMSO): l=36.5, 42.6, 45.9,
169.4. HRMS: m/z calcd for C4H7BrClNO (M+H+):
199.9478. Found: 199.9490.
1
oil. IR: w=1726, 1761, 1795 cm−1. H NMR (CDCl3):
l=2.19–2.28 (m, 1H), 2.50–2.60 (m, 1H), 3.78–3.84 (m,
1H), 3.92–3.98 (m, 1H), 4.42 (dd, J=6, 8 Hz, 1H), 5.31
(s, 2H), 7.31–7.45 (m, 5H). 13C NMR (CDCl3): l=29.4,
44.2, 55.5, 69.0, 128.7, 128.9, 129.0, 135.3, 151.6, 169.0.
HRMS: m/z calcd for C12H12ClNO3 (M+H+): 254.0584.
Found: 254.0588.
3.1.2. Benzyl 2-bromo-4-chlorobutanoylcarbamate, 5.
Bromine (55 mL, 1.07 mol) was added to 4-chlorobu-
tanoyl chloride (100 mL, 0.89 mol) stirred at 105–110°C
over 1 h. After a further 40 min, the solution was cooled
to <30°C. CH2Cl2 (150 mL) was added and the solution
added to a rapidly stirred mixture of aqueous ammonia
(0.88 specific gravity, 230 mL), water (230 mL) and
CH2Cl2 (750 mL) maintained at 20–30°C. The aqueous
phase was separated and extracted with CH2Cl2 (400 mL).
The combined organic phases were washed with aqueous
sodium chloride (23% w/w, 390 g), and concentrated in
vacuo. Toluene (450 mL) was added, followed by oxalyl
chloride (73 mL, 0.84 mol) at <30°C over 15 min. The
mixture was heated at 50–60°C for 135 min, cooled to
20°C and benzyl alcohol (88 mL, 0.85 mol) added at
20–30°C. The solution was cooled to 5°C to initiate
crystallisation. Isooctane (500 mL) was added over 20
min, the precipitate collected by filtration, washed with
isooctane (2×150 mL) and dried to give 5 (204 g, 68%)
as an off-white solid.21
3.1.5. Benzyl 3-bromo-2-oxopyrrolidine-1-carboxylate, 9.
A mixture of 5 (3.0 g, 9.0 mmol), sodium carbonate (1.14
g, 10.8 mmol) and benzyltributylammonium bromide
(0.12 g, 0.3 mmol) in ethyl acetate (30 mL) and water (30
mL) was vigorously stirred at 50°C. After 1.5 h, the
mixture was cooled to 25°C. The organic phase was
separated, dried over MgSO4, filtered and concentrated
in vacuo. Purification by flash column chromatography
using a gradient of ethyl acetate and isooctane (1:9–2:3)
as eluant gave 9 (1.1 g, 42%) as a colourless oil. IR:
1
w=1725, 1756, 1791 cm−1. H NMR (CDCl3): l=2.25–
2.34 (m, 1H), 2.52–2.61 (m, 1H), 3.84–3.97 (m, 2H), 4.21
(dd, J=4, 8 Hz, 1H), 5.31 (s, 2H), 7.32–7.46 (m, 5H). 13
C
NMR (CDCl3): l=29.3, 43.7, 44.4, 68.6, 128.3, 128.5,
128.6, 134.9, 169.1. HRMS: m/z calcd for C12H12BrNO3
(M+H+): 298.0079. Found: 289.0085.
Whilst this material was sufficiently pure to use in
subsequent chemistry, a sample was recrystallised from
tert-butylmethylether:isooctane to provide 5 as a white
3.1.6. Benzyl 3-azido-2-oxopyrrolidine-1-carboxylate, 10.
A mixture of 5 (50.0 g, 149 mmol), sodium azide (11.5
g, 177 mmol), sodium carbonate (19.0 g, 179 mmol) and
benzyltributylammonium bromide (2.0 g, 6.4 mmol) in
ethyl acetate (200 mL) and water (400 mL) was vigorously
stirred at 50°C. After 2.5 h, the mixture was cooled to
25°C. The organic phase was separated and the aqueous
1
solid; mp 91–92°C. IR: w=1703, 1752, 3254 cm−1. H
NMR (D6-DMSO): l=2.27–2.46 (m, 2H), 3.64–3.81 (m,
2H), 4.87 (br s, 1H), 5.18 (s, 2H), 7.34–7.44 (m, 5H), 11.15
(s, 1H). 13C NMR (D6-DMSO): l=35.7, 42.9, 45.2, 67.1,
128.6, 128.7, 128.8, 128.9, 135.9, 151.3. HRMS: m/z calcd
for C12H13BrClNO3 (M+H+): 333.9846. Found: 333.9827.

