An improved synthesis of enantiopure 2-azabicyclo[2.2.1]heptane-3-carboxylic acid

Article abstract of DOI:10.1016/S0957-4166(02)00048-4

A facile multigram scale preparation of (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid via stereoselective synthesis of the corresponding α-amino ester hydrochloride is detailed. Hitherto applied protocols for the synthesis of this cyclic proline

Full text of DOI:10.1016/S0957-4166(02)00048-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 25–28
An improved synthesis of enantiopure
2-azabicyclo[2.2.1]heptane-3-carboxylic acid
Vitali I. Tararov,a,* Renat Kadyrov,b Zenfira Kadyrova,a Natalia Dubrovinaa and Armin Bo¨rnera,*
aInstitut fu¨r Organische Katalyseforschung an der Universita¨t Rostock e.V., Buchbinderstr. 5/6, D-18055 Rostock, Germany
bDegussa AG, Projekthaus Katalyse, Gescha¨ftsbereich Creavis, Industriepark Hoechst, Geba¨ude G 830,
D-65926 Frankfurt/Main, Germany
Received 27 November 2001; accepted 30 January 2002
Abstract—A facile multigram scale preparation of (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid via stereoselective
synthesis of the corresponding a-amino ester hydrochloride is detailed. Hitherto applied protocols for the synthesis of this cyclic
proline analogue involving a tedious chromatographic purification step could thus be considerably improved upon. The specific
rotation of the a-amino acid reported in the literature has been revised. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion of the crude 3a by tedious flash chromatography in
order to obtain enantio- and diastereomerically pure
(1R,3S,4S)-3a. Therefore, this method is limited to
small-scale preparation.
The bicyclic proline analogue, exo-2-azabicyclo-
[2.2.1]heptane-3-carboxylic acid 1, has received much
interest in the field of peptide chemistry1 and in the
design of chiral ligands used in asymmetric catalysis.2
In our current work we required larger quantities of
enantiopure (1R,3S,4S)-1 and its ester 5. Although the
asymmetric synthesis of the free amino ester of 5 utiliz-
ing 3b as intermediate has been already reported by
Andersson et al. the large-scale preparation of this
compound is likewise hampered by the chromato-
graphic purification of 3b.5
In general, the syntheses of 1 reported to date1c,3 are
based on the finding that chiral imines of the type 2
react with cyclopentadiene to give the [4+2]-cycloadduct
3 with high diastereoselectivity (Scheme 1).4 As the
groups of Mellor and Andersson have shown,
(1R,3S,4S)-3a can be accessed by use of the enantio-
pure benzyl ester (R)-2a in the hetero-Diels–Alder reac-
tion.1c,3 Hydrogenation of the double bond and con-
comitant removal of the benzyl and phenylethyl groups
by hydrogenolysis in the presence of Pd/C affords
(1R,3S,4S)-1. The main disadvantage of this elegant
one-pot approach is associated with the prior purifica-
Herein we report a short and facile pathway for the
synthesis of the target compounds under the avoidance
of flash chromatography. A crucial issue of our
approach is based on the observation that catalytic
hydrogenation of the double bond in 3b can be
achieved
chemoselectively
without
significant
hydrogenolysis of the exocyclic NꢀC bond when low
loading of Pd/C is applied. Moreover, we found that
hydrochloride (1R,3S,4S)-4 is a readily crystallizing
solid offering therefore the opportunity to isolate it
directly
after
hydrogenation
and
subsequent
acidification.
In our first trials we synthesized 3b according to the
original protocol of Stella and Abraham.4a,b Thus,
imine (R)-2b was generated in situ from ethyl glyoxyl-
* Corresponding author. Fax: Int.+49-(0)381-4669324; e-mail: vitali.
tararov@ifok.uni-rostock.de; armin.boerner@ifok.uni-rostock.de
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00048-4

26
V. I. Tararo6 et al. / Tetrahedron: Asymmetry 13 (2002) 25–28
Scheme 1.
