Synthesis of (R)-quinuclidine-2-carboxylic acid in enantiomerically pure form

Article abstract of DOI:10.1016/j.tetlet.2008.02.035

Enantiomerically pure (R)-quinuclidine-2-carboxylic acid has been prepared by following two related 7 step synthetic routes in 16% and 19% overall yield, respectively, from a 1,2,4-trisubstituted piperidine that is easily prepared from inexpensive d-manni

Full text of DOI:10.1016/j.tetlet.2008.02.035

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2251–2253
Synthesis of (R)-quinuclidine-2-carboxylic acid
in enantiomerically pure form
*
*
´
´
´
´
´
Pablo Etayo, Ramon Badorrey, Marıa D. Dıaz-de-Villegas , Jose A. Galvez
Departamento de Quı´mica Orga´nica, Instituto de Ciencia de Materiales de Arago´n, Instituto Universitario de Cata´lisis Homoge´nea,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 19 December 2007; revised 5 February 2008; accepted 6 February 2008
Available online 10 February 2008
Abstract
Enantiomerically pure (R)-quinuclidine-2-carboxylic acid has been prepared by following two related 7 step synthetic routes in 16%
and 19% overall yield, respectively, from a 1,2,4-trisubstituted piperidine that is easily prepared from inexpensive D-mannitol.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Azabicyclo[2.2.2]octane; Intramolecular cyclisations; Piperidines; Stereoselective synthesis
Quinuclidine-2-carboxylic acid is an interesting bicyclic
amino acid with a close structural relationship to other
N
H
bicyclic amino acids used as chiral ligands in enantioselec-
tive catalysis1,2 or with biological activity.3 In this context
the potential use of this compound as an enantioselective
catalyst or an intermediate in the synthesis of chiral drugs
has recently been considered.4
In spite of this, synthetic methodologies described for
the synthesis of quinuclidine-2-carboxylic acid are scarce.
Since the first synthesis of the racemic compound,
described by Prelog and Cerkovnikov,5 only a few
approaches to the synthesis of this compound have been
reported in the literature.2,6 Recently, Mi and Corey4
obtained each enantiomer of this amino acid by chemical
and enzymatic resolution of racemic intermediates from
the synthetic pathway that they developed. We report
herein full details on the synthesis of enantiomerically pure
(R)-quinuclidine-2-carboxylic acid (1).
CO2H
1
(bromoethyl)]piperidine (Scheme 1). The appropriate sub-
stituent at C2 in the starting piperidine would provide the
carboxylic acid moiety of quinuclidine-2-carboxylic acid.
CH2Br
N
H
H
N
H
N
OR
CO2H
RO
PG OR
OR
1
2
3
O
CHCO2Et
We reasoned that the 1-azabicyclo[2.2.2]octane skeleton
could be obtained by intramolecular cyclisation of a 4-[2-
D-mannitol
H
H
N
N
OBn
OBn
OBn
OBn
CH3
Ph
CH3
Ph
*
Corresponding authors. Tel.: +34 976 762274; fax: +34 976 761202
4
5
(M.D.D.); tel.: +34 976 762273; fax: +34 976 761202 (J.A.G.).
PG = protecting group
´
E-mail addresses: loladiaz@unizar.es (M. D. Dıaz-de-Villegas),
´
Scheme 1. Retrosynthetic analysis for (R)-quinuclidine-2-carboxylic acid.
jagl@unizar.es (J. A. Galvez).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.035

2252
P. Etayo et al. / Tetrahedron Letters 49 (2008) 2251–2253
CO2Et
H
CH2OH
H
CHCO2Et
a
b
c
H
N
OBn
N
OBn
N
OBn
OBn
Boc OBn
Boc OBn
CH3
Ph
4 (E/Z = 97/3)
6 (cis/trans = 82/18)
7 (cis/trans = 82/18)
CH2Br
H
d,e
f
g
N
H
N
H
N
H
CO2H
N
OBn
HO
BnO
Boc OBn
OH
OBn
8 (cis/trans = 82/18)
9
10
1
Scheme 2. Reagents and conditions refer to 1 mmol of substrate: (a) Pd/C cat, H2, Boc2O (3 mmol), EtOH, 1 atm, rt, 15 h (83%); (b) LiBH4 (2 mmol),
Et2O, rt, 24 h, then satd aq NH4Cl (89%); (c) CBr4 (3 mmol) CH2Cl2, 0 °C, then PPh3/PS (3 mmol), reflux, 8 h (65%); (d) 1.2:1 CH2Cl2/TFA, rt, 2 h, then
satd aq NaHCO3 to basic pH; (e) Et3N (4 mmol), CH3CN, reflux, 6 h, then NaOH to basic pH (87% two steps); (f) Pd(OH)2/C cat, H2, 100:1 EtOH/
HClconcd, 1 atm, rt, 19 h, then NaOH to basic pH; (g) NaIO4 (4 mmol), RuCl3 (0.1 mmol), 2:2:3 CH3CN/CCl4/H2O, rt, 5 h, then Dowex 50WX8-200
(39%, two steps).