R. Barrett et al. / Tetrahedron: Asymmetry 14 (2003) 3627–3631
3631
phase back-extracted with ethyl acetate (2×200 ml). The
combined organic phases were dried over MgSO4, filtered
and concentrated in vacuo to give 10 as a purple oil. A
sample of 10 was purified by flash chromatography using
dichloromethane as eluant to give 10 as a colourless oil
2. Pass, M.; Abu-Rabie, S.; Baxter, A.; Conroy, R.; Coote,
S. J.; Craven, A. P.; Finch, H.; Hindley, S.; Kelly, H. A.;
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1
that solidified on standing. IR: w=1786, 2104 cm−1. H
NMR (CDCl3): l=1.81–1.92 (m, 1H), 2.29–2.38 (m, 1H),
3.59–3.66 (m, 1H), 3.82–3.87 (m, 1H), 4.21 (t, J=9 Hz,
1H), 5.28 (s, 2H), 7.31–7.44 (m, 5H). 13C NMR (CDCl3):
l=24.7, 43.0, 60.1, 68.5, 128.2, 128.5, 128.7, 134.9, 151.1,
170.1. HRMS: m/z calcd for C12H12N4O3 (M+H+):
261.0988. Found: 261.0994.
3.1.7. Benzyl (3R)-3-amino-2-oxopyrrolidine-1-carboxyl-
ate
(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioate
(2:1), 13. A mixture of 5 (50 g, 149 mmol), sodium
carbonate (19 g, 179 mmol), sodium azide (11.5 g, 177
mmol) and benzyltributylammonium bromide (2.0 g, 6.4
mmol) in ethyl acetate (200 mL) and water (400 mL) was
stirred vigorously at 50°C. After 2.5 h, the mixture was
cooled to 25°C. The organic phase was separated and the
aqueous phase back-extracted with ethyl acetate (2×200
mL). The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo. Ethyl acetate
(500 mL) was added, followed by a solution of
triphenylphosphine (40 g, 153 mmol) in ethyl acetate (100
mL) over 15 min, whilst the temperature rose to 40°C.
After a further 15 min at ca. 40°C, water (10 mL) was
added. After 3.5 h, 12 (45 g, 116 mmol), 3,5-dichloro-sal-
icylaldehyde (1.0 g, 5.2 mmol) and water (25 mL) were
added. The reaction mixture was heated at 60–66°C for
3.5 h, before cooling to 20°C overnight. The product was
filtered off, washed with ethyl acetate (200 mL) and dried
to give 13 (42.5 g, 67%) as a white solid;21 mp 178–179°C
(dec.). Chiral HPLC: 5.31 min [(S)-2, 1.1% a/a], 7.40 min
8. Bell, I. M.; Beshore, D. C.; Gallicchio, S. N.; Williams, T.
M. Tetrahedron Lett. 2000, 41, 1141.
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50, 2480.
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Tetrahedron 1981, 37, 437.
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17. Yoshioka, R.; Hiramatsu, H.; Okamura, K.; Tsujioka, I.;
Yamada, S. J. Chem. Soc., Perkin 2 2000, 10, 2121.
18. Samples of (R)-2 and (S)-2 were prepared from (R)- and
(S)-methionine, respectively, using the methodology out-
lined in Ref. 6.
1
[(R)-2, 98.9% a/a]. IR: w=1721, 1773 cm−1. H NMR
(D6-DMSO): l=1.70–1.82 (m, 2H), 2.22–2.29 (m, 2H),
2.34 (s, 6H), 3.49–3.57 (m, 2H), 3.69–3.75 (m, 2H),
3.77–3.82 (dd, J=8, 11 Hz, 2H), 5.24 (s, 2H), 5.59 (s, 2H),
7.29 (d, J=8 Hz, 4H), 7.32–7.44 (m, 10H), 7.80 (d, J=8
Hz, 4H). 13C NMR (D6-DMSO): l=21.5, 25.6, 43.0, 57.5,
71.6, 127.2, 128.1, 128.5, 128.8, 129.6, 129.6, 136.0, 165.1,
168.3. HRMS: m/z calcd for C12H15N2O3 (M+H+):
235.1083. Found: 235.1090. m/z calcd for C20H22 NO8
+
(M+NH4 ): 404.1345. Found: 404.1325. Anal. calcd for
C44H46N4O14: C, 61.8; H, 5.42; N, 6.55. Found: C, 61.5;
H, 5.40; N, 6.40%.
Acknowledgements
19. Design of experiments (DOE) analysis was performed using
Design-Expert® (Stat-Ease, Inc., Minneapolis, MN,
1.800.801.7191, www.statease.com).
We are grateful to Chris Jones, Nisha Mistry, Andrew
Ray, Alec Simpson and Dave Sugden for analytical
support.
20. A solution of (R)-2 in EtOAc was readily prepared by
treating 13 with aqueous sodium carbonate followed by
extraction into ethyl acetate. However, 11 was rapidly
formed when the extract was heated and/or concentrated.
21. Formal stability studies have not been performed on either
5 or 13. However, samples showed no change in either
appearance or impurity profile after storage for one year
in amber coloured glass bottles at <30°C.
References
1. Macdonald, S. J.; Belton, D. J.; Buckley, D. M.; Spooner,
J. E.; Anson, M. S.; Harrison, L. A.; Mills, K.; Upton, R.
J.; Dowle, M. D.; Smith, R. A.; Molloy, C. R.; Risley, C.
J. Med. Chem. 1998, 41, 3919.