Hydrolysis of the ethyl ester (1R,3S,4S)-5 with 5 M
aqueous HCl gave quantitatively the hitherto unknown
hydrochloride of a-amino acid (1R,3S,4S)-6. The free
base (1R,3S,4S)-1 was liberated by using Dowex 50×8
cation-exchange resin.
ate and (R)-phenylethylamine, followed by hetero-
Diels–Alder reaction, which was accelerated by
CF3COOH and BF3·Et2O (method A) at low tempera-
ture (−60°C). The crude product 3b was isolated and
then hydrogenated in the presence of 5% Pd/C (0.3–
0.4% by weight) at 50 bar H2 pressure in EtOH. After
separation of the catalyst an excess of concentrated
HCl was added and the volatiles were evaporated.
Finally, (1R,3S,4S)-4 crystallized after trituration of the
semi-solid hydrochloride with Et2O/i-PrOH (5:1 mix-
ture) and was isolated in an overall yield of 32%.
Surprisingly, we found that the specific rotation of our
product (1R,3S,4S)-1, [h]2D2=−1.2 (c 1, H2O), had the
opposite sign and a different absolute value in compari-
son with that reported in the literature, [h]2D5=+5.9 (c 1,
H2O).3 To confirm the correctness of our finding the
enantiomeric a-amino acid (1S,3R,4R)-1 was synthe-
sised starting from (S)-1-phenylethylamine. The specific
rotations of relevant enantiomeric intermediates and
products compounds are given in Table 1. These data
clearly show that specific rotations differ only in the
sign but not in the absolute values.
In order to improve the yield of the hydrochloride, in
our next trials we isolated the pure imine (R)-2b prior
to the hetero-Diels–Alder–reaction and reacted it with
cyclopentadiene in the presence of CF3COOH/
BF3·Et2O in CH2Cl2 (−60°C, method B) and aqueous
CF3COOH in DMF (ambient temperature, method C),6
respectively. The latter reaction has been reported to be
similarly effective and stereoselective as the previous.
The application of these procedures, followed by
hydrogenation and salt formation gave hydrochloride
(1R,3S,4S)-4 with overall yields of 31 and 47%, respec-
tively. Besides a good yield no polymeric side products
were found by application of method C. Thus, it con-
trasted advantageously method B where the formation
of polymeric impurities complicated isolation of the
hydrochloride 4.
To obtain additional evidence that the configurations
detailed in Scheme
1 are correct a sample of
(1R,3S,4S)-5 was transformed into the known amino
alcohol (1R,3S,4S)-7 according to Scheme 2.5
The specific rotation of (1R,3S,4S)-7, [h]2D4=+59.9 (c 1,
CHCl3), correlates with the specific rotation for its
Table 1. Comparison of specific rotations for enantiomeric
amino acids 1 and intermediates
Compound
[h]D22–25 (Solvent)a
(1R,3S,4S)-5
(1S,3R,4R)-5
(1R,3S,4S)-6
(1S,3R,4R)-6
(1R,3S,4S)-1
(1S,3R,4R)-1
+16.2 (MeOH)
−16.3 (MeOH)
+22.3 (MeOH)
−22.8 (MeOH)
−1.2 (H2O)
Hydrogenolytic cleavage of the 1-phenylethyl group of
the tertiary amine (1R,3S,4S)-4 proceeded cleanly in
the presence of Pd/C in ethanol at 15 bar H2 pressure.
Noteworthy is the fact that no side products which
might be expected to arise in acidic media, were
formed.7 Hence, a facile access to the multigram prepa-
ration of a-amino acid ester (1R,3S,4S)-5 was found.
+1.4 (H2O)
a c 1.

V. I. Tararo6 et al. / Tetrahedron: Asymmetry 13 (2002) 25–28
27
CH2Cl2 (600 mL) (R)-phenylethylamine (30.5 g, 0.25
mol) was added slowly (30 min) with stirring. When
the addition was complete the mixture was stirred for 1
h at the same temperature. The mixture was then
cooled to −60°C and CF3COOH (19.3 mL, 0.25 mol)
and BF3·Et2O (31 mL, 0.25 mol) were added followed
by freshly distilled cyclopentadiene (20 g, 0.25 mol).
The resulting mixture was kept at −60°C for an addi-
tional 2 h (after 1 h the mixture solidified). The reaction
mixture was allowed to warm to ambient temperature
and left overnight then treated with aqueous NaHCO3
(60 g in 500 mL of water). The layers were separated
and the aqueous phase was additionally extracted with
CH2Cl2. The combined organic extracts were washed
with H2O, dried over MgSO4, filtrated and evaporated
to give the crude product 3b (62.4 g).