In turn, 4-[2-(bromoethyl)]piperidine derivative could be
prepared from 4-ethoxycarbonylmethylidenepiperidine 4,
which is easily obtainable from inexpensive D-mannitol
through intermediate enaminone 5.7 The nature of the
azabicyclo[2.2.2]octane skeleton means that the absolute
configuration of the final product only depends on the
absolute configuration at C2 of the intermediate 2,4-dialkyl
piperidines.
Alternatively, compound 4 was converted into bicyclic
derivative 9 by the sequence shown in Scheme 3. Hydro-
genation of 4 using Pt/C as the catalyst followed by the
reduction of the obtained 75:25 cis/trans crude diastereo-
meric mixture of the saturated ester with LiAlH4, as previ-
ously described,14 gave compound 11. Crude 11 was then
submitted to N-debenzylation by hydrogenation using
Pd/C as the catalyst to afforded amine 12 as a 75:25 mix-
ture of cis and trans diastereoisomers. Subsequent reaction
of crude 12 with CBr4 and polystyrene-supported PPh3
followed by triethylamine-promoted cyclisation gave
diastereomerically pure bicyclic derivative 9. The inter-
mediates obtained did not require purification prior to
use in the following step and the overall yield for the
whole sequence was 51% (five steps). In this way,
(R)-quinuclidine-2-carboxylic acid 1 was obtained from
The synthesis of compound 1 began with a 97:3 E/Z
mixture of 4-ethoxycarbonylmethylidenepiperidine 4,
which was obtained as previously described.7c Heteroge-
neous catalytic hydrogenation of compound 4 in the pres-
ence of di-tert-butyl pyrocarbonate and using Pd/C as the
catalyst gave 83% isolated yield of compound 68 as an
82:18 mixture of cis and trans diastereoisomers, as deter-
1
mined by H NMR analysis of the crude reaction mixture.
Reduction of compound 6 with LiBH4 provided alcohol 79
as an 82:18 mixture of cis and trans diastereoisomers in
89% yield.
CH2OH
CHCO2Et
Reaction of 7 with CBr4 and polystyrene-supported
PPh3 afforded an 82:18 mixture of cis and trans diastereo-
isomers of the bromide 810 in 65% yield. N-Boc deprotec-
tion by treatment of 8 with trifluoroacetic acid and
subsequent triethylamine-promoted cyclisation gave dia-
stereomerically pure bicyclic derivative 911 in 87% yield.
It is worth mentioning that both diastereoisomers of
compound 8 led to the same diastereoisomer of compound
9. Compound 9 was converted into (R)-quinuclidine-2-
carboxylic acid by hydrogenolysis of O-benzyl ethers in
the presence of HCl using Pd(OH)2/C as the catalyst
followed by oxidative cleavage of the diol moiety of crude
1012 by treatment with an excess of NaIO4 in the presence
of RuCl3, a process that gave the desired compound 113 as
a white solid in 39% overall yield for the last two steps. The
complete synthetic pathway shown in Scheme 2 leads to
enantiomerically pure (R)-quinuclidine-2-carboxylic acid
1 in seven steps and gave an overall yield of 16%.
a, b
H
H
N
OBn
N
OBn
OBn
OBn
CH3
Ph
CH3
Ph
4 (E/Z = 97/3)
CH2OH
11 (cis/trans = 75/25)
c
d,e
N
H
H
N
H
OBn
BnO
OBn
OBn
12 (cis/trans = 75/25)
9
Scheme 3. Reagents and conditions refer to 1 mmol of substrate: (a) Pt/C
cat, H2, EtOH, 1 atm, rt, 5 h; (b) LiAlH4 (1.2 mmol), THF, rt, 1 h; then
satd aq NH4Cl; (c) Pd/C cat, H2, 15:2 EtOH/H2O, 1 atm, rt, 24 h; (d) CBr4
(3 mmol) CH2Cl2, 0 °C, then PPh3/PS (3 mmol), reflux, 8 h, then satd aq
NaHCO3 to basic pH; (e) Et3N (4 mmol), CH3CN, reflux, 6 h, then NaOH
to basic pH (51%, five consecutive steps).

P. Etayo et al. / Tetrahedron Letters 49 (2008) 2251–2253
2253
9. A pure sample of compound cis-7 was obtained by reduction of pure
4-alkoxycarbonylmethylidenepiperidine 4 in seven steps
with an overall yield of 19%.
25
cis-6. Selected data for cis-7: Oil, ½aꢀD +46.8 (c 0.89, CHCl3). 1H
NMR (400 MHz, CDCl3) d 0.95–1.03 (m, 1H), 1.25 (ddd, J = 11.8,
11.8, 11.4 Hz, 1H), 1.36 (s, 9H), 1.38–1.48 (m, 2H), 1.46–1.55 (m, 1H),
1.64 (ddd, J = 11.4, 6.8, 2.2 Hz, 1H), 1.66 (br s, 1H), 1.81–1.91 (m,
1H), 2.99 (ddd, J = 14.0, 10.6, 6.8 Hz, 1H), 3.54 (ddd, J = 6.2, 6.2,
1.6 Hz, 2H), 3.56 (dd, J = 10.4, 6.4 Hz, 1H), 3.63 (dd, J = 10.4,
3.1 Hz, 1H), 3.67–3.73 (m, 1H), 3.71–3.76 (m, 1H), 4.04 (ddd,
J = 11.8, 6.8, 4.9 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.50 (d,
J = 12.0 Hz, 1H), 454 (d, J = 11.8 Hz, 1H), 4.73 (d, J = 11.8 Hz,
1H), 7.16–7.29 (m, 10H); 13C NMR (100 MHz, CDCl3) d 27.5, 28.4,
29.0, 29.2, 38.2, 39.4, 54.2, 60.4, 71.5, 73.1, 73.4, 79.4, 80.1, 127.3,
In conclusion, enantiomerically pure (R)-quinuclidine-2-
carboxylic acid 1 can be obtained from natural sources in a
simple manner. The particular structure of the final
product makes it possible to obtain (R)-quinuclidine-
2-carboxylic acid from both diastereoisomers of chiral
intermediates obtained in the proposed routes. This situa-
tion allows the transformation of these diastereomeric mix-
tures without complicated chromatographic isolation
procedures. Given that the enantiomer of enaminone 5
has previously been obtained from commercially available
L-mannonic c-lactone,15 (S)-quinuclidine-2-carboxylic acid
could be obtained with equal efficiency.
127.5, 127.6, 127.6, 128.1, 128.3, 138.3, 138.8, 155.9. IR (neat, cmꢁ1
)
3435, 1684, 1247. HRMS (ESI+), m/z calcd for [C28H39NO5+Na]+:
492.2720. Found: 492.2697.
10. A pure sample of compound cis-8 was obtained by bromination of
25
pure cis-7. Selected data for cis-8: Oil, ½aꢀD +38.4 (c 0.64, CHCl3). 1H
NMR (500 MHz, CDCl3) d 0.98–1.06 (m, 1H), 1.33 (ddd, J = 12.3,
12.3, 12.3 Hz, 1H), 1.43 (s, 9H), 1.57–1.67 (m, 1H), 1.65–1.71 (m, 1H),
1.73–1.86 (m, 2H), 1.89–1.99 (m, 1H), 2.97 (ddd, J = 14.0, 10.6,
6.7 Hz, 1H), 3.36 (ddd, J = 7.1, 7.1, 1.3 Hz, 2H), 3.62 (dd, J = 10.5,
6.6 Hz, 1H), 3.69 (dd, J = 10.5, 3.3 Hz, 1H), 3.76 (ddd, J = 6.6, 4.3,
3.3 Hz, 1H), 3.77–3.83 (m, 1H), 4.08–4.15 (m, 1H), 4.52 (d,
J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 11.8 Hz,
1H), 4.80 (d, J = 11.8 Hz, 1H), 7.24–7.38 (m, 10H); 13C NMR
(125 MHz, CDCl3) d 28.4, 28.4, 28.7, 29.7, 30.9, 38.2, 39.5, 54.2, 71.5,
73.2, 73.5, 79.5, 80.1, 127.4, 127.5, 127.6, 127.7, 128.2, 128.3, 138.3,
138.8, 155.9. IR (neat, cmꢁ1) 1689, 1246. HRMS (ESI+), m/z calcd
for [C28H38BrNO4+Na]+: 554.1876. Found: 554.1854.