Scheme 2.
enantiomer (1S,3R,4R)-7, [h]2D6=−62.9 (c 1.03, CHCl3)
reported in the literature.5
2. Conclusion
In conclusion we have improved the stereoselective
synthesis of a-amino ester hydrochloride (1R,3S,4S)-5
and thus a fast and convenient access to enantiomeric
2-azabicyclo[2.2.1]heptane-3-carboxylic acids (1R,3S,
4S)-1 and (1S,3R,4R)-1, respectively, on multigram
scale avoiding chromatographic purification is dis-
closed. The specific rotation of (1R,3S,4S)-1 given in
the literature is also revised.
In a typical hydrogenation procedure the crude product
(17 g) was hydrogenated over Pd/C (5%, 0.6 g) in abs.
EtOH (10 mL) at 50 bar initial H2 pressure. After the
H2 uptake had ceased (typically after 4 h) the mixture
was filtered through Celite and the residue washed with
abs. EtOH. To the filtrate, conc. HCl (7 mL) was added
and then the mixture was evaporated. The procedure
was repeated several times with fresh portions of EtOH
until a semi-crystalline residue was formed. This was
treated with a Et2O/i-PrOH (5:1) mixture until crystals
precipitated. The mixture was kept overnight in a
freezer and then the mixture filtered. The solid collected
was washed successively with an Et2O/i-PrOH (5:1)
mixture and Et2O and dried to afford hydrochloride
(1R,3S,4S)-4 (7.3 g). When all of the starting material
was hydrogenated the hydrochloride was isolated in an
overall yield of 25.3 g (32.6%).
3. Experimental
NMR spectra were recorded using a Bruker ARX 400.
Chemical shifts (l, in ppm) are given for 1H NMR
relative to TMS as internal standard and for 13C NMR
relative to residual solvent peaks (77.36 ppm for
CDCl3, and 49.86 for CD3OD). Coupling constants (J)
are given in Hz. The optical rotation was measured on
a ‘gyromat-HP’ instrument (Fa. Dr. Kernchen). Melt-
ing points are corrected. Cyclopentadiene was obtained
from its dimer by heating at 200°C. The monomer was
received in a cooled flask and kept in dry ice. Ethyl
glyoxylate was depolymerised by distillation in vacuum
at 50 mbar (bath temperature 100°C) and used within a
few hours.
Method B. A solution of imine 2b (15 g, 0.073 mol) in
CH2Cl2 (100 mL) was cooled to −60°C and sequentially
treated with CF3COOH (5.7 mL, 0.074 mol), BF3·Et2O
(9.3 mL, 0.073 mol) and cyclopentadiene (7.3 g, 0.11
mol). When the addition was complete the reaction
mixture was stirred overnight at ambient temperature
and poured into a solution of NaHCO3 (20 g, 0.24 mol)
in water (300 mL). The product was extracted with
CH2Cl2. The organic layer was dried over MgSO4 and
evaporated to dryness. Hydrogenation of the crude
product in the presence of Pd/C (5%, 0.7 g) in abs.
EtOH (12 mL) under the conditions given above and
subsequent treatment with conc. HCl (8 mL) afforded
hydrochloride (1R,3S,4S)-4 (7.1 g, 31.4%).
3.1. Ethyl 2-[(R)-1-phenylethyl]iminoethanoate 2b
A cooled (0°C) solution of EtO2CCHO (25.6 g, 0.25
mol) in Et2O (150 mL) was treated by slow addition of
(R)-1-phenylethylamine (30.5 g, 0.25 mol), followed by
the addition of MgSO4 (45 g, 0.38 mol). The reaction
mixture was stirred overnight at ambient temperature,
then the solids were filtered off and washed with Et2O.
The filtrate was concentrated and the residue was dis-
tilled in vacuo to give imine 2b (41 g, 80%). Bp 95–
1
98°C/0.05 mbar. H NMR (CDCl3), l (ppm): 1.31 (3H,
Method C. A solution of imine 2b (15 g, 0.073 mol) in
DMF (48 mL) was treated with CF3COOH (5.7 mL,
0.074 mol), cyclopentadiene (9.7 g, 0.147 mol) and
water (0.04 g, 2.2 mmol). The mixture was stirred at
ambient temperature overnight, poured into aqueous
NaHCO3 (12.6 g, 0.15 mol) in water (300 mL). The
product was extracted with Et2O. The extract was
washed with conc. NaHCO3 solution and brine. After
evaporation of the solvents the crude product was
hydrogenated and pure material was isolated as
described above yielding hydrochloride (1R,3S,4S)-4
(10.7 g, 47%). An analytically pure sample was
obtained by recrystallization from EtOH–Et2O). Mp
t, J=7.0, CH3CH2), 1.59 (3H, d, J=6.7, CH3CH), 4.31
(2H, q, J=7.0, CH2CH3), 4.58 (1H, q, J=6.7,
CHCH3), 7.20–7.38 (5Harom., m), 7.72 (1H, s, CH=N).
13C NMR (CDCl3), l (ppm): 14.2 (CH3), 23.8 (CH3),
61.8 (CH2), 69.7 (CH), 128.7 (CH), 127.6 (CH), 126.9
(CH), 142.8 (C), 152.4 (CH), 163.3 (C).
3.2. Ethyl (1R,3S,4S)-2-[(R)-1-phenylethyl]-2-azabicyclo-
[2.2.1]heptane-3-carboxylate hydrochloride 4
Method A. To a cooled (0°C) mixture of ethyl glyoxy-
late (25.6 g, 0.25 mol), molecular sieves (4 A, 50 g) and
,

28
V. I. Tararo6 et al. / Tetrahedron: Asymmetry 13 (2002) 25–28
203–205°C. [h]2D2=−7.3 (c 1, MeOH). 1H NMR
(CD3OD), l (ppm): 0.97 (3H, t, J=7.1 Hz, CH3CH2),
1.77 (2H, d, J=6.7 Hz, CH3CH), 1.90–2.10 (5H, m),
2.22–2.36 (1H, m), 2.80 (1H, s), 3.80 (1H, s), 3.84–4.00
(2H, m, CH2CH3), 4.56 (1H, s), 4.61 (1H, q, J=6.7,
3.5. (1R,3S,4S)-2-Azabicyclo[2.2.1]heptane-3-carboxylic
acid 1
Hydrochloride 6 (1.5 g, 8.4 mmol) was transformed
into the free base using cation-exchange resin Dowex
50×8. After recrystallization from EtOH–Et2O analyti-
cally pure product was obtained (1.1 g, 90%). Mp
230–235°C (dec.). [h]2D2=−1.2 (c 1, H2O). 1H NMR
(CD3OD), l (ppm): 1.54–1.69 (2H, m), 1.70–1.93 (4H,
m), 2.93 (1H, s), 3.59 (1H, s), 4.16 (1H, s). 13C NMR
(CD3OD), l (ppm): 27.4 (CH2), 28.9 (CH2), 36.0 (CH2),
42.7 (CH), 60.3 (CH), 66.7 (CH), 174.1 (C). Anal. calcd
for C7H11NO2×0.25H2O: C, 57.72; H, 7.80; N, 9.62.
Found: C, 57.91; H, 7.82; N, 9.56%. (After drying
under vacuum at 80°C over P2O5 the elemental analysis
was consistent with the non-hydrated amino acid, calcd
for C7H11NO2: C, 59.56; H, 7.86; N, 9.92. Found: C,
59.58; H, 7.77; N, 9.75%)
CHCH3), 7.41–7.48 (3Harom., m), 7.63–7.71 (2Harom.
,
m). 13C NMR (CD3OD), l (ppm): 15.1 (CH3), 19.7
(CH3), 22.5 (CH2), 29.2 (CH2), 37.5 (CH2), 43.9 (CH),
64.6 (CH), 64.8 (CH2), 67.1 (CH), 72.3 (CH), 130.8
(CH), 131.1 (CH), 131.9 (CH), 137.4 (C), 169.9 (C).