Acknowledgements
´
This work was supported by the Gobierno de Aragon.
P.E. was supported by a Spanish MCYT Predoctoral
Fellowship.
References and notes
1. Sodergren, M. J.; Andersson, P. G. Tetrahedron Lett. 1996, 37, 7577–
7580.
2. Von Pracejus, H.; Kohl, G. Liebigs Ann. Chem. 1969, 722, 1–11.
25
11. Selected data for 9: Oil, ½aꢀD +30.1 (c 1.10, CHCl3). 1H NMR
´
´
3. See, for example: Portevin, B.; Benoist, A.; Reond, G.; Herve, Y.;
Vincent, M.; Lepagnol, J.; De Nanteuil, G. J. Med. Chem. 1996, 39,
2379–2391.
4. Mi, Y.; Corey, E. J. Tetrahedron Lett. 2006, 47, 2515–2516.
5. Prelog, V.; Cerkovnikov, E. Liebigs Ann. Chem. 1937, 532, 83–88.
6. (a) Renk, E.; Grob, C. A. Helv. Chim. Acta 1954, 37, 2119–2123; (b)
Rubstov, M. V.; Mikhlina, E. E. Zh. Obshch. Khim. 1955, 25, 2303–
2310; (c) Langstrom, B. Chem. Scripta 1974, 5, 170–173; (d)
Bulacinski, A. B. Pol. J. Chem. 1978, 52, 2181–2187.
(500 MHz, CDCl3) d 1.33 (dd, J = 12.0, 8.5 Hz, 1H), 1.46 (ddd,
J = 7.6, 7.6, 1.8 Hz, 2H), 1.51–1.57 (m, 2H), 1.57–1.65 (m, 1H), 1.78–
1.84 (m, 1H), 2.80 (ddd, J = 14.1, 7.1, 7.1 Hz, 1H), 3.00 (dd, J = 8.0,
5.9 Hz, 2H), 3.02–3.09 (m, 1H), 3.07 (ddd, J = 8.5, 8.5, 8.1 Hz, 1H),
3.52 (ddd, J = 8.1, 5.0, 3.4 Hz, 1H), 3.64 (dd, J = 10.5, 5.0 Hz, 1H)
3.72 (dd, J = 10.5, 3.4 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H) 4.56 (d,
J = 12.0 Hz, 1H), 4.68 (d, J = 12.1 Hz, 1H) 4.79 (d, J = 12.1 Hz, 1H)
7.22–7.41 (m, 10H); 13C NMR (125 MHz, CDCl3) d 21.7, 25.6, 26.6,
29.6, 42.7, 49.9, 57.4, 71.3, 72.6, 73.4, 79.3, 127.2, 127.5, 127.6, 127.8,
128.1, 128.3, 138.3, 139.1. IR (neat, cmꢁ1) 1602, 1551, 1203, 1092,
1021. HRMS (ESI+), m/z calcd for [C23H29NO2+H]+: 352.2271.
Found: 352.2255.
´
´
7. (a) Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez, J. A.
Tetrahedron Lett. 1997, 38, 2547–2550; (b) Badorrey, R.; Cativiela,
C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A. Tetrahedron 1999, 55,
12. NMR data for crude 10: 1H NMR (400 MHz, CDCl3) d 1.05 (dd,
J = 12.4, 8.3 Hz, 1H), 1.37–1,52 (m, 2H), 1.47–1,58 (m, 2H), 1.65–
1.77 (m, 1H), 1.78–1.85 (m, 1H), 2.68 (ddd, J = 13.5, 10.5, 3.2 Hz,
1H), 2.79 (ddd, J = 8.6, 8.6, 8.3 Hz, 1H), 2.87–2.97 (m, 1H), 2.88 (dd,
J = 7.2, 7.2 Hz, 2H), 3.35 (br s, 2H), 3.45–3.52 (m, 2H), 3.75–3.82 (m,
1H); 13C NMR (100 MHz, CDCl3) d 21.3, 25.7, 26.6, 29.4, 41.5, 49.5,
56.6, 62.7, 72.1.