Anal. calcd for C17H24ClNO2: C, 65.90; H, 7.81; N,
4.52. Found: C, 66.24; H, 7.62; N, 4.57%.
3.3. Ethyl (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-car-
boxylate hydrochloride 5
In a typical experiment hydrochloride (1R,3S,4S)-4
(17.7 g, 0.057 mol) were hydrogenated in the presence
of 5% Pd/C (1.7 g) in abs. EtOH (20 mL) at 15 bar H2
pressure. After 4 days the uptake of H2 ceased and the
mixture was filtered through Celite. The solids were
washed with abs. EtOH. The combined washing solu-
tions were evaporated and the residue was washed with
Et2O/EtOH, Et2O and dried to give amino acid ester
hydrochloride (1R,3S,4S)-5 (11.1 g, 94.5%). An analyti-
cally pure sample was obtained by recrystallization
from (EtOH–Et2O). Mp 153–154°C; [h]2D2=+16.2 (c 1,
MeOH). 1H NMR (CD3OD), l (ppm): 1.36 (3H, t,
J=7.1, CH3CH2), 1.67–1.80 (3H, m), 1.83–2.00 (3H,
m), 3.01 (1H, s), 4.13 (1H, s), 4.22 (1H, s), 4.29–4.41
(2H, m, CH2CH3). 13C NMR (CD3OD), l (ppm): 15.2
(CH3), 27.0 (CH2), 28.5 (CH2), 36.4 (CH2), 42.7 (CH),
61.3 (CH), 64.8 (CH), 65.1 (CH2), 170.7 (C). Anal.
calcd for C9H15ClNO2: C, 52.82; H, 7.39; N, 6.85.
Found: C, 53.01; H, 7.63; N, 6.91%.
Acknowledgements
Financial support from Degussa AG, Project House
Catalysis
(Frankfurt,
Germany),
the
Bmbf
(Fo¨rderkennzeichen 03C0304A) and the Fonds der
Chemischen Industrie is gratefully acknowledged.
References
1. (a) Gaitanopoulos, D. E.; Weinstock, J. J. Heterocyclic
Chem. 1985, 22, 957–959; (b) Ja¨ger, M.; Polborn, K.;
Steglich, W. Tetrahedron Lett. 1995, 36, 861–864; (c) Mel-
lor, J. M.; Richards, N. G. J.; Sargood, K. J.; Anderson,
D. W.; Chamberlin, S. G.; Davies, D. E. Tetrahedron Lett.
1995, 36, 6765–6768.
2. For a recent review, see: (a) Brandt, P.; Andersson, P. G.
Synlett 2000, 1092–1106; (b) Nordin, S. J. M.; Roth, P.;
Tarnai, T.; Alonso, D. A.; Brandt, P.; Anderson, P. G.
Chem. Eur. J. 2001, 7, 1431–1436.
3.4. (1R,3S,4S)-2-Azabicyclo[2.2.1]heptane-3-carboxylic
acid hydrochloride 6
3. So¨dergren, M. J.; Andersson, P. G. Tetrahedron Lett.
1996, 37, 7577–7580.
4. (a) Stella, L.; Abraham, H.; Feneau-Dupont, J.; Tinant,
B.; Declerq, J. P. Tetrahedron Lett. 1990, 31, 2603–2606;
(b) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707–
9718; (c) Waldmann, H.; Braun, M. Liebigs. Ann. Chem.
1991, 1045–1048.
5. Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.;
Andersson, P. G. J. Org. Chem. 1998, 63, 2749–2751.
6. Bailey, P. D.; Wilson, R. D.; Brown, G. R. J. Chem. Soc.,
Perkin Trans. 1 1991, 1337–1340.
A solution of hydrochloride 5 (1.3 g, 6.3 mmol) in
aqueous HCl (6 M, 10 mL) was heated under reflux for
6 h. Evaporation to dryness and subsequent recrystal-
lization of the residue from i-PrOH/Et2O gave analyti-
cally pure material (0.95 g, 84.9%). Mp 237–238°C
1
(dec.). [h]2D2=+22.3 (c 1, MeOH). H NMR (CD3OD),
l (ppm): 1.62–1.79 (3H, m), 1.83–1.97 (3H, m), 3.02
(1H, s), 4.05 (1H, s), 4.21 (1H, s). 13C NMR (CD3OD),
l (ppm): 27.1 (CH2), 28.6 (CH2), 36.32 (CH2), 42.7
(CH), 61.2 (CH), 64.8 (CH), 172.0 (C). Anal. calcd for
C7H12ClNO2: C, 47.33; H, 6.81; N, 7.89. Found: C,
47.85; H, 6.66; N, 7.96%.
7. Alonso, D. A.; Bertilsson, S. K.; Johansson, S. Y.; Nordin,
S. J. M.; So¨dergren, M. J.; Andersson, P. G. J. Org. Chem.
1999, 64, 2276–2280.