´
7601–7612; (c) Etayo, P.; Badorrey, R.; Dıaz-de-Villegas, M. D.;
´
Galvez, J. A. Chem. Commun. 2006, 3420–3422; (d) Etayo, P.;
Badorrey, R.; Dıaz-de-Villegas, M. D.; Galvez, J. A. J. Org. Chem.
´
´
2007, 72, 1005–1008.
8. A pure sample of compound cis-6 was obtained by hydrogenolytic
N-debenzylation of (2R,4S)-2-[(S)-1,2-dibenzyloxyethyl]-4-ethoxy-
carbonylmethyl-1-[(S)-1-phenylethyl]piperidine14 in the presence of
25
25
13. Selected data for 1: Mp 269–274 °C (lit.2 268–271 °C). ½aꢀD +119.8 (c
di-tert-butyl pyrocarbonate. Selected data for cis-6: Oil, ½aꢀD +47.1 (c
1.16, CHCl3). 1H NMR (400 MHz, CDCl3) d 0.97–1.08 (m, 1H), 1.16
(t, J = 7.1 Hz, 3H), 1.36 (ddd, J = 11.9, 11.9, 11.9 Hz, 1H), 1.37 (s,
9H), 1.63–1.70 (m, 1H), 1.84–2.03 (m, 2H), 2.16 (d, J = 6.8 Hz, 2H),
2.87–2.96 (m, 1H), 3.54 (dd, J = 10.4, 6.6 Hz, 1H), 3.62 (dd, J = 10.4,
3.2 Hz, 1H), 3.67–3.71 (m, 1H), 3.70–3.76 (m, 1H), 4.04 (c,
J = 7.1 Hz, 2H), 4.06–4.10 (m, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.49
(d, J = 12.0 Hz, 1H), 4.53 (d, J = 11.8 Hz, 1H), 4.72 (d, J = 11.8 Hz,
1H), 7.15–7.28 (m, 10H); 13C NMR (100 MHz, CDCl3) d 14.4, 28.1,
28.5, 28.6, 29.0, 38.1, 41.0, 54.1, 60.3, 71.6, 73.3, 73.5, 79.5, 80.3,
127.4, 127.6, 127.7, 127.7, 128.3, 128.4, 138.4, 138.9, 155.9, 172.4. IR
23
1.00, H2O) [lit.2 ½aꢀD +120.6 (c 1, H2O)]. 1H NMR (500 MHz, D2O) d
1.80–1.94 (m, 4H), 1.92–1.99 (m, 1H), 2.17–2.23 (m, 1H), 2.20–2.29
(m, 1H), 3.22–3.33 (m, 2H), 3.35–3.49 (m, 2H), 3.93 (ddd, J = 11.0,
9.0, 2.0 Hz, 1H); 13C NMR (125 MHz, D2O) d 20.5, 21.9, 22.4, 27.4,
44.1, 47.6, 59.6, 173.8. IR (KBr, cmꢁ1) 3700–2400, 1616. HRMS
(ESI+), m/z calcd for [C8H13NO2+H]+: 156.1019. Found: 156.1024.
Anal. Calcd for C8H13NO2:C, 61.91; H, 8.44; N, 9.03. Found: C,
61.99; H, 8.68; N, 8.88.
´
´
14. Etayo, P.; Badorrey, R.; Dıaz-de-Villegas, M. D.; Galvez, J. A.
Tetrahedron: Asymmetry 2007, 18, 2812–2819.
(neat, cmꢁ1
[C30H41NO6+Na]+: 534.2826. Found: 534.2812.
) 1733, 1690, 1246. HRMS (ESI+), m/z calcd for
´
´
15. Badorrey, R.; Cativiela, C.; Dıaz-de-Villegas, M. D.; Galvez, J. A.
Tetrahedron 2002, 58, 341–354.